|
1
|
Trojnar A, Domagała-Kulawik J. Current insights into the clinico-pathologic characteristics of lung cancer in women. Expert Rev Respir Med 2025; 19:301-312. [PMID: 40040469 DOI: 10.1080/17476348.2025.2475974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 01/14/2025] [Accepted: 03/03/2025] [Indexed: 03/06/2025]
Abstract
INTRODUCTION Lung cancer is responsible for premature cancer deaths in women and is the first cause of cancer deaths in women in many countries. The problem of lung cancer in women seems to be underestimated in many aspects, including low participation in clinical trials and screening tests. AREAS COVERED Current research progress has contributed to a better understanding of the issue and makes it possible to describe the problem in a new light. In our paper, the problem of lung cancer in women was discussed in a broad aspect, taking into account women's health, the harmful effects of smoking and the current diagnostic and treatment process. The results of treatment also differ in relation to sex. All these aspects of the diversity of women's lung cancer were presented on the basis of newest and most comprehensive literature. EXPERT OPINION Lung cancer in women is and will remain an important health problem worldwide, which is justified by epidemiological data, basic research and treatment results.
Collapse
Affiliation(s)
- Anna Trojnar
- Department of Internal Medicine, Pulmonary Diseases and Allergy, Medical University of Warsaw, Warsaw, Poland
| | | |
Collapse
|
|
2
|
I P R, T A B, A M S, A N G, E A B, A B R, V S K. Prognostic value of progesterone receptor expression in non-small cell lung cancer tissue. Ir J Med Sci 2025:10.1007/s11845-025-03917-4. [PMID: 40117033 DOI: 10.1007/s11845-025-03917-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 02/18/2025] [Indexed: 03/23/2025]
Abstract
BACKGROUND Progesterone receptors (PRs) play a role in the regulation of cell proliferation and are expressed in non-small cell lung cancer (NSCLC) tissue. Therefore, they represent a potential target for novel antitumor therapies. A survival analysis of NSCLC patients based on PR expression in tumor tissue may help assess the feasibility of using PR modulators in the treatment of this disease. AIM This study aims to evaluate the prognostic significance of PR expression in NSCLC to determine the potential utility of PR modulators as a therapeutic strategy. METHODS PR expression was assessed in 130 surgically resected NSCLC samples using immunofluorescence analysis combined with flow cytometry. Primary antibodies against PR (NBP2-4638, Novus Biologicals, USA) and secondary antibodies conjugated with DyLight650 (ab98729, Abcam, UK) were used. The percentage of PR-expressing cells was quantified using FlowJo software. Statistical analyses were conducted in GraphPad Prism and RStudio using the "survival" package. The prognostic impact of PR expression in NSCLC tissue was evaluated in the overall patient cohort and after excluding censored events (n = 56) to minimize the influence of confounding factors on survival analysis. RESULTS After excluding censored events and stratifying patients based on the median PR expression level (57%), survival analysis revealed that high PR expression in NSCLC tissue is associated with a poorer prognosis (p = 0.05). Patients with high PR expression (≥ 57%) had a median survival of 12.8 months, whereas those with low PR expression (< 57%) had a median survival of 25.8 months (HR = 1.7). CONCLUSIONS Elevated PR expression in NSCLC tumors is associated with reduced patient survival. These findings suggest that PR modulators may have potential therapeutic value for NSCLC patients with PR-positive tumors.
Collapse
Affiliation(s)
- Romanov I P
- N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russia.
| | - Bogush T A
- N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russia
| | - Scherbakov A M
- N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russia
- Gause Institute of New Antibiotics, Moscow, Russia
| | - Grishanina A N
- N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russia
| | - Bogush E A
- Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Ravcheeva A B
- N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russia
| | - Kosorukov V S
- N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russia
| |
Collapse
|
|
3
|
Zhang S, Zhang X, Huang W, Jiang G, Mo Y, Wei L, Fan P, Chen M, Jiang W. NUSAP1 is Upregulated by Estrogen to Promote Lung Adenocarcinoma Growth and Serves as a Therapeutic Target. Int J Biol Sci 2024; 20:5375-5395. [PMID: 39430250 PMCID: PMC11489181 DOI: 10.7150/ijbs.100188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 09/17/2024] [Indexed: 10/22/2024] Open
Abstract
Nucleolar and spindle-associated protein 1 (NUSAP1), a microtubule-associated protein, has been recently identified to exhibit aberrant expression patterns that correlate with malignant tumorigenesis and progression across various cancer types. However, the specific regulatory mechanisms and potential targeting therapies of NUSAP1 in lung adenocarcinoma (LUAD) remain largely elusive. In this study, by conducting bioinformatics analyses as well as in vitro and in vivo experiments, we identified that NUSAP1 was significantly upregulated in LUAD, with a notable correlation with poorer overall survival, higher scores for immunogenicity and immune infiltration, as well as increased sensitivity to conventional chemotherapeutic drugs such as paclitaxel, docetaxel and vinorelbine in LUAD. Functionally, NUSAP1 overexpression significantly promoted LUAD cell proliferation, while its knockdown markedly suppressed this process. Interestingly, our results revealed that NUSAP1 upregulation was mediated by estrogen via ERβ activation. Furthermore, we identified entinostat as a novel inhibitor of NUSAP1. Pharmacological targeting ERβ/NUSAP1 axis with fulvestrant (ERβ antagonist) or entinostat (novel NUSAP1 inhibitor) significantly reduced LUAD growth both in vitro and in vivo, which may represent effective alternative therapeutic strategies for patients with LUAD.
Collapse
Affiliation(s)
- Shaoping Zhang
- Department of Respiratory Oncology, Guangxi Medical University Cancer Hospital, Nanning 530021, China
- Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China
| | - Xiaozhen Zhang
- Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, Nanning 530021, China
| | - Wenjian Huang
- Department of Breast Surgery, the Sixth Affiliated Hospital of South China University of Technology, the Sixth Clinical College of South China University of Technology, Foshan 528225, China
| | - Ganling Jiang
- Department of pharmacy, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510145, China
| | - Yuanxin Mo
- Department of Respiratory Oncology, Guangxi Medical University Cancer Hospital, Nanning 530021, China
| | - Liuxia Wei
- Department of Medical Oncology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning 530000, China
| | - Pingming Fan
- Department of Breast Surgery, the First Affiliated Hospital of Hainan Medical University, Haikou 570102, Hainan, China
| | - Maojian Chen
- Department of Respiratory Oncology, Guangxi Medical University Cancer Hospital, Nanning 530021, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Wei Jiang
- Department of Respiratory Oncology, Guangxi Medical University Cancer Hospital, Nanning 530021, China
| |
Collapse
|
|
4
|
Yang J, Sun W, Cui G. Roles of the NR2F Family in the Development, Disease, and Cancer of the Lung. J Dev Biol 2024; 12:24. [PMID: 39311119 PMCID: PMC11417824 DOI: 10.3390/jdb12030024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Revised: 08/24/2024] [Accepted: 08/30/2024] [Indexed: 09/26/2024] Open
Abstract
The NR2F family, including NR2F1, NR2F2, and NR2F6, belongs to the nuclear receptor superfamily. NR2F family members function as transcription factors and play essential roles in the development of multiple organs or tissues in mammals, including the central nervous system, veins and arteries, kidneys, uterus, and vasculature. In the central nervous system, NR2F1/2 coordinate with each other to regulate the development of specific brain subregions or cell types. In addition, NR2F family members are associated with various cancers, such as prostate cancer, breast cancer, and esophageal cancer. Nonetheless, the roles of the NR2F family in the development and diseases of the lung have not been systematically summarized. In this review, we mainly focus on the lung, including recent findings regarding the roles of the NR2F family in development, physiological function, and cancer.
Collapse
Affiliation(s)
- Jiaxin Yang
- Department of Basic Research, Guangzhou National Laboratory, Guangzhou 510005, China;
- School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China;
| | - Wenjing Sun
- School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China;
| | - Guizhong Cui
- Department of Basic Research, Guangzhou National Laboratory, Guangzhou 510005, China;
- School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China;
| |
Collapse
|
|
5
|
Lipowicz JM, Malińska A, Nowicki M, Rawłuszko-Wieczorek AA. Genes Co-Expressed with ESR2 Influence Clinical Outcomes in Cancer Patients: TCGA Data Analysis. Int J Mol Sci 2024; 25:8707. [PMID: 39201394 PMCID: PMC11354723 DOI: 10.3390/ijms25168707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 08/02/2024] [Accepted: 08/07/2024] [Indexed: 09/02/2024] Open
Abstract
ERβ has been assigned a tumor suppressor role in many cancer types. However, as conflicting findings emerge, ERβ's tissue-specific expression and functional role have remained elusive. There remains a notable gap in compact and comprehensive analyses of ESR2 mRNA expression levels across diverse tumor types coupled with an exploration of its potential gene network. In this study, we aim to address these gaps by presenting a comprehensive analysis of ESR2 transcriptomic data. We distinguished cancer types with significant changes in ESR2 expression levels compared to corresponding healthy tissue and concluded that ESR2 influences patient survival. Gene Set Enrichment Analysis (GSEA) distinguished molecular pathways affected by ESR2, including oxidative phosphorylation and epithelial-mesenchymal transition. Finally, we investigated genes displaying similar expression patterns as ESR2 in tumor tissues, identifying potential co-expressed genes that may exert a synergistic effect on clinical outcomes, with significant results, including the expression of ACIN1, SYNE2, TNFRSF13C, and MDM4. Collectively, our results highlight the significant influence of ESR2 mRNA expression on the transcriptomic landscape and the overall metabolism of cancerous cells across various tumor types.
Collapse
Affiliation(s)
- Julia Maria Lipowicz
- Department of Histology and Embryology, Doctoral School, Poznan University of Medical Sciences, Święcickiego 6 Street, 60-781 Poznań, Poland;
| | - Agnieszka Malińska
- Department of Histology and Embryology, Poznan University of Medical Sciences, Święcickiego 6 Street, 60-781 Poznań, Poland
| | - Michał Nowicki
- Department of Histology and Embryology, Poznan University of Medical Sciences, Święcickiego 6 Street, 60-781 Poznań, Poland
| | | |
Collapse
|
|
6
|
Nagandla H, Thomas C. Estrogen Signals through ERβ in Breast Cancer; What We Have Learned since the Discovery of the Receptor. RECEPTORS (BASEL, SWITZERLAND) 2024; 3:182-200. [PMID: 39175529 PMCID: PMC11340209 DOI: 10.3390/receptors3020010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 08/24/2024]
Abstract
Estrogen receptor (ER) β (ERβ) is the second ER subtype that mediates the effects of estrogen in target tissues along with ERα that represents a validated biomarker and target for endocrine therapy in breast cancer. ERα was the only known ER subtype until 1996 when the discovery of ERβ opened a new chapter in endocrinology and prompted a thorough reevaluation of the estrogen signaling paradigm. Unlike the oncogenic ERα, ERβ has been proposed to function as a tumor suppressor in breast cancer, and extensive research is underway to uncover the full spectrum of ERβ activities and elucidate its mechanism of action. Recent studies have relied on new transgenic models to capture effects in normal and malignant breast that were not previously detected. They have also benefited from the development of highly specific synthetic ligands that are used to demonstrate distinct mechanisms of gene regulation in cancer. As a result, significant new information about the biology and clinical importance of ERβ is now available, which is the focus of discussion in the present article.
Collapse
Affiliation(s)
- Harika Nagandla
- Houston Methodist Neal Cancer Center, Houston Methodist Research Institute, Houston, TX 77030, USA
| | - Christoforos Thomas
- Houston Methodist Neal Cancer Center, Houston Methodist Research Institute, Houston, TX 77030, USA
| |
Collapse
|
|
7
|
Watanabe F, Sato S, Hirose T, Endo M, Endo A, Ito H, Ohba K, Mori T, Takahashi K. NRIP1 regulates cell proliferation in lung adenocarcinoma cells. J Biochem 2024; 175:323-333. [PMID: 38102728 DOI: 10.1093/jb/mvad107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 11/23/2023] [Indexed: 12/17/2023] Open
Abstract
Nuclear receptor interacting protein 1 (NRIP1) is a transcription cofactor that regulates the activity of nuclear receptors and transcription factors. Functional expression of NRIP1 has been identified in multiple cancers. However, the expression and function of NRIP1 in lung adenocarcinoma have remained unclear. Thus, we aimed to clarify the NRIP1 expression and its functions in lung adenocarcinoma cells. NRIP1 and Ki-67 were immunostained in the tissue microarray section consisting of 64 lung adenocarcinoma cases, and the association of NRIP1 immunoreactivity with clinical phenotypes was examined. Survival analysis was performed in lung adenocarcinoma data from The Cancer Genome Atlas (TCGA). Human A549 lung adenocarcinoma cell line with an NRIP1-silencing technique was used in vitro study. Forty-three of 64 cases were immunostained with NRIP1. Ki-67-positive cases were more frequent in NRIP1-positive cases as opposed to NRIP1-negative cases. Higher NRIP1 mRNA expression was associated with poor prognosis in the TCGA lung adenocarcinoma data. NRIP1 was mainly located in the nucleus of A549 cells. NRIP1 silencing significantly reduced the number of living cells, suppressed cell proliferation, and induced apoptosis. These results suggest that NRIP1 participates in the progression and development of lung adenocarcinoma. Targeting NRIP1 may be a possible therapeutic strategy against lung adenocarcinoma.
Collapse
Affiliation(s)
- Fumihiko Watanabe
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, 2-1, Seiryo, Aoba, 980-8575 Sendai, Japan
- Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University School of Medicine, 1, Hikarigaoka, Fukushima, 960-1295 Fukushima, Japan
| | - Shigemitsu Sato
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, 2-1, Seiryo, Aoba, 980-8575 Sendai, Japan
- Division of Integrative Renal Replacement Therapy, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, 1-15-1, Fukumuro, Miyagino, 983-8536 Sendai, Japan
| | - Takuo Hirose
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, 2-1, Seiryo, Aoba, 980-8575 Sendai, Japan
- Division of Integrative Renal Replacement Therapy, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, 1-15-1, Fukumuro, Miyagino, 983-8536 Sendai, Japan
- Division of Nephrology and Endocrinology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, 1-15-1, Fukumuro, Miyagino, 983-8536 Sendai, Japan
| | - Moe Endo
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, 2-1, Seiryo, Aoba, 980-8575 Sendai, Japan
| | - Akari Endo
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, 2-1, Seiryo, Aoba, 980-8575 Sendai, Japan
- Division of Nephrology and Endocrinology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, 1-15-1, Fukumuro, Miyagino, 983-8536 Sendai, Japan
| | - Hiroki Ito
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, 2-1, Seiryo, Aoba, 980-8575 Sendai, Japan
- Division of Nephrology and Endocrinology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, 1-15-1, Fukumuro, Miyagino, 983-8536 Sendai, Japan
| | - Koji Ohba
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, 2-1, Seiryo, Aoba, 980-8575 Sendai, Japan
| | - Takefumi Mori
- Division of Integrative Renal Replacement Therapy, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, 1-15-1, Fukumuro, Miyagino, 983-8536 Sendai, Japan
- Division of Nephrology and Endocrinology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, 1-15-1, Fukumuro, Miyagino, 983-8536 Sendai, Japan
| | - Kazuhiro Takahashi
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, 2-1, Seiryo, Aoba, 980-8575 Sendai, Japan
| |
Collapse
|
|
8
|
Chen J, Zhao R, Wang Y, Xiao H, Lin W, Diao M, He S, Mei P, Liao Y. G protein-coupled estrogen receptor activates PI3K/AKT/mTOR signaling to suppress ferroptosis via SREBP1/SCD1-mediated lipogenesis. Mol Med 2024; 30:28. [PMID: 38383297 PMCID: PMC10880371 DOI: 10.1186/s10020-023-00763-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Accepted: 11/25/2023] [Indexed: 02/23/2024] Open
Abstract
BACKGROUND Lung cancer is the leading cause of cancer-related death worldwide. The sex differences in the occurrence and fatality rates of non-small cell lung cancer (NSCLC), along with its association with estrogen dependence, suggest that estrogen receptors (ERs) contribute to the development of NSCLC. However, the influence of G protein-coupled estrogen receptor (GPER1) on NSCLC remains to be determined. Escape from ferroptosis is one of the hallmarks of tumor discovered in recent years. In this context, the present study evaluated whether GPER1 promotes NSCLC progression by preventing ferroptosis, and the underlying mechanism through which GPER1 protects against ferroptosis was also explored. METHODS The effects of GPER1 on the cytotoxicity of H2O2, the ferroptosis inducer RSL3, and Erastin were assessed using the CCK8 assay and plate cloning. Lipid peroxidation levels were measured based on the levels of MDA and BODIPY™581/591C11. GPER1 overexpression and knockdown were performed and G1 was used, and the expression of SCD1 and PI3K/AKT/mTOR signaling factors was measured. Immunofluorescence analysis and immunohistochemistry were performed on paired specimens to measure the correlation between the expression of GPER1 and SCD1 in NSCLC tissues. The effect of GPER1 on the cytotoxicity of cisplatin was measured in vitro using the CCK8 assay and in vivo using xenograft tumor models. RESULTS GPER1 and G1 alleviated the cytotoxicity of H2O2, reduced sensitivity to RSL3, and impaired lipid peroxidation in NSCLC tissues. In addition, GPER1 and G1 promoted the protein and mRNA expression of SCD1 and the activation of PI3K/AKT/mTOR signaling. GPER1 and SCD1 expression were elevated and positively correlated in NSCLC tissues, and high GPER1 expression predicted a poor prognosis. GPER1 knockdown enhanced the antitumor activity of cisplatin in vitro and in vivo. CONCLUSION GPER1 prevents ferroptosis in NSCLC by promoting the activation of PI3K/AKT/mTOR signaling, thereby inducing SCD1 expression. Therefore, treatments targeting GPER1 combined with cisplatin would exhibit better antitumor effects.
Collapse
Affiliation(s)
- Jiaping Chen
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Department of Cardiothoracic Surgery, Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital), Kunming, China
| | - Rong Zhao
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yangwei Wang
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Han Xiao
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Wei Lin
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Mingxin Diao
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Shiwen He
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Peiyuan Mei
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Yongde Liao
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| |
Collapse
|
|
9
|
Meng Y, Lin W, Wang N, Wei X, Mei P, Wang X, Zhang C, Huang Q, Liao Y. USP7-mediated ERβ stabilization mitigates ROS accumulation and promotes osimertinib resistance by suppressing PRDX3 SUMOylation in non-small cell lung carcinoma. Cancer Lett 2024; 582:216587. [PMID: 38097136 DOI: 10.1016/j.canlet.2023.216587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 11/27/2023] [Accepted: 12/04/2023] [Indexed: 12/20/2023]
Abstract
Osimertinib resistance is regarded as a major obstacle limiting survival benefits for patients undergoing treatment of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). However, the underlying mechanisms of acquired resistance remain unclear. In this study, we report that estrogen receptor β (ERβ) is highly expressed in osimertinib-resistant NSCLC and plays a pivotal role in promoting osimertinib resistance. We further identified ubiquitin-specific protease 7 (USP7) as a critical binding partner that deubiquitinates and upregulates ERβ in NSCLC. ERβ promotes osimertinib resistance by mitigating reactive oxygen species (ROS) accumulation. We found that ERβ mechanistically suppresses peroxiredoxin 3 (PRDX3) SUMOylation and thus confers osimertinib resistance onto NSCLC. Furthermore, we provide evidence showing that depletion of ERβ induces ROS accumulation and reverses osimertinib resistance in NSCLC both in vitro and in vivo. Thus, our results demonstrate that USP7-mediated ERβ stabilization suppresses PRDX3 SUMOylation to mitigate ROS accumulation and promote osimertinib resistance, suggesting that targeting ERβ may be an effective therapeutic strategy to overcome osimertinib resistance in NSCLC.
Collapse
Affiliation(s)
- Yunchong Meng
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - Wei Lin
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - Na Wang
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - Xiao Wei
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Peiyuan Mei
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - Xiaojun Wang
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - Chi Zhang
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - Quanfu Huang
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China.
| | - Yongde Liao
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China.
| |
Collapse
|
|
10
|
Gee K, Yendamuri S. Lung cancer in females-sex-based differences from males in epidemiology, biology, and outcomes: a narrative review. Transl Lung Cancer Res 2024; 13:163-178. [PMID: 38405003 PMCID: PMC10891406 DOI: 10.21037/tlcr-23-744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 01/19/2024] [Indexed: 02/27/2024]
Abstract
Background and Objective The role of biological sex is seldom considered in characterizing lung cancer, the deadliest cancer in both the United States and the world. Lung cancer has traditionally been regarded as a male disease; as such, research in female-specific phenomena is frequently conflicting or absent. Currently, disparities in lung cancer incidence are primarily driven by females, especially non-smokers and those of younger age. This narrative review provides insight into sex-specific characteristics of lung cancer, highlighting risk factors, diagnosis patterns, carcinogenesis, and treatment outcomes in females. Methods The PubMed database was searched on July 26, 2023 to identify research published between 2013 and 2023 in English. Sixty-three articles were considered relevant, and their full texts and citations were studied to compile information for this narrative review. Key Content and Findings Exposure-related risk factors, including personal tobacco use, are thought to impact female lung cancer risk more profoundly. However, studies on occupational exposures are underpowered to conclude risk in females. Data characterizing the effect of endogenous and exogenous hormonal exposures on female lung cancer risk remain two-sided. Screening guidelines are tailored to white males, exacerbating sex and race disparities. The effect of biological sex on carcinogenesis and the immune system response to cancer is not fully understood, though the female immune system clearly reacts more aggressively to lung cancer. In early-stage disease, females have greater survival in the perioperative setting and during follow-up of several years, attributed to favorable histopathology and healthier baseline status. Sex-specific response to systemic treatment continues to be optimized as lack of standardization in randomized trials makes interpreting results difficult when aggregated. Conclusions Biological sex plays a critical role in non-small cell lung cancer (NSCLC), though further study is needed to depict the complex web of factors that affect lung cancer risk, development, and outcomes. Female underrepresentation in studies has contributed to this lack of understanding. As these disparities are eliminated, we can move towards more effective treatment for both sexes in this pervasive yet deadly disease.
Collapse
Affiliation(s)
- Kaylan Gee
- Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
- Department of Surgery, University of Tennessee Graduate School of Medicine, Knoxville, TN, USA
| | - Sai Yendamuri
- Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
- Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY, USA
| |
Collapse
|
|
11
|
Hu Y, Xu Y, Zhang T, Han Q, Li L, Liu M, Li N, Shao G. Cisplatin-activated ERβ/DCAF8 positive feedback loop induces chemoresistance in non-small cell lung cancer via PTEN/Akt axis. Drug Resist Updat 2023; 71:101014. [PMID: 37913652 DOI: 10.1016/j.drup.2023.101014] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 10/20/2023] [Accepted: 10/20/2023] [Indexed: 11/03/2023]
Abstract
High levels of the estrogen receptor β (ERβ) predict poor prognosis following platinum-containing adjuvant chemotherapies in patients with non-small cell lung cancer (NSCLC). However, the precise role of ERβ remains elusive. In this study, we demonstrated that targeting ERβ could significantly increase the cytotoxicity of cisplatin both in vitro and in vivo. Mechanically, cisplatin directly binds to ERβ, which facilitates its homodimerization and nuclear translocation. ERβ activation transcriptionally represses the expression of DCAF8, an adaptor of CRL4 E3 ubiquitin ligase, which in turn attenuates the proteasomal degradation of ERβ, leading to ERβ accumulation; this positive feedback loop results in Akt activation and eventually cisplatin resistance in NSCLC through PTEN inhibition. Moreover, low expression of DCAF8 and high expression of ERβ are associated with treatment resistance in patients receiving cisplatin-containing adjuvant chemotherapy. The present results provide insights into the underlying mechanism of ERβ-induced cisplatin resistance and offer an alternative therapeutic strategy to improve the efficacy of platinum-based chemotherapy in patients with NSCLC.
Collapse
Affiliation(s)
- Yumeng Hu
- Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yongjie Xu
- Office of Cancer Screening, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Ting Zhang
- Department of Gynecology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China
| | - Qianying Han
- Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Li Li
- Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Mingyang Liu
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
| | - Ni Li
- Office of Cancer Screening, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
| | - Genze Shao
- Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
| |
Collapse
|
|
12
|
Hsu R, Chen D, Xia B, Feldman R, Cozen W, Raez LE, Borghaei H, Kim C, Nagasaka M, Mamdani H, Vanderwalde AM, Lopes G, Socinski MA, Wozniak AJ, Spira AI, Liu SV, Nieva JJ. Impact of gender and mutational differences in hormone receptor expressing non-small cell lung cancer. Front Oncol 2023; 13:1215524. [PMID: 37700839 PMCID: PMC10494442 DOI: 10.3389/fonc.2023.1215524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 08/07/2023] [Indexed: 09/14/2023] Open
Abstract
Background The incidence of lung cancer in the US has been decreasing but a bigger decline has been observed in men despite similar declines in tobacco use between men and women. Multiple theories have been proposed, including exposure to exogenous estrogens. Our study seeks to understand the relationship between hormone receptors (HR), gender, and the genomic landscape of non-small lung cancer (NSCLC). Methods 3,256 NSCLC tumor samples submitted for molecular profiling between 2013-2018 were retrospectively identified and assessed for HR expression. Hormone receptor (HR+) was defined as ≥ 1% nuclear staining of estrogen receptor-alpha (ER-a) or progesterone receptor (PR) by immunohistochemistry. DNA sequencing by NGS included cases sequenced by the Illumina MiSeq hot spot 47 gene panel (n=2753) and Illumina NextSeq 592 gene panel (n=503). An adjusted p-value (q-value) <0.05 was determined significant. Results HR+ was identified in 18.3% of NSCLC. HR+ occurred more commonly in women compared to men (19.6% vs 11.4%, p <0.0001, q <0.0001). EGFR mutations occurred more commonly in HR+ NSCLC than HR- NSCLC (20.2% vs. 14.6%, p = 0.002, q=0.007). Overall, men with EGFR mutations were affected by HR status with a higher prevalence in HR+ NSCLC while such differences were not seen in women. However, in women ages ≤45, there was a trend towards greater prevalence HR+ NSCLC (25.25% vs. 11.32%, q= 0.0942) and 10/25 (40.0%) of HR+ cases in young women were found to be EGFR mutated. KRAS mutations and ALK+ IHC expression occurred more in HR+ NSCLC whereas TP53 mutations occurred more in HR- NSCLC. Conclusions Women were more likely to have HR+ NSCLC than men and EGFR and KRAS mutations occurred more commonly in HR+ NSCLC. Additional studies with more strict inclusion criteria for HR+ are warranted to see if there is benefit to targeting HR in these subgroups.
Collapse
Affiliation(s)
- Robert Hsu
- Department of Internal Medicine, Division of Medical Oncology, University of Southern California, Los Angeles, CA, United States
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United States
| | - Denaly Chen
- Department of Internal Medicine, Division of Medical Oncology, University of Southern California, Los Angeles, CA, United States
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United States
| | - Bing Xia
- Department of Internal Medicine, Division of Medical Oncology, University of Southern California, Los Angeles, CA, United States
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United States
| | | | - Wendy Cozen
- Division of Hematology-Oncology, Department of Medicine, University of California Irvine School of Medicine, Chao Family Comprehensive Cancer Center, Orange, CA, United States
| | - Luis E. Raez
- Thoracic Oncology Program, Memorial Cancer Institute/Florida Atlantic University, Pembroke Pines, FL, United States
| | - Hossein Borghaei
- Department of Hematology-Oncology, Fox Chase Cancer Center, Philadelphia, PA, United States
| | - Chul Kim
- Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital, Washington, DC, United States
| | - Misako Nagasaka
- Division of Hematology-Oncology, Department of Medicine, University of California Irvine School of Medicine, Chao Family Comprehensive Cancer Center, Orange, CA, United States
| | - Hirva Mamdani
- Department of Oncology, Barbara Ann Karmanos Cancer Institute, Detroit, MI, United States
| | | | - Gilberto Lopes
- Department of Medical Oncology, Sylvester Comprehensive Cancer Center at the University of Miami, Miami, FL, United States
| | | | - Antoinette J. Wozniak
- Hillman Cancer Center, Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
| | - Alexander I. Spira
- US Oncology Research, Virginia Cancer Specialists, Fairfax, VA, United States
| | - Stephen V. Liu
- Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital, Washington, DC, United States
| | - Jorge J. Nieva
- Department of Internal Medicine, Division of Medical Oncology, University of Southern California, Los Angeles, CA, United States
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United States
| |
Collapse
|
|
13
|
Wu CC, Chung CH, Tzeng NS, Wu MJ, Tsao CH, Wu TH, Chien WC, Chen HC. The association between hormone therapy and the risk of lung cancer in postmenopausal women: a 16-year nationwide population-based study. Menopause 2023; 30:521-528. [PMID: 36854166 DOI: 10.1097/gme.0000000000002165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/02/2023]
Abstract
OBJECTIVE Although an association between hormone therapy (HT) and the risk of developing lung cancer has been reported, the results on the topic are inconsistent. Our study objective was to investigate whether postmenopausal women who undergo HT exhibit a risk of developing lung cancer. METHODS In this matched cohort study, we obtained the data of 38,104 postmenopausal women older than 45 years who were treated using HT between 2000 and 2015 from Taiwan's National Health Insurance Research Database, and 152,416 matched participants who were not treated using HT were enrolled as controls at a 1:4 ratio. RESULTS We used a Cox proportional hazards regression model to identify the risk of developing lung cancer during 16 years of follow-up, and the results indicate no significant difference in the proportion of postmenopausal women treated using HT ( P = 0.129) who developed lung cancer and that of those not treated using HT (0.866% [330 of 38,104] vs 0.950% [1,449 of 152,416]). After adjustment for age and other variables, the adjusted hazard ratio was 0.886 (95% CI, 0.666-1.305, P = 0.433), indicating no association between HT and lung cancer development in postmenopausal women. In a subgroup analysis, the risk of lung cancer was significantly lower in the women who were treated using HT when the HT cumulative dosage was ≥401 mg or when the therapy duration was ≥5 years compared with in those not treated using HT; the adjusted hazard ratios were 0.633 (95% CI, 0.475-0.930; P < 0.001) and 0.532 (95% CI, 0.330-0.934; P < 0.001), respectively, after adjustment. CONCLUSIONS Our results indicate that HT is not associated with the risk of lung cancer development in postmenopausal women; furthermore, a higher cumulative dosage and the long-term effects of HT reduce the risk of developing lung cancer.
Collapse
Affiliation(s)
- Chia-Chen Wu
- From the Division of Thoracic Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | | | | | - Min-Jung Wu
- School of Traditional Chinese Medicine, Chang Gung University, Taoyuan, Taiwan
| | | | | | | | - Hsin-Chien Chen
- Department of Otolaryngology-Head and Neck Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| |
Collapse
|
|
14
|
Hammouz RY, Orzechowska M, Anusewicz D, Bednarek AK. X or Y Cancer: An Extensive Analysis of Sex Differences in Lung Adenocarcinoma. Curr Oncol 2023; 30:1395-1415. [PMID: 36826068 PMCID: PMC9955992 DOI: 10.3390/curroncol30020107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 01/09/2023] [Accepted: 01/11/2023] [Indexed: 01/19/2023] Open
Abstract
Background: Cellular metabolism is a tightly controlled process during which cell growth and survival are maintained. Lung cancer is a disease with clear sex differences, where female patients have better survival rates than males. Evidence of sex differences is demonstrated in cancer risk, prognosis and response to different therapies, yet a sex-specific approach to cancer studies is not widely considered. These different tumour characteristics attributed to sex that impact disease outcome, including constitutional genetic and somatic molecular differences, make it essential to assess viral and hormonal influences. Methods: In silico analysis of lung adenocarcinoma (LUAD) TCGA data, including K-means clustering algorithm, dimensional reduction with principal component analysis and differential expression analysis using EdgeR (p < 0.05), were used to explore some robust sex differences in LUAD that exist in core signalling pathways and metabolic processes between males and females. The correlation of differentially expressed genes (DEGs) expression with immune abundance in the LUAD cohort was analysed on TIMER2.0 and adjusted by tumour purity utilising Cox proportional hazard. Multiple factorial analysis heatmap visualisation was used to examine endogenous steroid hormonal effects on LUAD patients with different smoking status and age groups. Results: We found 161 DEGs showing key differences in regulation of immune system and cellular homeostasis, key elements of divergent cancer progression, between the two sexes. We also found male and female LUAD patients to favour different metabolic intermediates for energy production to support tumourigenesis. Additionally, high levels of Tregs accompanied by DEGs correlated with better LUAD prognosis, and circulating hormonal transcriptional targets affect proliferation and progression in males and females differently. Finally, we examined the role of oestrogen protection in men and pre-/postmenopausal women. Conclusions: Further studies should focus on sex-specific changes and investigate sex-specific gene regulatory networks of these DEGs. Several lifestyle factors, including tobacco smoking and diet, differ between males and females. These factors might affect metabolic pathways and can influence the activity of epigenetic regulators, resulting in significant global epigenetic changes.
Collapse
|
|
15
|
Castellanos MR, Fanous E, Thaker R, Flory MJ, Seetharamu N, Dhar M, Starr A, Strange TJ. Expression patterns and clinical significance of estrogen receptor in non-small cell lung cancer. Pathol Res Pract 2023; 241:154298. [PMID: 36608623 DOI: 10.1016/j.prp.2022.154298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 12/29/2022] [Indexed: 12/31/2022]
Abstract
BACKGROUND Lung cancer death remains the highest among all malignancies. Gender differences show women have an increased cancer incidence while men have worse outcomes. These observations identified that some lung carcinomas express estrogen receptors (ER). This is a promising target as antiestrogen drugs can reduce tumors and improve survival. However, there is a limited understanding of ER distribution and its clinical significance to properly design antiestrogen drug clinical trials. Thus, we comprehensively analyzed ERα and ERβ expression patterns by gender, cancer cell type, and receptor location in lung cancer. METHODS We conducted a systematic review using the PubMed database from all-time through October 2022, using MeSH terms with the keywords "lung cancer," "estrogen receptor," and "immunohistochemistry." We identified 120 studies with 21 reports being evaluated based on our inclusion criteria. RESULTS We examined 4874 lung cancers from 5011 patients. ERβ is the predominant form of ER expressed, mainly found in the nucleus. The ERβ positivity rate is 51.5% in males versus 55.5% in females and was not statistically different. In contrast, ERα is predominately extranuclear in location, and ERα expression varies by gender. Males had a positivity rate of 31% versus 26.6% in females, which is statistically different. ERα is associated with a worse prognosis in some studies, while it had no effect in others. Overall, ERβ was associated with a better prognosis. CONCLUSION We characterized ER expression patterns in 4874 lung cancers. Over 50% expressed ERβ with equal rates in both sexes and was associated with a better prognosis. ERα expression was slightly higher in males (31%) than females (26.6%) and was associated with a poor prognosis. Our findings suggest estrogen signaling may be a promising drug target in lung cancer.
Collapse
Affiliation(s)
- Mario R Castellanos
- Division of Research, Department of Medicine, Staten Island University Hospital - Northwell Health, 475 Seaview Ave, Staten Island, NY 10305, USA; Department of Medicine, Staten Island University Hospital, Northwell Health, Staten Island, NY 10305, USA.
| | - Ereeny Fanous
- Division of Research, Department of Medicine, Staten Island University Hospital - Northwell Health, 475 Seaview Ave, Staten Island, NY 10305, USA.
| | - Rina Thaker
- Touro College of Osteopathic Medicine, Middletown, NY, United States.
| | - Michael J Flory
- Biostatistics & Research Design, NYS Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA.
| | - Nagashree Seetharamu
- Division of Medical Oncology & Hematology, Northwell Health Cancer Institute, Donald & Barbara Zucker School of Medicine at Hofstra/Northwell, Lake Success, NY 11042, USA.
| | - Meekoo Dhar
- Division of Hematology/Oncology, Florina Cancer Center, Staten Island University Hospital, Northwell Health, Staten Island, NY 10305, USA.
| | - Adam Starr
- Division of Hematology/Oncology, Florina Cancer Center, Staten Island University Hospital, Northwell Health, Staten Island, NY 10305, USA.
| | - Theodore J Strange
- Department of Medicine, Staten Island University Hospital, Northwell Health, Staten Island, NY 10305, USA.
| |
Collapse
|
|
16
|
Takada I, Miyazaki T, Goto Y, Kanzawa H, Matsubara T, Namikawa-Kanai H, Shigefuku S, Ono S, Nakajima E, Morishita Y, Honda A, Furukawa K, Ikeda N. Involvement of 27-hydroxycholesterol on the progression of non-small cell lung cancer via the estrogen receptor. Am J Cancer Res 2022; 12:4241-4253. [PMID: 36225627 PMCID: PMC9548011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Accepted: 08/03/2022] [Indexed: 06/16/2023] Open
Abstract
The oxysterol 27-hydroxycholesterol (27HC) promotes the proliferation of breast cancer cells as a selective estrogen receptor modulator (SERM), but it is mostly produced by alveolar macrophages in vivo. The present study evaluated hypothesis that 27HC may also promote the proliferation of lung cancer cells. In the tumor and nontumor regions of lung tissue from 23 patients with non-small cell lung cancer (NSCLC) who underwent lung cancer surgery, we compared the 27HC content and its synthetic and catabolic enzyme expressions (CYP27A1 and CYP7B1), the expressions of the estrogen receptor (ER) gene and its target gene cMYC by using high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS), real-time RT-PCR, and immunohistochemical staining. In addition, we evaluated the effects of 27HC and β-estradiol (E2) treatments on the proliferation of a cultured lung cancer cell line (H23 cells) expressing ERβ. In squamous cell carcinoma and in adenocarcinoma, the 27HC content was significantly higher in the tumor region than in the nontumor region, and in cancer grade III than in the other cancer grades. CYP27A1-positive macrophages were histologically detected in the nontumor regions of both cancer types, whereas the gene and protein expressions of ERβ, as well as the CYP7B1 and cMYC genes, were significantly increased in the tumor tissues. In cultured H23 cells, proliferation was significantly increased by 27HC and E2 treatments for 48 h. Similar to breast cancer, the present results supported idea that the 27HC produced from alveolar macrophages promotes the proliferation of lung cancer cells highly expressing ER through the SERM action. Therefore, 27HC should be an important target for cancer therapy of NSCLC.
Collapse
Affiliation(s)
- Ikki Takada
- Division of Thoracic Surgery, Department of Surgery, Tokyo Medical UniversityTokyo, Japan
| | - Teruo Miyazaki
- Joint Research Center, Tokyo Medical University Ibaraki Medical CenterIbaraki, Japan
| | - Yushi Goto
- Department of Thoracic Surgery, Tokyo Medical University Ibaraki Medical CenterIbaraki, Japan
| | - Hiroya Kanzawa
- Department of Thoracic Surgery, Tokyo Medical University Ibaraki Medical CenterIbaraki, Japan
| | - Taisuke Matsubara
- Division of Thoracic Surgery, Department of Surgery, Tokyo Medical UniversityTokyo, Japan
| | - Haruka Namikawa-Kanai
- Division of Thoracic Surgery, Department of Surgery, Tokyo Medical UniversityTokyo, Japan
| | - Shunsuke Shigefuku
- Division of Thoracic Surgery, Department of Surgery, Tokyo Medical UniversityTokyo, Japan
| | - Shotaro Ono
- Department of Thoracic Surgery, Tokyo Medical University Ibaraki Medical CenterIbaraki, Japan
| | - Eiji Nakajima
- Division of Thoracic Surgery, Department of Surgery, Tokyo Medical UniversityTokyo, Japan
| | - Yukio Morishita
- Diagnostic Pathology Division, Tokyo Medical University Ibaraki Medical CenterIbaraki, Japan
| | - Akira Honda
- Joint Research Center, Tokyo Medical University Ibaraki Medical CenterIbaraki, Japan
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical CenterIbaraki, Japan
| | - Kinya Furukawa
- Department of Thoracic Surgery, Tokyo Medical University Ibaraki Medical CenterIbaraki, Japan
| | - Norihiko Ikeda
- Division of Thoracic Surgery, Department of Surgery, Tokyo Medical UniversityTokyo, Japan
| |
Collapse
|
|
17
|
Concurrent Androgen Deprivation Therapy for Prostate Cancer Improves Survival for Synchronous or Metachronous Non-Small Cell Lung Cancer: A SEER-Medicare Database Analysis. Cancers (Basel) 2022; 14:cancers14133206. [PMID: 35804979 PMCID: PMC9265064 DOI: 10.3390/cancers14133206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 06/27/2022] [Accepted: 06/28/2022] [Indexed: 11/17/2022] Open
Abstract
Introduction: The crosstalk between receptor kinase signaling, such as EGFR and androgen receptor signaling, suggests a potential interaction between androgen deprivation therapy (ADT) and lung cancer outcome. Methods: We employed the SEER−Medicare data of lung cancer patients diagnosed between 1988 and 2005 to test for an association between ADT for prostate cancer and lung cancer outcome. We employed the Kaplan−Meier method and Cox proportional hazard with log-rank test model to assess any significant impact of ADT on survival. Results: We included data from 367,750 lung cancer patients; 17.4%, 2.9%, 33.6% and 46.1% with stages I, II, III and IV, respectively; 84.5% were >65 years; 57.2% males; 84.2% Caucasians and 9.3% Blacks. There were 11,061 patients (3%) with an initial prostate cancer diagnosis followed by lung cancer (P-L group); 3017 (0.8%) with an initial diagnosis of lung cancer and subsequent prostate cancer diagnosis (L-P group); the remainder had only lung cancer (L group). Stage I lung cancer was most common in the L-P group compared to the L and P-L groups—54% vs. 17.13% vs. 17.92%, p < 0.0001 for L-P, L and P-L, respectively. The median OS for lung cancer diagnosis was 93 months versus 10 and 9 months, respectively, for the L-P, L and P-L subgroups. ADT was associated with improved survival on multivariate analysis, especially in Caucasian patients (HR of death: 0.86; 95% CI: 0.76−0.97; p = 0.012). Conclusion: ADT was associated with improved outcome for NSCLC, in line with the hypothesis of a role for the androgen receptor in lung cancer. Our findings support a systematic evaluation of the potential benefit of ADT as a therapy for lung cancer.
Collapse
|
|
18
|
Li H, Chen H, Shi J, Fan Q, Zhou Z, Tang X, Wang Y, Liu Y. ERβ overexpression may not be a direct prognostic factor in patients with NSCLC: A meta-analysis. Int J Biol Markers 2022; 37:249-259. [PMID: 35730164 DOI: 10.1177/03936155221105521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Overall survival of non-small cell lung cancer (NSCLC) patients remains disappointingly low. The estrogen receptor (ER) was considered a promising therapeutic target for NSCLC. Numerous studies have linked expression of ERβ to lung cancer outcome. However, results are conflicting regarding the association of ERβ with surviving lung cancer. METHOD The aim of this meta-analysis was to evaluate the prognostic aspect of ERβ expression on survival among NSCLC patients. We performed a final analysis of prognostic value of overexpression ERβ on 3500 patients from 18 evaluable studies (from January 1, 2000 to May 1, 2021). The reference category is specified as low ERβ expression levels. Summarized hazard ratios were calculated. RESULTS Our study showed that the pooled hazard ratios of ERβ overexpression for overall survival in NSCLC was 0.81 (95% confidence interval (CI): 0.64-1.02, P = 0.07) by univariate analysis and 1.06 (95% CI: 0.83-1.36, P = 0.63) by multivariate analysis. Pooled hazard ratio by univariate analysis in Asian studies was 0.73 (95%CI: 0.59-0.89, P = 0.002). Pooled hazard ratio by univariate analysis was 0.75 (95% CI: 0.61-0.93, P = 0.009) from seven studies reported for nuclear ERβ. No significant results were found in subgroups by multivariate analysis. No significant results were found in studies outside Asia or in studies reported for cytoplasmic ERβ. CONCLUSION Our results suggested that expression of ERβ might not be a direct prognostic factor for NSCLC patients. More detailed prospective studies are needed to identify direct prognostic factors in these patients.
Collapse
Affiliation(s)
- Hui Li
- Department of Pharmacy, 71107Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Haishegn Chen
- Department of Pharmacy, 71107Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Jing Shi
- Department of Pharmacy, 71107Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Qing Fan
- Department of Pharmacy, 71107Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Zhongxia Zhou
- Department of Pharmacy, 71107Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Xiufeng Tang
- Department of Pharmacy, 71107Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Yanhong Wang
- Department of Pharmacy, 71107Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Yuguo Liu
- Department of Pharmacy, 71107Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| |
Collapse
|
|
19
|
Targeting Nuclear Receptors in Lung Cancer—Novel Therapeutic Prospects. Pharmaceuticals (Basel) 2022; 15:ph15050624. [PMID: 35631448 PMCID: PMC9145966 DOI: 10.3390/ph15050624] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 05/10/2022] [Accepted: 05/13/2022] [Indexed: 01/27/2023] Open
Abstract
Lung cancer, the second most commonly diagnosed cancer, is the major cause of fatalities worldwide for both men and women, with an estimated 2.2 million new incidences and 1.8 million deaths, according to GLOBOCAN 2020. Although various risk factors for lung cancer pathogenesis have been reported, controlling smoking alone has a significant value as a preventive measure. In spite of decades of extensive research, mechanistic cues and targets need to be profoundly explored to develop potential diagnostics, treatments, and reliable therapies for this disease. Nuclear receptors (NRs) function as transcription factors that control diverse biological processes such as cell growth, differentiation, development, and metabolism. The aberrant expression of NRs has been involved in a variety of disorders, including cancer. Deregulation of distinct NRs in lung cancer has been associated with numerous events, including mutations, epigenetic modifications, and different signaling cascades. Substantial efforts have been made to develop several small molecules as agonists or antagonists directed to target specific NRs for inhibiting tumor cell growth, migration, and invasion and inducing apoptosis in lung cancer, which makes NRs promising candidates for reliable lung cancer therapeutics. The current work focuses on the importance of various NRs in the development and progression of lung cancer and highlights the different small molecules (e.g., agonist or antagonist) that influence NR expression, with the goal of establishing them as viable therapeutics to combat lung cancer.
Collapse
|
|
20
|
Sun H, Liu M, Yang X, Ren Y, Dai H, Wang C. Construction and validation of prognostic nomograms for elderly patients with metastatic non-small cell lung cancer. THE CLINICAL RESPIRATORY JOURNAL 2022; 16:380-393. [PMID: 35514033 PMCID: PMC9366578 DOI: 10.1111/crj.13491] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Revised: 03/09/2022] [Accepted: 04/12/2022] [Indexed: 12/25/2022]
Abstract
BACKGROUND Metastatic non-small cell lung cancer (NSCLC) is mostly seen in older patients and is associated with poor prognosis. There is no reliable method to predict the prognosis of elderly patients (≥60 years old) with metastatic NSCLC. The aim of our study was to develop and validate nomograms which accurately predict survival in this group of patients. METHODS NSCLC patients diagnosed between 2010 and 2015 were all identified from the Surveillance, Epidemiology, and End Results (SEER) database. Nomograms were constructed by significant clinicopathological variables (p < 0.05) selected in multivariate Cox analysis regression. RESULTS A total of 9584 patients met the inclusion criteria and were randomly allocated in the training (n = 6712) and validation (n = 2872) cohorts. In training cohort, independent prognostic factors included age, gender, race, grade, tumor site, pathology, T stage, N stage, radiotherapy, surgery, chemotherapy, and metastatic site (p < 0.05) for lung cancer-specific survival (LCSS) and overall survival (OS) were identified by the Cox regression. Nomograms for predicting 1-, 2-, and 3-years LCSS and OS were established and showed excellent predictive performance with a higher C-index than that of the 7th TNM staging system (LCSS: training cohort: 0.712 vs. 0.534; p < 0.001; validation cohort: 0.707 vs. 0.528; p < 0.001; OS: training cohort: 0.713 vs. 0.531; p < 0.001; validation cohort: 0.710 vs. 0.528; p < 0.001). The calibration plots showed good consistency from the predicted to actual survival probabilities both in training cohort and validation cohort. Moreover, the decision curve analysis (DCA) achieved better net clinical benefit compared with TNM staging models. CONCLUSIONS We established and validated novel nomograms for predicting LCSS and OS in elderly patients with metastatic NSCLC with desirable discrimination and calibration ability. These nomograms could provide personalized risk assessment for these patients and assist in clinical decision.
Collapse
Affiliation(s)
- Haishuang Sun
- Department of Respiratory Medicine, The First Hospital of Jilin University, Changchun, China.,Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital; National Center for Respiratory Medicine; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences; National Clinical Research Center for Respiratory Diseases, Beijing, China.,Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Min Liu
- Department of Radiology, China-Japan Friendship Hospital, Beijing, China
| | - Xiaoyan Yang
- Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital; National Center for Respiratory Medicine; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences; National Clinical Research Center for Respiratory Diseases, Beijing, China.,Capital Medical University, Beijing, China
| | - Yanhong Ren
- Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital; National Center for Respiratory Medicine; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences; National Clinical Research Center for Respiratory Diseases, Beijing, China.,Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Huaping Dai
- Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital; National Center for Respiratory Medicine; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences; National Clinical Research Center for Respiratory Diseases, Beijing, China.,Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chen Wang
- Department of Respiratory Medicine, The First Hospital of Jilin University, Changchun, China.,Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital; National Center for Respiratory Medicine; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences; National Clinical Research Center for Respiratory Diseases, Beijing, China.,Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| |
Collapse
|
|
21
|
Estrogens, Cancer and Immunity. Cancers (Basel) 2022; 14:cancers14092265. [PMID: 35565393 PMCID: PMC9101338 DOI: 10.3390/cancers14092265] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 04/28/2022] [Accepted: 04/28/2022] [Indexed: 02/05/2023] Open
Abstract
Sex hormones are included in many physiological and pathological pathways. Estrogens belong to steroid hormones active in female sex. Estradiol (E2) is the strongest female sex hormone and, with its receptors, contributes to oncogenesis, cancer progression and response to treatment. In recent years, a role of immunosurveillance and suppression of immune response in malignancy has been well defined, forming the basis for cancer immunotherapy. The interplay of sex hormones with cancer immunity, as well as the response to immune checkpoint inhibitors, is of interest. In this review, we investigate the impact of sex hormones on natural immune response with respect to main active elements in anticancer immune surveillance: dendritic cells, macrophages, lymphocytes and checkpoint molecules. We describe the main sex-dependent tumors and the contribution of estrogen in their progression, response to treatment and especially modulation of anticancer immune response.
Collapse
|
|
22
|
Kaewjanthong P, Sooksai S, Sasano H, Hutvagner G, Bajan S, McGowan E, Boonyaratanakornkit V. Cell-penetrating peptides containing the progesterone receptor polyproline domain inhibits EGF signaling and cell proliferation in lung cancer cells. PLoS One 2022; 17:e0264717. [PMID: 35235599 PMCID: PMC8890653 DOI: 10.1371/journal.pone.0264717] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 02/15/2022] [Indexed: 01/10/2023] Open
Abstract
Non-small cell lung cancer (NSCLC) accounts for the majority (80-85%) of all lung cancers. All current available treatments have limited efficacy. The epidermal growth factor receptor (EGFR) plays a critical role in the development and progression of NSCLC, with high EGFR expression associated with increased cell proliferation and poor prognosis. Thus, interfering with EGFR signaling has been shown to effectively reduce cell proliferation and help in the treatment of NSCLC. We previously demonstrated that the progesterone receptor (PR) contains a polyproline domain (PPD) that directly interacts with Src homology 3 (SH3) domain-containing molecules and expression of PR-PPD peptides inhibits NSCLC cell proliferation. In this study, we investigated whether the introduction of PR-PPD by cell-penetrating peptides (CPPs) could inhibit EGF-induced cell proliferation in NSCLC cells. PR-PPD was attached to a cancer-specific CPP, Buforin2 (BR2), to help deliver the PR-PPD into NSCLC cells. Interestingly, addition of BR2-2xPPD peptides containing two PR-PPD repeats was more effective in inhibiting NSCLC proliferation and significantly reduced EGF-induced phosphorylation of Erk1/2. BR2-2xPPD treatment induced cell cycle arrest by inhibiting the expression of cyclin D1 and CDK2 genes in EGFR-wild type A549 cells. Furthermore, the combination treatment of EGFR-tyrosine kinase inhibitors (TKIs), including Gefitinib or Erlotinib, with BR2-2xPPD peptides further suppressed the growth of NSCLC PC9 cells harboring EGFR mutations as compared to EGFR-TKIs treatment alone. Importantly, BR2-2xPPD peptides mediated growth inhibition in acquired Gefitinib- and Erlotinib- resistant lung adenocarcinoma cells. Our data suggests that PR-PPD is the minimal protein domain sufficient to inhibit NSCLC cell growth and has the potential to be developed as a novel NSCLC therapeutic agent.
Collapse
Affiliation(s)
- Panthita Kaewjanthong
- Department of Clinical Chemistry and Graduate Program in Clinical Biochemistry and Molecular Medicine, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand
| | - Sarintip Sooksai
- The Institute of Biotechnology and Genetic Engineering, Chulalongkorn University, Bangkok, Thailand
| | - Hironobu Sasano
- Department of Anatomic Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Gyorgy Hutvagner
- School of Biomedical Engineering, Faculty of Engineering and IT, University of Technology Sydney, Australia
| | - Sarah Bajan
- School of Biomedical Engineering, Faculty of Engineering and IT, University of Technology Sydney, Australia
- School of Health and Behavioural Sciences, University of the Sunshine Coast, Australia
- Sunshine Coast Health Institute, Birtinya, Australia
| | - Eileen McGowan
- School of Life Sciences, University of Technology Sydney, Sydney, Australia
| | - Viroj Boonyaratanakornkit
- Department of Clinical Chemistry and Graduate Program in Clinical Biochemistry and Molecular Medicine, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand
- Age-related Inflammation and Degeneration Research Unit, Chulalongkorn University, Bangkok, Thailand
| |
Collapse
|
|
23
|
Siegfried JM. Sex and Gender Differences in Lung Cancer and Chronic Obstructive Lung Disease. Endocrinology 2022; 163:6470418. [PMID: 34927202 DOI: 10.1210/endocr/bqab254] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Indexed: 11/19/2022]
Abstract
Two highly prevalent pulmonary diseases, lung cancer and chronic obstructive lung disease (COPD), show both sex and gender differences in their presentations and outcomes. Sex differences are defined as biological differences associated with the male vs female genotype, and gender differences are defined as behavioral or social differences that primarily arise because of gender identity. The incidence of both lung cancer and COPD has increased dramatically in women over the past 50 years, and both are associated with chronic pulmonary inflammation. Development of COPD is also a risk factor for lung cancer. In this review, the main differences in lung cancer and COPD biology observed between men and women will be summarized. Potential causative factors will be discussed, including the role of estrogen in promoting pro-growth and inflammatory phenotypes which may contribute to development of both lung cancer and COPD. Response of the innate and adaptive immune system to estrogen is a likely factor in the biology of both lung cancer and COPD. Estrogen available from synthesis by reproductive organs as well as local pulmonary estrogen synthesis may be involved in activating estrogen receptors expressed by multiple cell types in the lung. Estrogenic actions, although more pronounced in women, may also have importance in the biology of lung cancer and COPD in men. Effects of estrogen are also timing and context dependent; the multiple cell types that mediate estrogen action in the lungs may confer both positive and negative effects on disease processes.
Collapse
Affiliation(s)
- Jill M Siegfried
- Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA
- Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA
| |
Collapse
|
|
24
|
Liu S, Hu C, Li M, An J, Zhou W, Guo J, Xiao Y. Estrogen receptor beta promotes lung cancer invasion via increasing CXCR4 expression. Cell Death Dis 2022; 13:70. [PMID: 35064116 PMCID: PMC8782891 DOI: 10.1038/s41419-022-04514-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 12/16/2021] [Accepted: 01/06/2022] [Indexed: 12/24/2022]
Abstract
Lung cancer is one of the most lethal malignant tumors in the world. The high recurrence and mortality rate make it urgent for scientists and clinicians to find new targets for better treatment of lung cancer. Early studies indicated that estrogen receptor β (ERβ) might impact the progression of non-small-cell lung cancer (NSCLC). However, the detailed mechanisms, especially its linkage to the CXCR4-mediated cell invasion, remain unclear. Here we found that ERβ could promote NSCLC cell invasion via increasing the circular RNA (circRNA), circ-TMX4, expression via directly binding to the 5′ promoter region of its host gene TMX4. ERβ-promoted circ-TMX4 could then sponge and inhibit the micro RNA (miRNA, miR), miR-622, expression, which can then result in increasing the CXCR4 messenger RNA translation via a reduced miRNA binding to its 3′ untranslated region (3′UTR). The preclinical study using an in vivo mouse model with orthotopic xenografts of NSCLC cells confirmed the in vitro data, and the human NSCLC database analysis and tissue staining also confirmed the linkage of ERβ/miR-622/CXCR4 signaling to the NSCLC progression. Together, our findings suggest that ERβ can promote NSCLC cell invasion via altering the ERβ/circ-TMX4/miR-622/CXCR4 signaling, and targeting this newly circ-TMX4/miR-622/CXCR4 signaling may help us find new treatment strategies to better suppress NSCLC progression.
Collapse
Affiliation(s)
- Shiqing Liu
- Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China.,Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Chengping Hu
- Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China.,Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Min Li
- Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China.,Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Jian An
- Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China.,Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Wolong Zhou
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Jia Guo
- Health Management Centre, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Yao Xiao
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China. .,Department of General Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China. .,International Joint Research Center of Minimally Invasive Endoscopic Technology Equipment & Standards, Changsha, 410008, China.
| |
Collapse
|
|
25
|
Abstract
Estrogen receptors (ERs) are known to play an important role in the proper development of estrogen-sensitive organs, as well as in the development and progression of various types of cancer. ERα, the first ER to be discovered, has been the focus of most cancer research, especially in the context of breast cancer. However, ERβ expression also plays a significant role in cancer pathophysiology, notably its seemingly protective nature and loss of expression with oncogenesis and progression. Although ERβ exhibits antitumor activity in breast, ovarian, and prostate cancer, its expression is associated with disease progression and worse prognosis in lung cancer. The function of ERβ is complicated by the presence of multiple isoforms and single nucleotide polymorphisms, in addition to tissue-specific functions. This mini-review explores current literature on ERβ and its mechanism of action and clinical implications in breast, ovarian, prostate, and lung cancer.
Collapse
Affiliation(s)
- Nicole M Hwang
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, PA 15261, USA
- UPMC Hillman Cancer Center, Research Center, Pittsburgh, PA 15232, USA
| | - Laura P Stabile
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, PA 15261, USA
- UPMC Hillman Cancer Center, Research Center, Pittsburgh, PA 15232, USA
| |
Collapse
|
|
26
|
Abstract
Lung cancer represents the world's leading cause of cancer deaths. Sex differences in the incidence and mortality rates for various types of lung cancers have been identified, but the biological and endocrine mechanisms implicated in these disparities have not yet been determined. While some cancers such as lung adenocarcinoma are more commonly found among women than men, others like squamous cell carcinoma display the opposite pattern or show no sex differences. Associations of tobacco product use rates, susceptibility to carcinogens, occupational exposures, and indoor and outdoor air pollution have also been linked to differential rates of lung cancer occurrence and mortality between sexes. While roles for sex hormones in other types of cancers affecting women or men have been identified and described, little is known about the influence of sex hormones in lung cancer. One potential mechanism identified to date is the synergism between estrogen and some tobacco compounds, and oncogene mutations, in inducing the expression of metabolic enzymes, leading to enhanced formation of reactive oxygen species and DNA adducts, and subsequent lung carcinogenesis. In this review, we present the literature available regarding sex differences in cancer rates, associations of male and female sex hormones with lung cancer, the influence of exogenous hormone therapy in women, and potential mechanisms mediated by male and female sex hormone receptors in lung carcinogenesis. The influence of biological sex on lung disease has recently been established, thus new research incorporating this variable will shed light on the mechanisms behind the observed disparities in lung cancer rates, and potentially lead to the development of new therapeutics to treat this devastating disease.
Collapse
Affiliation(s)
- Nathalie Fuentes
- National Institute of Allergy and Infectious Diseases, Bethesda, MD 20852, USA
| | - Miguel Silva Rodriguez
- Department of Environmental and Occupational Health, Indiana University, School of Public Health, Bloomington, IN 47405, USA
| | - Patricia Silveyra
- Department of Environmental and Occupational Health, Indiana University, School of Public Health, Bloomington, IN 47405, USA
| |
Collapse
|
|
27
|
Akyu Takei R, Tomihara K, Yamazaki M, Moniruzzaman R, Heshiki W, Sekido K, Tachinami H, Sakurai K, Yonesi A, Imaue S, Fujiwara K, Noguchi M. Protumor role of estrogen receptor expression in oral squamous cell carcinoma cells. Oral Surg Oral Med Oral Pathol Oral Radiol 2021; 132:549-565. [PMID: 34518137 DOI: 10.1016/j.oooo.2021.04.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Revised: 01/26/2021] [Accepted: 04/18/2021] [Indexed: 10/21/2022]
Abstract
OBJECTIVE Accumulating evidence has demonstrated the protumor role of estrogen receptor (ER)-mediated signaling in multiple cancer types, which is distinct from this signaling in sex steroid-dependent organs. However, its role in oral squamous cell carcinoma (OSCC) remains unclear. STUDY DESIGN We assessed the expression of ERα and ERβ in human OSCC tissues by immunohistochemistry and evaluated the expression of both receptors in OSCC cell lines by immunoblotting and flow cytometry. To further assess the contribution of ER-mediated signals to oral cancer progression, proliferation, invasion, and chemosensitivity, cell lines were stimulated with the ER agonist β-estradiol. RESULTS Immunohistochemical analysis of OSCC tissues showed that ERβ was present in the cytoplasm and nuclei of OSCC cells. In contrast, ERα was not detected in any of the cases analyzed. Additionally, the proliferation and invasiveness of OSCC cells were significantly elevated following stimulation with β-estradiol. Chemotherapeutic agent-induced apoptosis of cancer cells was attenuated by pretreatment with β-estradiol. CONCLUSIONS ER-mediated signaling plays a crucial role in oral cancer progression by facilitating the proliferation, invasion, and chemoresistance of OSCC cells, indicating its potential for developing novel targeted therapies for this type of cancer.
Collapse
Affiliation(s)
- Rie Akyu Takei
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan; Department of Oral and Maxillofacial Surgery, Saiseikai Toyama Hospital, Toyama, Japan
| | - Kei Tomihara
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan.
| | - Manabu Yamazaki
- Division of Oral Pathology, Department of Tissue Regeneration and Reconstruction, Niigata University, Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Rohan Moniruzzaman
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan
| | - Wataru Heshiki
- Department of Oral and Maxillofacial Surgery, Regional Independent Administrative Corporation Naha City Hospital, Naha, Japan
| | - Katsuhisa Sekido
- Department of Oral and Maxillofacial Surgery, Toyama Red Cross Hospital, Toyama, Japan
| | - Hidetake Tachinami
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan
| | - Kotaro Sakurai
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan
| | - Amirmoezz Yonesi
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan
| | - Shuichi Imaue
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan
| | - Kumiko Fujiwara
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan
| | - Makoto Noguchi
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan
| |
Collapse
|
|
28
|
Meng W, Liao Y, Chen J, Wang Y, Meng Y, Li K, Xiao H. Upregulation of estrogen receptor beta protein but not mRNA predicts poor prognosis and may be associated with enhanced translation in non-small cell lung cancer: a systematic review and meta-analysis. J Thorac Dis 2021; 13:4281-4300. [PMID: 34422356 PMCID: PMC8339768 DOI: 10.21037/jtd-21-658] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 06/19/2021] [Indexed: 12/25/2022]
Abstract
Background An increasing number of original studies suggest that estrogen receptor beta (ERβ) expression may be related to non-small cell lung cancer (NSCLC) prognosis; however, the evidence remains inconclusive and conflicting. We aimed to systematically evaluate the expression and prognostic value of ERβ in NSCLC, and to explain the inconsistency between ERβ protein and mRNA level. Methods PubMed, Embase, and Web of Science databases were searched for studies (published before October 6, 2020) reporting the prognostic value of ERβ protein expression in NSCLC. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) for overall survival (OS) were calculated. Transcriptome and survival data of lung adenocarcinoma patients were obtained from public databases for differential expression and survival analyses. Immunohistochemistry (IHC) was performed to examine the ERβ protein expression in 39 NSCLC patients. Western blotting and RT-qPCR were performed to analyze ERβ expression in two paired NSCLC and normal adjacent tissue samples. The effect of methyltransferase-like 13 (METTL3) on ERβ expression was investigated in a lung cancer cell line. Results Meta-analysis of 23 studies with a total of 3744 patients demonstrated that high protein expression of overall ERβ and cytoplasmic ERβ indicated poor OS (HR: 1.05, 95% CI: 1.00 to 1.10; HR: 1.48, 95% CI: 1.13 to 1.95) in NSCLC. For lung adenocarcinoma especially, high protein expression of both overall/cytoplasmic ERβ and nuclear ERβ suggested poor OS (HR: 1.54, 95% CI: 1.05 to 2.25; HR: 1.36, 95% CI: 1.03 to 1.80). Bioinformatics analysis indicated the expression of ERβ mRNA was not associated with the prognosis of lung adenocarcinoma. Analysis of public databases showed that ERβ mRNA is not highly expressed in tumor tissues, however, IHC results revealed that ERβ protein is highly expressed in NSCLC tissues. We validated this inconsistency in ERβ expression in paired tumors and normal adjacent tissues from patients. Moreover, METTL3 knockdown in the A549 cell line downregulated ERβ protein expression but not ERβ mRNA expression. Conclusions Our study elucidated the inconsistency between ERβ protein and mRNA expression levels and their prognostic values. The results indicated that METTL3-driven enhanced translation in NSCLC may cause this inconsistency.
Collapse
Affiliation(s)
- Wangyang Meng
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yongde Liao
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiaping Chen
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yangwei Wang
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yunchong Meng
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kuo Li
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Han Xiao
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
29
|
Słowikowski BK, Jankowski M, Jagodziński PP. The smoking estrogens - a potential synergy between estradiol and benzo(a)pyrene. Biomed Pharmacother 2021; 139:111658. [PMID: 34243627 DOI: 10.1016/j.biopha.2021.111658] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 04/20/2021] [Accepted: 04/21/2021] [Indexed: 02/04/2023] Open
Abstract
According to recent statistics, Lung Cancer (LC) is one of the most frequently diagnosed tumor types, representing nearly 12% of all global cancer cases. Moreover, in recent years, an increased mortality rate and incidence of this cancer were observed, especially among nonsmokers. Lung cancer patients are often characterized by poor prognosis and low survival rates, which encourages the scientific community to investigate the biochemical and molecular processes leading to the development of this malignancy. Furthermore, the mechanisms of LC formation and progression are not yet fully elucidated due to their high complexity, as well as a multitude of environmental, genetic, and molecular factors involved. Even though LC's association with exposure to cigarette smoke is indisputable, current research provides evidence that the development of this cancer can also be affected by the presence of estrogens and their interaction with several tobacco smoke components. Hence, the main goal of this brief review was to investigate reports of a possible synergy between 17β estradiol (E2), the most biologically active estrogen, and benzo(a)pyrene (BaP), a strongly carcinogenic compound produced as a result of incomplete tobacco combustion. The literature sources demonstrate a possible carcinogenic synergy between estrogens, especially E2, and BaP, a toxic tobacco smoke component. Therefeore, the combined effect of disturbed estrogen production in cancer cells, as well as the molecular influence exerted by BaP, could explain the increased aggressiveness and rate of LC development. Summarizing, the synergistic effect of these risk factors is an interesting area of further research.
Collapse
Affiliation(s)
- Bartosz Kazimierz Słowikowski
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Święcickiego 6 Street, 60-781 Poznan, Poland.
| | - Maurycy Jankowski
- Department of Anatomy, Poznan University of Medical Sciences, Święcickiego 6 Street, 60-781 Poznan, Poland
| | - Paweł Piotr Jagodziński
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Święcickiego 6 Street, 60-781 Poznan, Poland
| |
Collapse
|
|
30
|
The Sex-Related Interplay between TME and Cancer: On the Critical Role of Estrogen, MicroRNAs and Autophagy. Cancers (Basel) 2021; 13:cancers13133287. [PMID: 34209162 PMCID: PMC8267629 DOI: 10.3390/cancers13133287] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 06/17/2021] [Accepted: 06/25/2021] [Indexed: 01/18/2023] Open
Abstract
The interplay between cancer cells and the tumor microenvironment (TME) has a fundamental role in tumor progression and response to therapy. The plethora of components constituting the TME, such as stroma, fibroblasts, endothelial and immune cells, as well as macromolecules, e.g., hormones and cytokines, and epigenetic factors, such as microRNAs, can modulate the survival or death of cancer cells. Actually, the TME can stimulate the genetically regulated programs that the cell puts in place under stress: apoptosis or, of interest here, autophagy. However, the implication of autophagy in tumor growth appears still undefined. Autophagy mainly represents a cyto-protective mechanism that allows cell survival but, in certain circumstances, also leads to the blocking of cell cycle progression, possibly leading to cell death. Since significant sex/gender differences in the incidence, progression and response to cancer therapy have been widely described in the literature, in this review, we analyzed the roles played by key components of the TME, e.g., estrogen and microRNAs, on autophagy regulation from a sex/gender-based perspective. We focused our attention on four paradigmatic and different forms of cancers-colon cancer, melanoma, lymphoma, and lung cancer-concluding that sex-specific differences may exert a significant impact on TME/cancer interaction and, thus, tumor growth.
Collapse
|
|
31
|
Reyes-García J, Montaño LM, Carbajal-García A, Wang YX. Sex Hormones and Lung Inflammation. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1304:259-321. [PMID: 34019274 DOI: 10.1007/978-3-030-68748-9_15] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Inflammation is a characteristic marker in numerous lung disorders. Several immune cells, such as macrophages, dendritic cells, eosinophils, as well as T and B lymphocytes, synthetize and release cytokines involved in the inflammatory process. Gender differences in the incidence and severity of inflammatory lung ailments including asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis (PF), lung cancer (LC), and infectious related illnesses have been reported. Moreover, the effects of sex hormones on both androgens and estrogens, such as testosterone (TES) and 17β-estradiol (E2), driving characteristic inflammatory patterns in those lung inflammatory diseases have been investigated. In general, androgens seem to display anti-inflammatory actions, whereas estrogens produce pro-inflammatory effects. For instance, androgens regulate negatively inflammation in asthma by targeting type 2 innate lymphoid cells (ILC2s) and T-helper (Th)-2 cells to attenuate interleukin (IL)-17A-mediated responses and leukotriene (LT) biosynthesis pathway. Estrogens may promote neutrophilic inflammation in subjects with asthma and COPD. Moreover, the activation of estrogen receptors might induce tumorigenesis. In this chapter, we summarize the most recent advances in the functional roles and associated signaling pathways of inflammatory cellular responses in asthma, COPD, PF, LC, and newly occurring COVID-19 disease. We also meticulously deliberate the influence of sex steroids on the development and progress of these common and severe lung diseases.
Collapse
Affiliation(s)
- Jorge Reyes-García
- Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, CDMX, Mexico City, Mexico.,Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA
| | - Luis M Montaño
- Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, CDMX, Mexico City, Mexico
| | - Abril Carbajal-García
- Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, CDMX, Mexico City, Mexico
| | - Yong-Xiao Wang
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA.
| |
Collapse
|
|
32
|
Rodriguez-Lara V, Avila-Costa MR. An Overview of Lung Cancer in Women and the Impact of Estrogen in Lung Carcinogenesis and Lung Cancer Treatment. Front Med (Lausanne) 2021; 8:600121. [PMID: 34079807 PMCID: PMC8165182 DOI: 10.3389/fmed.2021.600121] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 03/30/2021] [Indexed: 12/31/2022] Open
Abstract
Lung cancer incidence and mortality have significantly increased in women worldwide. Lung adenocarcinoma is the most common form of lung cancer globally. This type of lung cancer shows differences by sex, including the mutational burden, behavior, clinical characteristics, and response to treatment. The effect of sex on lung cancer patients' survival is still controversial; however, lung adenocarcinoma is considered a different disease in women and men. Moreover, lung adenocarcinoma is strongly influenced by estrogen and is also different depending on the hormonal status of the patient. Young pre-menopausal women have been explored as an independent group. They presented in more advanced stages at diagnosis, exhibited more aggressive tumors, and showed poor survival compared to men and post-menopausal women, supporting the role of sex hormones in this pathology. Several reports indicate the estrogen's role in lung carcinogenesis and tumor progression. Thus, there are currently some clinical trials testing the efficacy of antihormonal therapy in lung cancer treatment. This mini review shows the updated data about lung cancer in women, its characteristics, the etiological factors that influence carcinogenesis, and the critical role of estrogen in lung cancer and treatment.
Collapse
Affiliation(s)
- Vianey Rodriguez-Lara
- Department of Cell and Tissue Biology, Faculty of Medicine, Universidad Nacional Autonoma de Mexico, Mexico City, Mexico
| | - Maria Rosa Avila-Costa
- Neuromorphology Laboratory, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autonoma de Mexico, Mexico City, Mexico
| |
Collapse
|
|
33
|
Liau CS, Mogan P, Thomas W. Oestrogen actions contribute to female gender-specific risks in the development of lung carcinoma. J Steroid Biochem Mol Biol 2021; 208:105786. [PMID: 33189851 DOI: 10.1016/j.jsbmb.2020.105786] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 10/09/2020] [Accepted: 11/03/2020] [Indexed: 01/10/2023]
Abstract
Lung cancer is increasing in incidence particularly among women, associated with a global change in smoking habits. Steroid hormones, particularly oestrogen exert an influence on tumour progression in tissues where their target receptor is expressed. Oestrogen receptor, particularly ERβ is highly expressed in the lung and becomes more highly expressed in lung carcinogenesis. Genes involved in the process of lung carcinoma progression and signalling cascades linked to invasion and angiogenesis are modulated by oestrogen receptors. This review intends to collate recently published evidence identifying a role for oestrogen in the initiation and progression of lung carcinoma and how these two processes are differentially affected by circulating oestrogens both in women and in men. Circulating oestrogens may be a significant risk factor in women's susceptibility to lung carcinoma and also provide an additional approach for more targeted therapy.
Collapse
Affiliation(s)
- Chi Sun Liau
- Perdana University - Royal College of Surgeons in Ireland School of Medicine, Perdana University, Bukit Damansara, Kuala Lumpur, Malaysia
| | - Praveena Mogan
- Perdana University - Royal College of Surgeons in Ireland School of Medicine, Perdana University, Bukit Damansara, Kuala Lumpur, Malaysia
| | - Warren Thomas
- Perdana University - Royal College of Surgeons in Ireland School of Medicine, Perdana University, Bukit Damansara, Kuala Lumpur, Malaysia; Molecular Medicine Laboratories, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland.
| |
Collapse
|
|
34
|
Pinton G, Manzotti B, Balzano C, Moro L. Expression and clinical implications of estrogen receptors in thoracic malignancies: a narrative review. J Thorac Dis 2021; 13:1851-1863. [PMID: 33841973 PMCID: PMC8024832 DOI: 10.21037/jtd-20-2277] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Thoracic malignancies represent a significant global health burden with incidence and mortality increasing year by year. Thoracic cancer prognosis and treatment options depend on several factors, including the type and size of the tumor, its location, and the overall health status of patients. Gender represents an important prognostic variable in thoracic malignancies. One of the greatest biological differences between women and men is the presence of female sex hormones, and an increasing number of studies suggest that estrogens may play either a causative or a protective role in thoracic malignancies. Over the past 60 years since the discovery of the first nuclear estrogen receptor (ER) isoform α and the almost 20 years since the discovery of the second estrogen receptor, ERβ, different mechanisms governing estrogen action have been identified and characterized. This literature review reports the published data regarding the expression and function of ERs in different thoracic malignancies and discuss sex disparity in clinical outcomes. From this analysis emerges that further efforts are warranted to better elucidate the role of sex hormones in thoracic malignancies, and to reduce disparities in care between genders. Understanding the mechanisms by which gender-related differences can affect and interfere with the onset and evolution of thoracic malignancies and impact on response to therapies could help to improve the knowledge needed to develop increasingly personalized and targeted treatments.
Collapse
Affiliation(s)
- Giulia Pinton
- Department of Pharmaceutical Sciences, University of Piemonte Orientale, 28100 Novara, Italy
| | - Beatrice Manzotti
- Department of Pharmaceutical Sciences, University of Piemonte Orientale, 28100 Novara, Italy
| | - Cecilia Balzano
- Department of Pharmaceutical Sciences, University of Piemonte Orientale, 28100 Novara, Italy
| | - Laura Moro
- Department of Pharmaceutical Sciences, University of Piemonte Orientale, 28100 Novara, Italy
| |
Collapse
|
|
35
|
Zhong L, Zhang C, Jia W, Zhang P. Diagnostic and therapeutic ERβ, HER2, BRCA biomakers in the histological subtypes of lung adenocarcinoma according to the IASLC/ATS/ERS classification. Ann Diagn Pathol 2021; 51:151700. [PMID: 33465722 DOI: 10.1016/j.anndiagpath.2020.151700] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 12/21/2020] [Indexed: 10/22/2022]
Abstract
Several studies revealed that non-small cell lung cancers (NSCLCs) frequently express ER, PR, HER2 and carry BRCA mutation. However, these markers in histological subtypes of lung adenocarcinoma have not been thoroughly investigated. We retrospectively evaluated a total of 640 lung adenocarcinoma samples for ERα, ERβ, PR and HER2 expression by immunohistochemistry and western-blotting, for EGFR and BRCA mutation by real-time PCR and sequencing. Furthermore, HER2 amplification and mutation were explored in samples harboring immunopositivity HER2 using fluorescence in situ hybridization and real-time PCR, respectively. The micropapillary and invasive mucinous predominant adenocarcinoma were frequently detected the higher level of cytoplasmic ERβ (64.9% and 56.6%), HER2 (68.1% and 60.1%) protein expression. But, amplification of HER2 was detected in only three cases (3/110, 2.7%) and 26 HER2 mutations in 110 cases were identified (23.6%) in the HER2 immunopositivity patients. Logistic regression analysis showed that cytoplasmic ERβ (P = 0.032) and HER2 (P = 0.015) expression were independently associated with EGFR mutation. 8 patients (8/640, 1.25%) harbored pathogenic BRCA mutations, 6 with germline BRCA mutations and 2 with somatic BRCA1 mutations were detected with lacking ERβ, PR and HER2 expression. Acinar predominant adenocarcinoma had the higher percentage of BRCA mutations than other subtypes. A systematic examination of ERβ, HER2 and BRCA biomarkers could potentially be useful to diagnosis and identify patients with the histological subtypes of lung adenocarcinoma, who might benefit from the further individualized treatment of anti-hormone, anti-HER2 and/or PARP inhibitors therapeutics.
Collapse
Affiliation(s)
- Lin Zhong
- Department of Pathology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116001, PR China
| | - Chunfang Zhang
- Department of Pathology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116001, PR China
| | - Wenting Jia
- Department of Pathology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116001, PR China
| | - Pengxin Zhang
- Department of Pathology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116001, PR China.
| |
Collapse
|
|
36
|
Jin K, Hung RJ, Thomas S, Le Marchand L, Matsuo K, Seow A, Shen H, Kok WP, Yuan JM, Wu M, Li L, Zhao JK, Zhang ZF. Hormonal factors in association with lung cancer among Asian women: A pooled analysis from the International Lung Cancer Consortium. Int J Cancer 2020; 148:2241-2254. [PMID: 33210298 DOI: 10.1002/ijc.33405] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 10/21/2020] [Accepted: 10/22/2020] [Indexed: 12/15/2022]
Abstract
Two thousand sixty-four lung cancer cases and 5342 controls were evaluated in this International Lung Cancer Consortium (ILCCO) pooled analysis on estrogen-related hormonal factors and lung cancer in Asian women. Random effect of study site and fixed effect of age, smoking status, comprehensive smoking index and family history of lung cancer were adjusted for in the multivariable logistic regression models. We found that late onset of menarche conferred elevated odds of lung cancer with adjusted odds ratio (OR) of 1.24 (95% confidence interval [CI] = 1.05, 1.45) for 17 years or older, compared to 14 years or younger. Late onset of menopause at 55 years old or older was associated with lung cancer with OR = 1.24 (95% CI = 1.02, 1.51). Nonnatural menopause was associated with an OR of 1.39 (95% CI = 1.13, 1.71). More live births showed reversed association with lung cancer (ORs of 5 or more live births: 0.71 (95% CI = 0.60, 0.84), compared to 0-2 live births (Ptrend < 0.001). A later first child delivery seemed associated with an increased susceptibility: OR of 21 to 25 years old: 1.23 (95% CI = 1.06, 1.40), 26 or older: 1.27 (95% CI = 1.06, 1.52), Ptrend = .010). The use of oral contraceptives appeared to be protective with an OR of 0.69 (95% CI = 0.57, 0.83). Stronger for adenocarcinoma than squamous cell carcinoma, these relationships were not clearly modified by smoking status, probably because of lower prevalence of smoking. This is a first and largest pooling study of lung cancer among Asian women and the results suggested potential roles of hormone-related pathways in the etiology of this disease.
Collapse
Affiliation(s)
- Kexin Jin
- Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, California, USA
| | - Rayjean J Hung
- Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
| | - Sera Thomas
- Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
| | - Loic Le Marchand
- Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA
| | - Keitaro Matsuo
- Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.,Department of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Adeline Seow
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore
| | - Hongbing Shen
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.,Collaborative Innovation Center for Cancer Personalized Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention & Treatment, Cancer Center, Nanjing Medical University, Nanjing, China
| | - Woon-Puay Kok
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore.,Health Service and Systems Research, Duke-NUS Medical School, Singapore
| | - Jian-Min Yuan
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.,Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA
| | - Ming Wu
- Department of Non-communicable Chronic Disease Control, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China
| | - Liming Li
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Jin-Kou Zhao
- Department of Non-communicable Chronic Disease Control, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China
| | - Zuo-Feng Zhang
- Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, California, USA.,David Geffen School of Medicine, Center for Human Nutrition, UCLA, Los Angeles, California, USA.,Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, USA
| |
Collapse
|
|
37
|
Yu H, Gu D, Qian P. Prognostic value of ESR2 expression on adjuvant chemotherapy in completely resected NSCLC. PLoS One 2020; 15:e0243891. [PMID: 33332474 PMCID: PMC7746143 DOI: 10.1371/journal.pone.0243891] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Accepted: 11/30/2020] [Indexed: 11/18/2022] Open
Abstract
Background Prognostic biomarker, which can inform the treatment outcome of adjuvant chemotherapy (ACT) after complete resection of early-stage non-small cell lung cancer (NSCLC), is urgently needed for the personalized treatment of these patients. Patients and methods The prognostic value of gene expression of the estrogen receptor (ER) on the effect of ACT in completely resected NSCLC was investigated in the present study. Two independent datasets from Gene Expression Omnibus (GEO) with a total of 309 patients were included in this study. The prognostic value of ER gene expression on ACT’s efficacy was evaluated by survival analysis and Cox hazards models. Results We found a consistent and significant prognostic value of ERβ (ESR2) expression for ACT’s efficacy in completely resected NSCLC in both of the two independent cohorts. After multivariate adjustment, a significant survival benefit of ACT was observed in patients with low expression of ESR2, with a hazard ratio (HR) of 0.19 (95%CI 0.05–0.82, p = 0.026) in the discovery cohort and an HR of 0.27 (95%CI 0.10–0.76, p = 0.012) in the validation group. No significant benefit of ACT in the subgroup of patients with high expression of ESR2 was observed, with an HR of 0.80 (95%CI 0.31–2.09, p = 0.644) in the discovery cohort and an HR of 1.05 (95%CI 0.48–2.29, p = 0.896) in the validation group. Conclusion A significant survival benefit from ACT was observed in patients with low ESR2 expression. No significant survival benefit was observed in patients with high ESR2 expression. Detection of ESR2 expression in NSCLC may help personalize its treatment after complete resection.
Collapse
Affiliation(s)
- Hongliang Yu
- Department of Radiation Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China
| | - Dayong Gu
- Department of Radiation Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China
| | - Pudong Qian
- Department of Radiation Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China
- * E-mail:
| |
Collapse
|
|
38
|
Coco S, Boccardo S, Mora M, Fontana V, Vanni I, Genova C, Alama A, Salvi S, Dal Bello MG, Bonfiglio S, Rijavec E, Sini C, Barletta G, Biello F, Carli F, Cavalieri Z, Burrafato G, Longo L, Ballestrero A, Grossi F. Radiation-Related Deregulation of TUBB3 and BRCA1/2 and Risk of Secondary Lung Cancer in Women With Breast Cancer. Clin Breast Cancer 2020; 21:218-230.e6. [PMID: 33008754 DOI: 10.1016/j.clbc.2020.09.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 08/05/2020] [Accepted: 09/02/2020] [Indexed: 01/15/2023]
Abstract
INTRODUCTION Breast cancer survivors are at increased risk of developing unrelated primary cancers, particularly lung cancer. Evidence indicates that sex hormones as well as a deregulation of DNA-repair pathways may contribute to lung cancer onset. We investigated whether the hormone status and expression of markers involved in DNA repair (BRCA1/2, ERCC1, and P53R2), synthesis (TS and RRM1), and cell division (TUBB3) might be linked to lung cancer risk. PATIENTS AND METHODS Thirty-seven breast cancer survivors with unrelated lung cancer and 84 control subjects comprising women with breast cancer (42/84) or lung cancer (42/84) were enrolled. Immunohistochemistry on tumor tissue was performed. Geometric mean ratio was used to assess the association of marker levels with patient groups. RESULTS Estrogen receptor was expressed in approximately 90% of the breast cancer group but was negative in the majority of the lung cancer group, a result similar to the lung cancer control group. Likewise, ER isoform β was weakly expressed in the lung cancer group. Protein analysis of breast cancer versus control had a significantly lower expression of BRCA1, P53R2, and TUBB3. Likewise, a BRCA1 reduction was observed in the lung cancer group concomitant with a BRCA2 increase. Furthermore, BRCA2 and TUBB3 increased in ipsilateral lung cancer in women who had previously received radiotherapy for breast cancer. CONCLUSION The decrease of DNA-repair proteins in breast cancer could make these women more susceptible to therapy-related cancer. The increase of BRCA2 and TUBB3 in lung cancer from patients who previously received radiotherapy for breast cancer might reflect a tissue response to exposure to ionizing radiation.
Collapse
Affiliation(s)
- Simona Coco
- Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
| | - Simona Boccardo
- Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | | | - Vincenzo Fontana
- Clinical Epidemiology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Irene Vanni
- Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy; Department of Internal Medicine and Medical Specialties (DIMI), University of Genoa
| | - Carlo Genova
- Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy; Department of Internal Medicine and Medical Specialties (DIMI), University of Genoa
| | - Angela Alama
- Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | | | | | - Silvia Bonfiglio
- Centre for Translational Genomics and Bioinformatics, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Erika Rijavec
- UOC Oncologia Medica, IRCCS Cà Granda Foundation, Ospedale Maggiore Policlinico, Milan, Italy
| | - Claudio Sini
- Oncologia Medica e CPDO, ASSL di Olbia-ATS Sardegna, Olbia, Italy
| | - Giulia Barletta
- Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | | | | | - Zita Cavalieri
- Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | | | - Luca Longo
- Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Alberto Ballestrero
- Department of Internal Medicine and Medical Specialties (DIMI), University of Genoa
| | - Francesco Grossi
- UOC Oncologia Medica, IRCCS Cà Granda Foundation, Ospedale Maggiore Policlinico, Milan, Italy
| |
Collapse
|
|
39
|
Enwere EK, Dean ML, Li H, D'Silva A, Bebb DG. The prevalence and prognostic significance of estrogen receptor beta expression in non-small cell lung cancer. Transl Lung Cancer Res 2020; 9:496-506. [PMID: 32676313 PMCID: PMC7354142 DOI: 10.21037/tlcr.2020.03.34] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Background Estrogen receptor beta (ERβ) is the predominant estrogen receptor (ER) expressed in non-small cell lung cancer (NSCLC); however, due to methodological disparities among prior studies, the prognostic value of ERβ expression in NSCLC remains unclear. Our objective was to apply improved detection and analysis techniques to assess the prognostic value of ERβ expression in NSCLC. Methods A tissue microarray (TMA) was used which contained resected and biopsy specimens from 299 patients diagnosed at a single center with stages I-IV NSCLC. Sections of this array were stained using high-sensitivity fluorescence immunohistochemistry, with the well-validated PPG5/10 monoclonal antibody. Digital images of the stained array slides were analyzed using software-based image analysis, which reported ERβ expression as a continuous variable in different subcellular domains. Results There were no differences in ERβ expression between male and female patients. High expression of ERβ was not a prognostic factor, but was significantly associated with stage IV disease in both tumor and stroma (P<0.001). In multivariable analysis, a high nuclear/cytoplasmic (N/C) ratio of ERβ expression was significantly associated with shorter overall survival, based on expression in the tumor [hazard ratio (HR): 1.65; 95% confidence interval (CI): 1.25-2.19; P<0.001] and in the stroma (HR: 1.57; 95% CI: 1.16-2.12; P=0.003). Conclusions These results suggest that subcellular localization of ERβ, but not absolute expression, is a prognostic factor in NSCLC.
Collapse
Affiliation(s)
- Emeka K Enwere
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Michelle L Dean
- Translational Laboratories, Tom Baker Cancer Center, Calgary, Alberta, Canada
| | - Haocheng Li
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Department of Oncology, Tom Baker Cancer Center, Calgary, Alberta, Canada
| | - Adrijana D'Silva
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - D Gwyn Bebb
- Translational Laboratories, Tom Baker Cancer Center, Calgary, Alberta, Canada.,Department of Oncology, Tom Baker Cancer Center, Calgary, Alberta, Canada
| |
Collapse
|
|
40
|
Fontaine-Delaruelle C, Mazières J, Cadranel J, Mastroianni B, Dubos-Arvis C, Dumont P, Monnet I, Pichon E, Locatelli-Sanchez M, Dixmier A, Coudert B, Fraboulet S, Foucher P, Dansin E, Baize N, Vincent M, Missy P, Morin F, Moro-Sibilot D, Couraud S. Somatic profile in lung cancers is associated to reproductive factors in never-smokers women: Results from the IFCT-1002 BioCAST study. Respir Med Res 2020; 77:58-66. [PMID: 32416585 DOI: 10.1016/j.resmer.2020.01.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 12/30/2019] [Accepted: 01/24/2020] [Indexed: 01/07/2023]
Abstract
BACKGROUND Lung cancer in women is on the rise, with a higher proportion occurring in lifelong never-smokers. Lung cancer in never-smokers (LCINS) exhibits a high frequency of driver oncogene alterations. In this study, we aimed to investigate whether exposure to reproductive factors in women with LCINS may modulate the molecular pattern. METHODS All newly diagnosed LCINSs were included in a prospective, observational study (IFCT-1002 BioCAST). Each patient responded to a questionnaire including reproductive factors. Biomarker test results were also collected. RESULTS Two hundred and sixty women were included in this analysis, and 166 alterations were characterized. EGFR mutation frequency proved greater among patients with late menarche (74% in age>14 vs. 40% and 41% for 12-14 and ≤12 years, respectively; P=0.020) and tended to decrease with increasingly late age at menopause. In multivariate analysis, EGFR mutation frequency increased by 23% per increment of 1 year of age at menarche (P=0.048), and by 9% for each year at age at first birth (P=0.035). ALK alteration frequency was greater in women with high parity (50% in≥5 vs. 12% and 7% for 1-4 and nulliparity, respectively; P=0.021). CONCLUSION In a cohort of women LCINSs, female hormonal factors appear to impact molecular pattern.
Collapse
Affiliation(s)
- C Fontaine-Delaruelle
- Service de pneumologie aiguë spécialisée et cancérologie thoracique, hôpital Lyon Sud, institut de cancérologie des hospices civils de Lyon, Pierre-Bénite, France
| | - J Mazières
- Service de pneumologie, université Paul-Sabatier, hôpital Larrey, centre hospitalier universitaire, Toulouse, France
| | - J Cadranel
- Service de pneumologie, hôpital Tenon, AP-HP, Paris, France
| | - B Mastroianni
- Service de pneumologie, institut de cancérologie des hospices civils de Lyon, hôpital Louis-Pradel, Bron, France
| | - C Dubos-Arvis
- UCP d'oncologie thoracique, centre de lutte contre le cancer François-Baclesse, Caen, France
| | - P Dumont
- Service de pneumologie, centre hospitalier de Chauny, Chauny, France
| | - I Monnet
- OncoThoParisEst, service de pneumologie, CHI de Créteil, UPEC, Créteil, France
| | - E Pichon
- Service de pneumologie, hôpital Bretonneau, CHRU de Tours, Tours, France
| | - M Locatelli-Sanchez
- Service de pneumologie aiguë spécialisée et cancérologie thoracique, hôpital Lyon Sud, institut de cancérologie des hospices civils de Lyon, Pierre-Bénite, France
| | - A Dixmier
- Service de pneumologie et oncologie thoracique, centre hospitalier régional d'Orléans, Orléans, France
| | - B Coudert
- Oncologie médicale, centre G.F.-Leclerc, Dijon, France
| | - S Fraboulet
- Service de pneumologie, hôpital Foch, Suresnes, France
| | - P Foucher
- Fédération d'oncologie thoracique, hôpital du Bocage, CHU Dijon-Bourgogne, Dijon, France
| | - E Dansin
- Département de cancérologie générale, centre Oscar-Lambret, Lille, France
| | - N Baize
- Unité transversale de thérapeutiques innovantes en oncologie médicale (UTTIOM), CHU d'Angers, Angers, France
| | - M Vincent
- Service de pneumologie et cancérologie thoracique, centre hospitalier Saint-Joseph et Saint-Luc, Lyon, et Minapath Développement Insavalor, Villeurbanne, France
| | - P Missy
- Intergroupe francophone de cancérologie thoracique (IFCT), Paris, France
| | - F Morin
- Intergroupe francophone de cancérologie thoracique (IFCT), Paris, France
| | - D Moro-Sibilot
- Intergroupe francophone de cancérologie thoracique (IFCT), Paris, France; Clinique de pneumologie et oncologie thoracique, CHU Grenoble-Alpes, La Tronche, France
| | - S Couraud
- Service de pneumologie aiguë spécialisée et cancérologie thoracique, hôpital Lyon Sud, institut de cancérologie des hospices civils de Lyon, Pierre-Bénite, France; EMR 3738 ciblage thérapeutique en oncologie, faculté de médecine Lyon Sud, université Lyon 1, Oullins, France.
| | | |
Collapse
|
|
41
|
Hu Z, Zou X, Qin S, Li Y, Wang H, Yu H, Sun S, Wu X, Wang J, Chang J. Hormone receptor expression correlates with EGFR gene mutation in lung cancer in patients with simultaneous primary breast cancer. Transl Lung Cancer Res 2020; 9:325-336. [PMID: 32420072 PMCID: PMC7225161 DOI: 10.21037/tlcr-20-513] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Background The coexistence of double primaries of lung cancer (LC) and breast cancer (BC) are not uncommon in women, but there has been limited research conducted of their molecular association. To decipher the internal pathogenesis of LC in patients with concurrent BC and LC, this study explored the clinical factors and relationship between hormone receptor (HR) expression and epidermal growth factor receptor (EGFR) gene mutation. Methods The clinicopathological characteristics of 400 female patients clinically diagnosed with double primary LC and BC at Fudan University Shanghai Cancer Center were collected. Pathological discrimination was performed to further confirm the double primaries in patients with available tissues. LC samples were then examined to detect EGFR gene mutation status by PCR-based assays and HR expression by immunohistochemistry (IHC). As a control cohort, the characteristics of 114 consecutive patients with LC only were compared with the double-primary patient group. Results A total of 169 patients were pathologically confirmed with simultaneous LC and BC between January 2010 and October 2018. The dominant LC subtype was adenocarcinoma (ADC) (95.1%), and invasive ductal carcinoma (IDC) was the main BC subtype (71.0%). Synchronous and metachronous double primary BC-LC cases accounted for 39.1% and 60.9% of the patients, respectively. The absence of family cancer history was associated with a shorter interval between the two primary cancer diagnoses. Among 64 patients with EGFR mutations, 34.4% had HR-positive LC tissue, compared with 0/24 (0%) of those with EGFR wild-type LC (P<0.001). All of the patients with positive HR expression harbored an activating EGFR mutation (n=22); however, no correlation was observed in the control cohort. Conclusions Double primary BC-LC patients have distinctive clinicopathological features compared to those with LC only. The expression of HRs is significantly correlated with EGFR mutation status of LC tissues.
Collapse
Affiliation(s)
- Zhihuang Hu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.,Institute of Thoracic Oncology, Fudan University, Shanghai 200032, China
| | - Xuan Zou
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Shanshan Qin
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Center for Tumor Diagnosis and Therapy, Jinshan Hospital of Fudan University, Shanghai 201508, China
| | - Yuan Li
- Institute of Thoracic Oncology, Fudan University, Shanghai 200032, China.,Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Huijie Wang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Hui Yu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Si Sun
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Xianghua Wu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Jialei Wang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Jianhua Chang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.,Institute of Thoracic Oncology, Fudan University, Shanghai 200032, China
| |
Collapse
|
|
42
|
Female reproductive factors and the risk of lung cancer in postmenopausal women: a nationwide cohort study. Br J Cancer 2020; 122:1417-1424. [PMID: 32203211 PMCID: PMC7188895 DOI: 10.1038/s41416-020-0789-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 02/18/2020] [Accepted: 02/27/2020] [Indexed: 02/08/2023] Open
Abstract
Background Reproductive factors and hormone use in postmenopausal women have been hypothesised to affect the risk of developing lung cancer, but the epidemiological evidence is inconsistent. Methods Using the Korean National Health Insurance System database, we identified 4,775,398 postmenopausal women older than 40 years who had undergone both cardiovascular health- and cancer screening between 1 January 2009 and 31 December 2014. Information about reproductive factors was obtained from a self-administered questionnaire. The risk of lung cancer was estimated using Cox proportional hazard regression models. Results During a median follow-up of 4.4 years, 16,556 women (15,223 non-smokers) were diagnosed with lung cancer. The risk of lung cancer was not significantly influenced by early menarche age (adjusted hazard ratio [aHR] 1.03 for menarche ≥18 vs. ≤14; 95% confidence interval [CI], 0.98–1.09) or late age at menopause (aHR 1.02 for menopause ≥55 vs. <40; 95% CI, 0.91–1.14). Furthermore, the number of children, duration of breastfeeding and use of hormone replacement therapy were not associated with the risk of lung cancer. Conclusions No statistically significant association was found between reproductive factors and the risk of lung cancer in postmenopausal Korean women.
Collapse
|
|
43
|
Smida T, Bruno TC, Stabile LP. Influence of Estrogen on the NSCLC Microenvironment: A Comprehensive Picture and Clinical Implications. Front Oncol 2020; 10:137. [PMID: 32133288 PMCID: PMC7039860 DOI: 10.3389/fonc.2020.00137] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 01/27/2020] [Indexed: 12/15/2022] Open
Abstract
Lung cancer mortality represents the leading cause of cancer related deaths in the United States and worldwide. Almost half of these deaths occur in female patients, making lung cancer the most common cause of cancer mortality in women with a higher annual mortality rate than breast, uterine, and ovarian cancers combined. The distinct epidemiological, histological and biological presentation of non-small cell lung cancer (NSCLC) in women combined with extensive preclinical data have demonstrated that the female sex hormone β-estradiol (E2) plays an important role in NSCLC tumorigenesis, prognosis, and treatment response. Estrogen receptors are widely expressed on stromal and immune cells, and estrogen-linked signaling pathways are known to be involved in regulating the response of both the innate and adaptive immune system. Immune evasion has been recognized as a “hallmark” of cancer and immunotherapy has re-defined standard of care treatment for NSCLC. Despite these advancements, the low response rates observed in patients treated with immune checkpoint inhibitors has led to a search for mediators of immunosuppression and ways to augment the action of these agents. We focus on emerging data describing sex differences that modulate immunotherapy efficacy in NSCLC, immunosuppressive properties of E2 that lead to a pro-tumor microenvironment (TME), and the translational potential of altering the immune microenvironment by targeting the estrogen signaling pathway. E2-induced modulation affects multiple cell types within the TME, including cancer-associated fibroblasts, tumor infiltrating myeloid cells, and tumor infiltrating lymphocytes, all of which interplay with lung tumor cells via E2 and estrogen receptor engagement, ultimately shaping the TME that may, in part, be responsible for the sex-based disparities observed in NSCLC. An improved understanding of the role of the estrogen pathway in NSCLC anti-cancer immunity may lead to novel therapeutic approaches for altering the TME to improve the efficacy of immunotherapy agents.
Collapse
Affiliation(s)
- Tanner Smida
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, United States
| | - Tullia C Bruno
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, United States.,UPMC Hillman Cancer Center, Pittsburgh, PA, United States
| | - Laura P Stabile
- UPMC Hillman Cancer Center, Pittsburgh, PA, United States.,Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, United States
| |
Collapse
|
|
44
|
Somasundaram A, Rothenberger NJ, Stabile LP. The Impact of Estrogen in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1277:33-52. [PMID: 33119863 DOI: 10.1007/978-3-030-50224-9_2] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Tumor immune escape is now a hallmark of cancer development, and therapies targeting these pathways have emerged as standard of care. Specifically, immune checkpoint signal blockade offers durable responses and increased overall survival. However, the majority of cancer patients still do not respond to checkpoint blockade immune therapy leading to an unmet need in tumor immunology research. Sex-based differences have been noted in the use of cancer immunotherapy suggesting that sex hormones such as estrogen may play an important role in tumor immune regulation. Estrogen signaling already has a known role in autoimmunity, and the estrogen receptor can be expressed across multiple immune cell populations and effect their regulation. While it has been well established that tumor cells such as ovarian carcinoma, breast carcinoma, and even lung carcinoma can be regulated by estrogen, research into the role of estrogen in the regulation of tumor-associated immune cells is still emerging. In this chapter, we discuss the role of estrogen in the tumor immune microenvironment and the possible immunotherapeutic implications of targeting estrogen in cancer patients.
Collapse
Affiliation(s)
- Ashwin Somasundaram
- Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh, Pittsburgh, PA, USA.,Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA.,UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Natalie J Rothenberger
- Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh, Pittsburgh, PA, USA.,Geisinger Commonwealth School of Medicine, Scranton, PA, USA
| | - Laura P Stabile
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA. .,Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
| |
Collapse
|
|
45
|
Lee JH, Kim HK, Shin BK. Expression of female sex hormone receptors and its relation to clinicopathological characteristics and prognosis of lung adenocarcinoma. J Pathol Transl Med 2020; 54:103-111. [PMID: 31718122 PMCID: PMC6986970 DOI: 10.4132/jptm.2019.10.12] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Revised: 09/22/2019] [Accepted: 10/12/2019] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Adenocarcinoma (ADC) of the lung exhibits different clinicopathological characteristics in men and women. Recent studies have suggested that these differences originate from the expression of female sex hormone receptors in tumor cells. The aim of the present study was to evaluate the immunohistochemical expression of female sex hormone receptors in lung ADC and determine the expression patterns in patients with different clinicopathological characteristics. METHODS A total of 84 patients with lung ADC who underwent surgical resection and/or core biopsy were recruited for the present study. Immunohistochemical staining was performed for estrogen receptor α (ERα), estrogen receptor β (ERβ), progesterone receptor (PR), epidermal growth factor receptor (EGFR), EGFR E746- A750 del, and EGFR L858R using tissue microarray. RESULTS A total of 39 (46.4%) ERα-positive, 71 (84.5%) ERβ-positive, and 46 (54.8%) PR-positive lung ADCs were identified. In addition, there were 81 (96.4%) EGFR-positive, 14 (16.7%) EGFR E746-A750 del-positive, and 34 (40.5%) EGFR L858R-positive cases. The expression of female sex hormone receptors was not significantly different in clinicopathologically different subsets of lung ADC. CONCLUSIONS Expression of female sex hormone receptors is not associated with the prognosis and clinicopathological characteristics of patients with lung ADC.
Collapse
Affiliation(s)
- Jin Hwan Lee
- Department of Pathology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Han Kyeom Kim
- Department of Pathology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Bong Kyung Shin
- Department of Pathology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| |
Collapse
|
|
46
|
Almotlak AA, Farooqui M, Siegfried JM. Inhibiting Pathways Predicted From a Steroid Hormone Gene Signature Yields Synergistic Antitumor Effects in NSCLC. J Thorac Oncol 2019; 15:62-79. [PMID: 31606604 DOI: 10.1016/j.jtho.2019.09.195] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 09/26/2019] [Accepted: 09/30/2019] [Indexed: 01/06/2023]
Abstract
INTRODUCTION Mounting evidence supports a role for estrogen signaling in NSCLC progression. We previously reported a seven-gene signature that predicts prognosis in estrogen receptor β positive (ERβ+) NSCLC. The signature defines a network comprised of ER and human EGFR-2/3 (HER2/HER3) signaling. METHODS We tested the efficacy of combining the pan-HER inhibitor, dacomitinib, with the estrogen antagonist, fulvestrant, in ERβ+ NSCLC models with differing genotypes. We assessed the potency of this combination on xenograft growth and survival of host mice, and the ability to reverse the gene signature associated with poor outcome. RESULTS Synergy was observed between dacomitinib and fulvestrant in three human ERβ+ NSCLC models: 201T (wild-type EGFR), A549 (KRAS mutant), and HCC827 (EGFR 19 deletion) with combination indices of 0.1-0.6. The combination, but not single agents, completely reversed the gene signature associated with poor prognosis in a mechanism that is largely mediated by activator protein 1 downregulation. In vivo, the combination also induced tumor regression and reversed the gene signature. In HCC827 xenografts treated with the combination, survival of mice was prolonged after therapy discontinuation, tumors that recurred were less aggressive, and two mechanisms of HER inhibitor resistance involving c-Met activation and PTEN loss were blocked. CONCLUSIONS The combination of an ER blocker and a pan-HER inhibitor provides synergistic efficacy in different models of ERβ+ NSCLC. Our data support the use of this combination clinically, considering its ability to induce potent antitumor effects and produce a gene signature that predicts better clinical outcomes.
Collapse
Affiliation(s)
- Abdulaziz A Almotlak
- Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota; Department of Pharmacology, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Mariya Farooqui
- Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota
| | - Jill M Siegfried
- Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota; Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota; Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.
| |
Collapse
|
|
47
|
Asavasupreechar T, Chan MSM, Saito R, Miki Y, Boonyaratanakornkit V, Sasano H. Sex steroid metabolism and actions in non-small cell lung carcinoma. J Steroid Biochem Mol Biol 2019; 193:105440. [PMID: 31386890 DOI: 10.1016/j.jsbmb.2019.105440] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 07/29/2019] [Accepted: 07/30/2019] [Indexed: 02/06/2023]
Abstract
Despite recent development in targeted therapies, lung cancer still remains the leading cause of cancer death. Therefore, a better understanding of its pathogenesis and progression could contribute to improving the eventual clinical outcome of the patients. Results of recently published several in vitro and clinical studies indicated the possible involvement of sex steroids in both development and progression of non-small cell lung carcinoma (NSCLC). Therefore we summarized the reported clinical relevant information of the sex steroids, their receptors and steroid metabolizing enzymes related to NSCLC in this mini-review. In addition, we also reviewed the potential "endocrine therapy", targeting sex steroid actions and/or metabolism in NSCLC patients.
Collapse
Affiliation(s)
| | - Monica S M Chan
- Department of Anatomic Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Ryoko Saito
- Department of Anatomic Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yasuhiro Miki
- Department of Anatomic Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Viroj Boonyaratanakornkit
- Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand; Age-Related Inflammation and Degeneration Research Unit, Chulalongkorn University, Bangkok, Thailand
| | - Hironobu Sasano
- Department of Anatomic Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.
| |
Collapse
|
|
48
|
Gao X, Cai Y, Wang Z, He W, Cao S, Xu R, Chen H. Estrogen receptors promote NSCLC progression by modulating the membrane receptor signaling network: a systems biology perspective. J Transl Med 2019; 17:308. [PMID: 31511014 PMCID: PMC6737693 DOI: 10.1186/s12967-019-2056-3] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Accepted: 09/04/2019] [Indexed: 12/13/2022] Open
Abstract
Background Estrogen receptors (ERs) are thought to play an important role in non-small cell lung cancer (NSCLC). However, the effect of ERs in NSCLC is still controversial and needs further investigation. A new consideration is that ERs may affect NSCLC progression through complicated molecular signaling networks rather than individual targets. Therefore, this study aims to explore the effect of ERs in NSCLC from the perspective of cancer systems biology. Methods The gene expression profile of NSCLC samples in TCGA dataset was analyzed by bioinformatics method. Variations of cell behaviors and protein expression were detected in vitro. The kinetic process of molecular signaling network was illustrated by a systemic computational model. At last, immunohistochemical (IHC) and survival analysis was applied to evaluate the clinical relevance and prognostic effect of key receptors in NSCLC. Results Bioinformatics analysis revealed that ERs might affect many cancer-related molecular events and pathways in NSCLC, particularly membrane receptor activation and signal transduction, which might ultimately lead to changes in cell behaviors. Experimental results confirmed that ERs could regulate cell behaviors including cell proliferation, apoptosis, invasion and migration; ERs also regulated the expression or activation of key members in membrane receptor signaling pathways such as epidermal growth factor receptor (EGFR), Notch1 and Glycogen synthase kinase-3β/β-Catenin (GSK3β/β-Catenin) pathways. Modeling results illustrated that the promotive effect of ERs in NSCLC was implemented by modulating the signaling network composed of EGFR, Notch1 and GSK3β/β-Catenin pathways; ERs maintained and enhanced the output of oncogenic signals by adding redundant and positive-feedback paths into the network. IHC results echoed that high expression of ERs, EGFR and Notch1 had a synergistic effect on poor prognosis of advanced NSCLC. Conclusions This study indicated that ERs were likely to promote NSCLC progression by modulating the integrated membrane receptor signaling network composed of EGFR, Notch1 and GSK3β/β-Catenin pathways and then affecting tumor cell behaviors. It also complemented the molecular mechanisms underlying the progression of NSCLC and provided new opportunities for optimizing therapeutic scheme of NSCLC.
Collapse
Affiliation(s)
- Xiujuan Gao
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, No. 13, HangKong Road, Wuhan, 430030, Hubei, China.,The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, 430030, Hubei, China
| | - Yue Cai
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, No. 13, HangKong Road, Wuhan, 430030, Hubei, China.,The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, 430030, Hubei, China
| | - Zhuo Wang
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, No. 13, HangKong Road, Wuhan, 430030, Hubei, China.,The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, 430030, Hubei, China
| | - Wenjuan He
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, No. 13, HangKong Road, Wuhan, 430030, Hubei, China.,The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, 430030, Hubei, China
| | - Sisi Cao
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, No. 13, HangKong Road, Wuhan, 430030, Hubei, China.,The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, 430030, Hubei, China
| | - Rong Xu
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, No. 13, HangKong Road, Wuhan, 430030, Hubei, China.,The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, 430030, Hubei, China
| | - Hui Chen
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, No. 13, HangKong Road, Wuhan, 430030, Hubei, China. .,The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, 430030, Hubei, China.
| |
Collapse
|
|
49
|
Velez MA, Burns TF, Stabile LP. The estrogen pathway as a modulator of response to immunotherapy. Immunotherapy 2019; 11:1161-1176. [PMID: 31361169 DOI: 10.2217/imt-2019-0024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Lung cancer is the leading cause of cancer deaths worldwide, with a 5-year survival rate of about 18%. Thus, there is a great need for novel therapeutic approaches to treat non-small-cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICIs) have improved outcomes for a subset of patients, especially those with high programmed death-ligand 1 expression and/or high tumor mutational burden, but have failed in the majority of patients. Increasing evidence suggests that the estrogen signaling pathway may be a therapeutic target in metastatic NSCLC and that the estrogen pathway may play a role in sex-based responses to ICIs. This report will review the epidemiologic, preclinical and clinical data on the estrogen pathway in NSCLC, its implications in sex-based responses to ICIs and the potential use of antiestrogen therapy in combination with ICIs.
Collapse
Affiliation(s)
- Maria A Velez
- Department of Internal Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Timothy F Burns
- Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.,Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh, Pittsburgh, PA, USA.,UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Laura P Stabile
- Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.,UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| |
Collapse
|
|
50
|
Cheng TYD, Darke AK, Redman MW, Zirpoli GR, Davis W, Payne Ondracek R, Bshara W, Omilian AR, Kratzke R, Reid ME, Molina JR, Kolesar JM, Chen Y, MacRae RM, Moon J, Mack P, Gandara DR, Kelly K, Santella RM, Albain KS, Ambrosone CB. Smoking, Sex, and Non-Small Cell Lung Cancer: Steroid Hormone Receptors in Tumor Tissue (S0424). J Natl Cancer Inst 2019; 110:734-742. [PMID: 29346580 DOI: 10.1093/jnci/djx260] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Accepted: 11/08/2017] [Indexed: 01/07/2023] Open
Abstract
Background To what extent steroid hormones contribute to lung cancer in male and female never smokers and smokers is unclear. We examined expression of hormone receptors in lung tumors by sex and smoking. Methods Patients with primary non-small cell lung cancer were recruited into an Intergroup study in the United States and Canada, led by SWOG (S0424). Tumors from 813 cases (450 women and 363 men) were assayed using immunohistochemistry for estrogen receptor (ER)-α, ER-β, progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Linear regression was used to examine differences in expression by sex and smoking status. Cox proportional hazard models were used to estimate survival associated with the receptors. All statistical tests were two-sided. Results In ever smokers, postmenopause and oral contraceptive use were associated with lower nuclear ER-β (P = .02) and total (nuclear + cytoplasmic) PR expression (P = .02), respectively. Women had lower cytoplasmic ER-α (regression coefficient [β], or differences in H-scores = -15.8, P = .003) and nuclear ER-β (β = -12.8, P = .04) expression than men, adjusting for age, race, and smoking. Ever smokers had both higher cytoplasmic ER-α (β = 45.0, P < .001) and ER-β (β = 25.9, P < .001) but lower total PR (β = -42.1, P < .001) than never smokers. Higher cytoplasmic ER-α and ER-β were associated with worse survival (hazard ratio = 1.73, 95% confidence interval [CI] = 1.15 to 2.58, and HR = 1.59, 95% CI = 1.08 to 2.33, respectively; quartiles 4 vs 1). Conclusions Lower expression of nuclear ER-β in women supports the estrogen hypothesis in lung cancer etiology. Increasing cytoplasmic ER-α and ER-β and decreasing PR protein expression may be mechanisms whereby smoking disrupts hormone pathways.
Collapse
Affiliation(s)
- Ting-Yuan David Cheng
- Department of Cancer Prevention and Control and Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY.,Department of Epidemiology, University of Florida, Gainesville, FL
| | - Amy K Darke
- SWOG Statistical Center/Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Mary W Redman
- SWOG Statistical Center/Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Gary R Zirpoli
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Warren Davis
- Department of Cancer Prevention and Control and Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY
| | - Rochelle Payne Ondracek
- Department of Cancer Prevention and Control and Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY
| | - Wiam Bshara
- Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY
| | - Angela R Omilian
- Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY
| | - Robert Kratzke
- Department of Medicine, University of Minnesota, Minneapolis, MN
| | - Mary E Reid
- Department of Cancer Prevention and Control and Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY
| | | | - Jill M Kolesar
- School of Pharmacy, University of Wisconsin-Madison, Madison, WI
| | - Yuhchyau Chen
- Department of Radiation Oncology, University of Rochester Medical Center, Rochester, NY
| | | | - James Moon
- SWOG Statistical Center/Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Philip Mack
- Department of Internal Medicine, UC Davis Comprehensive Cancer Center, Sacramento, CA
| | - David R Gandara
- Department of Internal Medicine, UC Davis Comprehensive Cancer Center, Sacramento, CA
| | - Karen Kelly
- Department of Internal Medicine, UC Davis Comprehensive Cancer Center, Sacramento, CA
| | - Regina M Santella
- Department of Environmental Health Sciences, Columbia University, New York, NY
| | - Kathy S Albain
- Loyola University Chicago Stritch School of Medicine, Maywood, IL
| | - Christine B Ambrosone
- Department of Cancer Prevention and Control and Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY
| |
Collapse
|