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Gomes GMDA, Xu M, Syeda AKR, Raudonis R, Almasi S, Vijayan VV, Gujar S, Dong X, Cheng Z, Pulinilkunnil T, El Hiani Y. Targeting TRPML3 inhibits proliferation and invasion, and enhances doxorubicin sensitivity by disrupting lysosomal acidification and mitochondrial function in triple-negative breast cancer. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2025; 1872:119979. [PMID: 40348344 DOI: 10.1016/j.bbamcr.2025.119979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 04/22/2025] [Accepted: 04/27/2025] [Indexed: 05/14/2025]
Abstract
TNBC remains the most aggressive and therapy-resistant type of breast cancer, for which efficient targeted therapies have not been developed yet. Here, we identified TRPML3 (ML3) as a potential therapeutic target in TNBC. Our data showed that ML3 is significantly upregulated in TNBC cells compared with nontumorigenic control cells. ML3 knockdown (KD) impairs TNBC cell proliferation by inducing cell cycle arrest and caspase-dependent apoptosis. ML3 KD also inhibits TNBC cell migration and invasion. Mechanistically, ML3 KD reduces lysosomal number and enhances lysosomal acidification, which in turn activates mTORC1, thereby inhibiting autophagy initiation and flux. This disruption negatively impacts mitochondrial function, as evidenced by reduced ATP production, increased ROS and NO production, and mitochondrial fragmentation. Importantly, ML3 KD enhances TNBC cell sensitivity to doxorubicin and paclitaxel. The finding suggests that targeting ML3 disrupts lysosomal and mitochondrial homeostasis and enhance chemosensitivity, presenting ML3 as a potential therapeutic vulnerability in TNBC enhancing chemosensitivity.
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Affiliation(s)
| | - Mengnan Xu
- Department of Physiology and Biophysics, Dalhousie University, Halifax, NS, Canada.
| | | | - Renee Raudonis
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
| | | | - Vishnu Vijay Vijayan
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
| | - Shashi Gujar
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
| | - Xianping Dong
- Department of Physiology and Biophysics, Dalhousie University, Halifax, NS, Canada
| | - Zhenyu Cheng
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
| | | | - Yassine El Hiani
- Department of Physiology and Biophysics, Dalhousie University, Halifax, NS, Canada.
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Sirhan Z, Abu Nada A, Anabtawi N, Thyagarajan A, Sahu RP. Metformin-Based Combination Approaches for Triple-Negative Breast Cancer. Pharmaceutics 2025; 17:558. [PMID: 40430851 PMCID: PMC12115292 DOI: 10.3390/pharmaceutics17050558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2025] [Revised: 04/18/2025] [Accepted: 04/23/2025] [Indexed: 05/29/2025] Open
Abstract
Numerous anti-diabetic medications, including metformin, have been explored for their anticancer effects because of the substantial correlation between diabetes and cancer incidence. Metformin has recently gained interest for its anticancer effects against malignancies such as breast cancer, one of the leading causes of death among women worldwide. The cancer-related characteristics of cell proliferation, invasion, migration, and apoptosis are all targeted by metformin. Among breast cancer patients, triple-negative breast cancer (TNBC) is linked to an increased risk of early recurrence and metastases and has poor prognosis. In addition, TNBC has fewer treatment options compared to other breast cancer subtypes because it lacks hormone receptors and human epidermal growth factor receptor 2 (HER2), and it often develops resistance to available treatment options. The current review highlights the recent updates on the mechanistic insights and the efficacy of metformin and metformin-based approaches for the treatment of TNBC. We logically discuss the experimental evidence from the in vitro and in vivo studies exploring metformin's effects on metabolic pathways, and then its combination with other therapeutic agents, targeting cell signaling pathways, and approaches to enhance metformin's effects. We also present clinical studies that underscore the beneficial outcomes of metformin or its combination with other agents in TNBC patients.
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Affiliation(s)
- Zaid Sirhan
- Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA;
| | - Aya Abu Nada
- Department of Pharmacy, Sidra Medicine, Doha P.O. Box 26999, Qatar;
| | - Nadeen Anabtawi
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA;
| | - Anita Thyagarajan
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine Wright State University, Dayton, OH 45435, USA;
| | - Ravi P. Sahu
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine Wright State University, Dayton, OH 45435, USA;
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de Moraes FCA, Souza MEC, Sano VKT, Moraes RA, Melo AC. Association of tumor-infiltrating lymphocytes with clinical outcomes in patients with triple-negative breast cancer receiving neoadjuvant chemotherapy: a systematic review and meta-analysis. Clin Transl Oncol 2025; 27:974-987. [PMID: 39154313 DOI: 10.1007/s12094-024-03661-8] [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: 06/29/2024] [Accepted: 07/30/2024] [Indexed: 08/19/2024]
Abstract
OBJECTIVE Triple-negative breast cancer (TNBC) presents a clinical challenge as an aggressive tumor, correlated with unfavorable prognosis. Tumor-infiltrating lymphocytes (TILs) have garnered interest as a potential prognostic biomarker. However, the disparity in outcomes between varying TILs rates remains inadequately explored. METHODS PubMed, Scopus, Web of Science, and Cochrane databases were searched for studies about the prognostic value of TILs in patients with TNBC receiving neoadjuvant chemotherapy. The hazard ratios (HRs) or odds ratios (ORs) were computed for binary endpoints, with 95% confidence intervals (CIs). RESULTS Twenty-nine studies were included, involving a population of six thousand one hundred sixty-one (80.41%) with TNBC. The cut-off TILs value ranged from 10 to 60%, with 50% being the most related value. Compared with the low-TIL expression group, the disease-free survival (DFS) (HR 0.71; 95% CI 0.61-0.82; p < 0.00001) and overall survival (OS) (HR 0.76; 95% CI 0.63-0.90; p = 0.002) rates showed significant improvement with higher TIL infiltrations. In the subgroup analyses of the lymphocyte subtypes CD4 + and CD8 + , there was statistical significance favoring higher TILs rates in both subtypes, each associated with improved DFS (HR 0.48; 95% CI 0.33-0.71; p = 0.0002) and OS (HR 0.53; 95% CI 0.36-0.78; p = 0.001), regardless of which cell subtype was predominantly infiltrated. The complete pathological response analysis showed better rates for the higher TIL group than the control for both the TIL (OR 1.29; 95% CI 1.13-1.48; p = 0.0003) and Ki-67 (OR 2.74; 95% CI 2.01-3.73; p < 0.00001) analyses. CONCLUSION Higher expressions of TILs in patients with TNBC were associated with improved significantly DFS, OS, and pCR outcomes.
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Affiliation(s)
| | | | | | | | - Ana C Melo
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX, USA
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Qi P, Sun Y, Pang Y, Liu J, Cai X, Huang S, Xu Q, Wang Q, Zhou X. Diagnostic Utility of a 90-Gene Expression Assay (Canhelp-Origin) for Patients with Metastatic Cancer with an Unclear or Unknown Diagnosis. Mol Diagn Ther 2025; 29:81-89. [PMID: 39333459 DOI: 10.1007/s40291-024-00746-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/15/2024] [Indexed: 09/29/2024]
Abstract
BACKGROUND Metastatic cancers with unclear or unknown origins pose significant challenges in diagnosis and management, frequently leading to suboptimal outcomes. Studies have demonstrated that a 90-gene expression assay is effective in predicting the primary origin and guiding the site-specific therapy to improve prognosis. This study aimed to evaluate the clinical effectiveness of a 90-gene expression assay in patients with unclear or unknown diagnoses. METHODS The study encompassed patients for whom a 90-gene expression assay was requested as part of standard care. Data on patient demographics, tumor characteristics, and clinical history were collected. The assay's performance was evaluated by comparing its predicted tumor type with the final histopathological diagnosis. RESULTS Among 303 cases analyzed, a 90-gene expression assay successfully identified a molecular-based tumor type for 295 (97.4%) patients. Comparison with histopathological diagnosis revealed an overall agreement of 88.5% (170/192). In patients with a single suspected primary site (n = 140), the assay confirmed the suspected diagnosis in 90.7% of cases. For those with a differential diagnosis (n = 52), the assay narrowed down the possibilities in 82.7% of cases. Moreover, in cases where the histopathology report indicated cancer of unknown primary (n = 103), the assay offered a molecular tumor type prediction with potential clinical significance. CONCLUSIONS This study demonstrates the significant impact of a 90-gene expression assay on diagnosis and potential treatment selection for difficult-to-diagnose patients, highlighting its clinical value as a standardized molecular approach to streamline further diagnostic testing for patients with metastatic cancer of unclear or unknown origin. Further prospective study is required to assess whether employing molecular diagnostic classifiers enhances clinical outcomes in these patients.
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Affiliation(s)
- Peng Qi
- Department of Pathology, Fudan University Shanghai Cancer Center, Fudan University, No. 270 Dongan Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 Dongan Road, Shanghai, 200032, People's Republic of China
| | - Yifeng Sun
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 Dongan Road, Shanghai, 200032, People's Republic of China
- Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, People's Republic of China
- Canhelp Genomics Research Center, Canhelp Genomics Co., Ltd., No.22 Xinyan Road, Hangzhou, 310000, People's Republic of China
| | - Yue Pang
- Department of Pathology, Fudan University Shanghai Cancer Center, Fudan University, No. 270 Dongan Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 Dongan Road, Shanghai, 200032, People's Republic of China
| | - Jing Liu
- Department of Pathology, Fudan University Shanghai Cancer Center, Fudan University, No. 270 Dongan Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 Dongan Road, Shanghai, 200032, People's Republic of China
| | - Xu Cai
- Department of Pathology, Fudan University Shanghai Cancer Center, Fudan University, No. 270 Dongan Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 Dongan Road, Shanghai, 200032, People's Republic of China
| | - Shenglin Huang
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 Dongan Road, Shanghai, 200032, People's Republic of China
- Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, People's Republic of China
| | - Qinghua Xu
- Canhelp Genomics Research Center, Canhelp Genomics Co., Ltd., No.22 Xinyan Road, Hangzhou, 310000, People's Republic of China.
| | - Qifeng Wang
- Department of Pathology, Fudan University Shanghai Cancer Center, Fudan University, No. 270 Dongan Road, Shanghai, 200032, People's Republic of China.
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 Dongan Road, Shanghai, 200032, People's Republic of China.
| | - Xiaoyan Zhou
- Department of Pathology, Fudan University Shanghai Cancer Center, Fudan University, No. 270 Dongan Road, Shanghai, 200032, People's Republic of China.
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 Dongan Road, Shanghai, 200032, People's Republic of China.
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Liu J, Sun Y, Qi P, Wo Y, Pang Y, Xu Q, Xu M, Huang S, Wang Q. Gene expression profiling for the diagnosis of male breast cancer. BMC Cancer 2024; 24:1584. [PMID: 39731080 DOI: 10.1186/s12885-024-13358-4] [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: 08/09/2024] [Accepted: 12/17/2024] [Indexed: 12/29/2024] Open
Abstract
BACKGROUND Male breast cancer (MBC) is a rare malignancy, but its global incidence has shown a notable increase in recent decades. Factors such as limited health literacy, inadequate health education, and reluctance to seek medical attention contribute to the late-stage diagnosis of most MBC patients. Consequently, there is an urgent need for a highly specific and sensitive diagnostic approach to MBC. METHODS This retrospective study enrolled 20 patients with 30 surgical or biopsy MBC specimens from August 2020 to August 2023. The 90-gene expression assay was performed to determine the tissue of origin. Predicted tumor types were then compared to the reference diagnosis for accuracy calculation. The differentially expressed genes were identified between male and female breast cancer. RESULT The 90-gene expression assay demonstrated an overall accuracy of 96.7% (29/30) when compared with the pathological diagnosis. For primary, lymph node metastatic, and distant metastatic tumors, the accuracies were 100% (15/15), 90.9% (10/11), and 100% (4/4), respectively. Five genes (RPS4Y1, PI15, AZGP1, PRRX1, and AGR2) were up-regulated, and six (XIST, PIGR, SFRP1, PLA2G2A, S100A2, and CHI3L1) were down-regulated in MBC. CONCLUSION Our findings highlight the promising performance of the 90-gene expression assay in accurately identifying the tumor origin in MBC. Incorporating this assay into pathological diagnoses has the potential to empower oncologists with precision treatment options, ultimately enhancing the care and outcomes for patients with MBC.
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Affiliation(s)
- Jing Liu
- Department of Pathology, Fudan University Shanghai Cancer Center, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yifeng Sun
- Department of Pathology, Fudan University Shanghai Cancer Center, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
- Canhelp Genomics Research Center, Canhelp Genomics Co., Ltd, Hangzhou, China
| | - Peng Qi
- Department of Pathology, Fudan University Shanghai Cancer Center, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yixin Wo
- Canhelp Genomics Research Center, Canhelp Genomics Co., Ltd, Hangzhou, China
| | - Yue Pang
- Department of Pathology, Fudan University Shanghai Cancer Center, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Qinghua Xu
- Canhelp Genomics Research Center, Canhelp Genomics Co., Ltd, Hangzhou, China
| | - Midie Xu
- Department of Pathology, Fudan University Shanghai Cancer Center, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Shenglin Huang
- Department of Pathology, Fudan University Shanghai Cancer Center, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Qifeng Wang
- Department of Pathology, Fudan University Shanghai Cancer Center, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
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Park H, Kim H, Park W, Cho WK, Kim N, Kim TG, Im YH, Ahn JS, Park YH, Kim JY, Nam SJ, Kim SW, Lee JE, Yu J, Chae BJ, Lee SK, Ryu JM. Oncological outcomes in patients with residual triple-negative breast cancer after preoperative chemotherapy. Radiat Oncol J 2024; 42:210-217. [PMID: 39354824 PMCID: PMC11467479 DOI: 10.3857/roj.2024.00087] [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: 01/25/2024] [Revised: 06/26/2024] [Accepted: 07/02/2024] [Indexed: 10/03/2024] Open
Abstract
PURPOSE This study aimed to evaluate the clinical outcomes and prognostic implications of regional nodal irradiation (RNI) after neoadjuvant chemotherapy (NAC) in patients with residual triple-negative breast cancer (TNBC). MATERIALS AND METHODS We analyzed 152 patients with residual TNBC who underwent breast-conserving surgery after NAC between December 2008 and December 2017. Most patients (n = 133; 87.5%) received taxane-based chemotherapy. Adjuvant radiotherapy (RT) was administered at a total dose of 45-65 Gy in 15-30 fractions to the whole breast, with some patients also receiving RT to regional nodes. Survival was calculated using the Kaplan-Meier method, and prognostic factors influencing survival were analyzed using the Cox proportional-hazards model. RESULTS During a median follow-up of 66 months (range, 9 to 179 months), the 5-year disease-free survival (DFS) rate was 68.0%. The 5-year locoregional recurrence-free survival, distant metastasis-free survival, and overall survival rates were 83.6%, 72.6%, and 78.7%, respectively. In the univariate analysis, the cN stage, ypT stage, ypN stage, axillary operation type, and RT field were associated with DFS. Multivariate analysis revealed that higher ypT stage (hazard ratio [HR] = 2.0; 95% confidence interval [CI] 1.00-3.82; p = 0.049) and ypN stage (HR = 4.7; 95% CI 1.57-14.24; p = 0.006) were associated with inferior DFS. Among clinically node-positive patients, those who received RT to the breast only had a 5-year DFS of 73.7%, whereas those who received RNI achieved a DFS of 59.6% (p = 0.164). There were no differences between the DFS and RNI. CONCLUSION In patients with residual TNBC, higher ypT and ypN stages were associated with poorer outcomes after NAC. RNI did not appear to improve DFS. More intensive treatments incorporating systemic therapy and RT should be considered for these patients.
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Affiliation(s)
- Hyunki Park
- Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Haeyoung Kim
- Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Won Park
- Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Won Kyung Cho
- Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Nalee Kim
- Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Tae Gyu Kim
- Department of Radiation Oncology, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Republic of Korea
| | - Young-Hyuck Im
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jin Seok Ahn
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Yeon Hee Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Ji-Yeon Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Seok Jin Nam
- Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Seok Won Kim
- Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jeong Eon Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jonghan Yu
- Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Byung Joo Chae
- Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Sei Kyung Lee
- Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jai-Min Ryu
- Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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Liu X, Zhang X, Jiang S, Mo M, Wang Q, Wang Y, Zhou L, Hu S, Yang H, Hou Y, Chen Y, Lu X, Wang Y, Zhou X, Li W, Chang C, Yang X, Chen K, Cao J, Xu Q, Sun Y, Luo J, Luo Z, Hu X. Site-specific therapy guided by a 90-gene expression assay versus empirical chemotherapy in patients with cancer of unknown primary (Fudan CUP-001): a randomised controlled trial. Lancet Oncol 2024; 25:1092-1102. [PMID: 39068945 DOI: 10.1016/s1470-2045(24)00313-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 05/20/2024] [Accepted: 05/22/2024] [Indexed: 07/30/2024]
Abstract
BACKGROUND Empirical chemotherapy remains the standard of care in patients with unfavourable cancer of unknown primary (CUP). Gene-expression profiling assays have been developed to identify the tissue of origin in patients with CUP; however, their clinical benefit has not yet been demonstrated. We aimed to evaluate the efficacy and safety of site-specific therapy directed by a 90-gene expression assay compared with empirical chemotherapy in patients with CUP. METHODS This randomised controlled trial was conducted at Fudan University Shanghai Cancer Center (Shanghai, China). We enrolled patients aged 18-75 years, with previously untreated CUP (histologically confirmed metastatic adenocarcinoma, squamous cell carcinoma, poorly differentiated carcinoma, or poorly differentiated neoplasms) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, who were not amenable to local radical treatment. Patients were randomly assigned (1:1) by the Pocock and Simon minimisation method to receive either site-specific therapy or empirical chemotherapy (taxane [175 mg/m2 by intravenous infusion on day 1] plus platinum [cisplatin 75 mg/m2 or carboplatin area under the curve 5 by intravenous infusion on day 1], or gemcitabine [1000 mg/m2 by intravenous infusion on days 1 and 8] plus platinum [same as above]). The minimisation factors were ECOG performance status and the extent of the disease. Clinicians and patients were not masked to interventions. The tumour origin in the site-specific therapy group was predicted by the 90-gene expression assay and treatments were administered accordingly. The primary endpoint was progression-free survival in the intention-to-treat population. The trial has been completed and the analysis is final. This study is registered with ClinicalTrials.gov (NCT03278600). FINDINGS Between Sept 18, 2017, and March 18, 2021, 182 patients (105 [58%] male, 77 [42%] female) were randomly assigned to receive site-specific therapy (n=91) or empirical chemotherapy (n=91). The five most commonly predicted tissues of origin in the site-specific therapy group were gastro-oesophagus (14 [15%]), lung (12 [13%]), ovary (11 [12%]), cervix (11 [12%]), and breast (nine [10%]). At the data cutoff date (April 30, 2023), median follow-up was 33·3 months (IQR 30·4-51·0) for the site-specific therapy group and 30·9 months (27·6-35·5) for the empirical chemotherapy group. Median progression-free survival was significantly longer with site-specific therapy than with empirical chemotherapy (9·6 months [95% CI 8·4-11·9] vs 6·6 months [5·5-7·9]; unadjusted hazard ratio 0·68 [95% CI 0·49-0·93]; p=0·017). Among the 167 patients who started planned treatment, 46 (56%) of 82 patients in the site-specific therapy group and 52 (61%) of 85 patients in the empirical chemotherapy group had grade 3 or worse treatment-related adverse events; the most frequent of these in the site-specific therapy and empirical chemotherapy groups were decreased neutrophil count (36 [44%] vs 42 [49%]), decreased white blood cell count (17 [21%] vs 26 [31%]), and anaemia (ten [12%] vs nine [11%]). Treatment-related serious adverse events were reported in five (6%) patients in the site-specific therapy group and two (2%) in the empirical chemotherapy group. No treatment-related deaths were observed. INTERPRETATION This single-centre randomised trial showed that site-specific therapy guided by the 90-gene expression assay could improve progression-free survival compared with empirical chemotherapy among patients with previously untreated CUP. Site-specific prediction by the 90-gene expression assay might provide more disease information and expand the therapeutic armamentarium in these patients. FUNDING Clinical Research Plan of Shanghai Hospital Development Center, Program for Shanghai Outstanding Academic Leader, and Shanghai Anticancer Association SOAR PROJECT. TRANSLATION For the Chinese translation of the abstract see Supplementary Materials section.
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Affiliation(s)
- Xin Liu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiaowei Zhang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shiyu Jiang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Miao Mo
- Department of Cancer Prevention, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Qifeng Wang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yanli Wang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Liangping Zhou
- Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Silong Hu
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Huijuan Yang
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yifeng Hou
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yong Chen
- Department of Musculoskeletal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xueguan Lu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yu Wang
- Department of Head & Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiaoyan Zhou
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wentao Li
- Department of Interventional Radiology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Cai Chang
- Department of Ultrasound, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiujiang Yang
- Department of Endoscopy, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Ke Chen
- Department of Endoscopy, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jun Cao
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Qinghua Xu
- The Canhelp Genomics Research Center, Canhelp Genomics, Hangzhou, China
| | - Yifeng Sun
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; The Canhelp Genomics Research Center, Canhelp Genomics, Hangzhou, China; Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Jianfeng Luo
- Department of Biostatistics, School of Public Health, Fudan University, Shanghai, China
| | - Zhiguo Luo
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Xichun Hu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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Chen JY, Li JD, He RQ, Huang ZG, Chen G, Zou W. Bibliometric analysis of phosphoglycerate kinase 1 expression in breast cancer and its distinct upregulation in triple-negative breast cancer. World J Clin Oncol 2024; 15:867-894. [PMID: 39071464 PMCID: PMC11271732 DOI: 10.5306/wjco.v15.i7.867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 05/27/2024] [Accepted: 06/24/2024] [Indexed: 07/16/2024] Open
Abstract
BACKGROUND Phosphoglycerate kinase 1 (PGK1) has been identified as a possible biomarker for breast cancer (BC) and may play a role in the development and advancement of triple-negative BC (TNBC). AIM To explore the PGK1 and BC research status and PGK1 expression and mechanism differences among TNBC, non-TNBC, and normal breast tissue. METHODS PGK1 and BC related literature was downloaded from Web of Science Core Collection Core Collection. Publication counts, key-word frequency, cooperation networks, and theme trends were analyzed. Normal breast, TNBC, and non-TNBC mRNA data were gathered, and differentially expressed genes obtained. Area under the summary receiver operating characteristic curves, sensitivity and specificity of PGK1 expression were determined. Kaplan Meier revealed PGK1's prognostic implication. PGK1 co-expressed genes were explored, and Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Disease Ontology applied. Protein-protein interaction networks were constructed. Hub genes identified. RESULTS PGK1 and BC related publications have surged since 2020, with China leading the way. The most frequent keyword was "Expression". Collaborative networks were found among co-citations, countries, institutions, and authors. PGK1 expression and BC progression were research hotspots, and PGK1 expression and BC survival were research frontiers. In 16 TNBC vs non-cancerous breast and 15 TNBC vs non-TNBC datasets, PGK1 mRNA levels were higher in 1159 TNBC than 1205 non-cancerous breast cases [standardized mean differences (SMD): 0.85, 95% confidence interval (95%CI): 0.54-1.16, I² = 86%, P < 0.001]. PGK1 expression was higher in 1520 TNBC than 7072 non-TNBC cases (SMD: 0.25, 95%CI: 0.03-0.47, I² = 91%, P = 0.02). Recurrence free survival was lower in PGK1-high-expression than PGK1-low-expression group (hazard ratio: 1.282, P = 0.023). PGK1 co-expressed genes were concentrated in ATP metabolic process, HIF-1 signaling, and glycolysis/gluconeogenesis pathways. CONCLUSION PGK1 expression is a research hotspot and frontier direction in the BC field. PGK1 may play a strong role in promoting cancer in TNBC by mediating metabolism and HIF-1 signaling pathways.
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Affiliation(s)
- Jing-Yu Chen
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Jian-Di Li
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Rong-Quan He
- Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Zhi-Guang Huang
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Gang Chen
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Wen Zou
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
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Wang C, Chen S, Zhang R, Chen M, Yang X, He Y, Shangguan Z, Mao Q, Zhang Z, Ying S. Apolipoprotein A-1 downregulation promotes basal-like breast cancer cell proliferation and migration associated with DNA methylation. Oncol Lett 2024; 28:295. [PMID: 38737975 PMCID: PMC11082839 DOI: 10.3892/ol.2024.14428] [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: 11/10/2023] [Accepted: 03/18/2024] [Indexed: 05/14/2024] Open
Abstract
Apolipoprotein A-I (APOA1) performs different roles in different subtypes of breast cancer. It is hypothesized to function as a tumor suppressor in basal-like breast cancer (BLBC). However, the specific role of APOA1 in BLBC and its underlying mechanisms remain unknown. The findings of the present study demonstrated a positive correlation between the expression level of APOA1 and the overall survival of patients with BLBC. Ectopic expression of APOA1 effectively inhibits the proliferation and metastasis of BLBC cells in vitro, and these effects are closely related to DNA methylation. To the best of our knowledge, the present study is the first to report increased methylation of the promoter region and decreased methylation of the structural genes of APOA1 in BLBC cells. These alterations resulted in the downregulation of APOA1 expression and suppression of BLBC tumor growth. Collectively, the results of the present study suggested that APOA1 mRNA expression is negatively regulated by DNA methylation in BLBC. Therefore, low expression of APOA1 may be a potential risk biomarker to predict survival in patients with BLBC.
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Affiliation(s)
- Cong Wang
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310006, P.R. China
| | - Shiliang Chen
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310006, P.R. China
| | - Ranran Zhang
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310006, P.R. China
| | - Mengqing Chen
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Xiaoxiao Yang
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310006, P.R. China
| | - Yibo He
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310006, P.R. China
| | - Zuifei Shangguan
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310006, P.R. China
| | - Qifen Mao
- Department of Clinical Laboratory, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang 310012, P.R. China
| | - Zhezhong Zhang
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310006, P.R. China
| | - Sunke Ying
- Department of Clinical Laboratory, The First People's Hospital of Yongkang, Jinhua, Zhejiang 321300, P.R. China
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Akshatha CR, Halanaik D, Nachiappa Ganesh R, Kishore N, Ganesan P, Kayal S, Kumar H, Dubashi B. Assessment of novel prognostic biomarkers to predict pathological complete response in patients with non-metastatic triple-negative breast cancer using a window of opportunity design. Ther Adv Med Oncol 2024; 16:17588359241248329. [PMID: 38800567 PMCID: PMC11127577 DOI: 10.1177/17588359241248329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 04/03/2024] [Indexed: 05/29/2024] Open
Abstract
Background Triple-negative breast cancer (TNBC) includes approximately 20% of all breast cancer and is characterized by its aggressive nature, high recurrence rates, and visceral metastasis. Pathological complete response (pCR) is an established surrogate endpoint for survival. The window of opportunity studies provide valuable information on the disease biology prior to definitive treatment. Objectives To study the association of dynamic change in pathological, imagining, and genomic biomarkers that can prognosticate pCR. The study aims to develop a composite prognostic score. Design Clinical, interventional, and prognostic biomarker study using the novel window of opportunity design. Methods The study aims to enroll 80 treatment-naïve, pathologically confirmed TNBC patients, administering a single dose of paclitaxel and carboplatin during the window period before neoadjuvant chemotherapy (NACT). Tumor tissue will be obtained through a tru-cut biopsy, and positron emission tomography and computed tomography scans will be performed for each patient at two time points aiming to evaluate biomarker alterations. This will be followed by the administration of standard dose-dense NACT containing anthracyclines and taxanes, with the study culminating in surgery to assess pCR. Results The study would develop a composite prognostic risk score derived from the dynamic change in the Ki-67, tumor-infiltrating lymphocytes, Standardized Uptake Value (SUV max), Standardized Uptake Value for lean body mass (SUL max), and gene expression level pre- and post-intervention during the window period prior to the start of definitive treatment. This outcome will aid in categorizing the disease biology into risk categories. Trial registration The current study is approved by the Institutional Ethics Committee [Ethics: Protocol. no. JIP/IEC/2020/019]. This study was registered with ClinicalTrials.gov [CTRI Registration: CTRI/2022/06/043109]. Conclusion The validated biomarker score will help to personalize NACT protocols in patients in TNBC planned for definitive treatment.
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Affiliation(s)
| | | | | | | | | | - Smita Kayal
- Department of Medical Oncology, JIPMER, Puducherry, India
| | | | - Biswajit Dubashi
- Department of Medical Oncology, JIPMER, Dhanvantri Nagar, Puducherry 605006, India
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11
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Moitra P, Skrodzki D, Molinaro M, Gunaseelan N, Sar D, Aditya T, Dahal D, Ray P, Pan D. Context-Responsive Nanoparticle Derived from Synthetic Zwitterionic Ionizable Phospholipids in Targeted CRISPR/Cas9 Therapy for Basal-like Breast Cancer. ACS NANO 2024; 18:9199-9220. [PMID: 38466962 DOI: 10.1021/acsnano.4c01400] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/13/2024]
Abstract
The majority of triple negative breast cancers (TNBCs) are basal-like breast cancers (BLBCs), which tend to be more aggressive, proliferate rapidly, and have poor clinical outcomes. A key prognostic biomarker and regulator of BLBC is the Forkhead box C1 (FOXC1) transcription factor. However, because of its functional placement inside the cell nucleus and its structural similarity with other related proteins, targeting FOXC1 for therapeutic benefit, particularly for BLBC, continues to be difficult. We envision targeted nonviral delivery of CRISPR/Cas9 plasmid toward the efficacious knockdown of FOXC1. Keeping in mind the challenges associated with the use of CRISPR/Cas9 in vivo, including off-targeting modifications, and effective release of the cargo, a nanoparticle with context responsive properties can be designed for efficient targeted delivery of CRISPR/Cas9 plasmid. Consequently, we have designed, synthesized, and characterized a zwitterionic amino phospholipid-derived transfecting nanoparticle for delivery of CRISPR/Cas9. The construct becomes positively charged only at low pH, which encourages membrane instability and makes it easier for nanoparticles to exit endosomes. This has enabled effective in vitro and in vivo downregulation of protein expression and genome editing. Following this, we have used EpCAM aptamer to make the system targeted toward BLBC cell lines and to reduce its off-target toxicity. The in vivo efficacy, biodistribution, preliminary pharmacokinetics, and biosafety of the optimized targeted CRISPR nanoplatform is then validated in a rodent xenograft model. Overall, we have attempted to knockout the proto-oncogenic FOXC1 expression in BLBC cases by efficient delivery of CRISPR effectors via a context-responsive nanoparticle delivery system derived from a designer lipid derivative. We believe that the nonviral approach for in vitro and in vivo delivery of CRISPR/Cas9 targeted toward FOXC1, studied herein, will greatly emphasize the therapeutic regimen for BLBC.
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Affiliation(s)
- Parikshit Moitra
- Department of Nuclear Engineering, The Pennsylvania State University, University Park, Pennsylvania 16802, United States
- Department of Pediatrics, Centre of Blood Oxygen Transport & Hemostasis, University of Maryland-Baltimore School of Medicine, Baltimore, Maryland 21201, United States
- Center for Infectious Disease Dynamics, The Pennsylvania State University, University Park, Pennsylvania 16802, United States
| | - David Skrodzki
- Department of Pediatrics, Centre of Blood Oxygen Transport & Hemostasis, University of Maryland-Baltimore School of Medicine, Baltimore, Maryland 21201, United States
- Department of Materials Science and Engineering, The Pennsylvania State University, University Park, Pennsylvania 16802, United States
| | - Matthew Molinaro
- Department of Engineering Science and Mechanics, The Pennsylvania State University, University Park, Pennsylvania 16802, United States
| | - Nivetha Gunaseelan
- Department of Biomedical Engineering, The Pennsylvania State University, University Park, Pennsylvania 16802, United States
| | - Dinabandhu Sar
- Department of Bioengineering, University of Illinois, Urbana-Champaign, Urbana, Illinois 61801, United States
| | - Teresa Aditya
- Department of Nuclear Engineering, The Pennsylvania State University, University Park, Pennsylvania 16802, United States
- Center for Infectious Disease Dynamics, The Pennsylvania State University, University Park, Pennsylvania 16802, United States
| | - Dipendra Dahal
- Department of Pediatrics, Centre of Blood Oxygen Transport & Hemostasis, University of Maryland-Baltimore School of Medicine, Baltimore, Maryland 21201, United States
| | - Priyanka Ray
- Department of Chemical & Biochemical Engineering, University of Maryland-Baltimore County, Baltimore County, Maryland 21250, United States
| | - Dipanjan Pan
- Department of Nuclear Engineering, The Pennsylvania State University, University Park, Pennsylvania 16802, United States
- Department of Pediatrics, Centre of Blood Oxygen Transport & Hemostasis, University of Maryland-Baltimore School of Medicine, Baltimore, Maryland 21201, United States
- Center for Infectious Disease Dynamics, The Pennsylvania State University, University Park, Pennsylvania 16802, United States
- Department of Materials Science and Engineering, The Pennsylvania State University, University Park, Pennsylvania 16802, United States
- Department of Biomedical Engineering, The Pennsylvania State University, University Park, Pennsylvania 16802, United States
- Department of Bioengineering, University of Illinois, Urbana-Champaign, Urbana, Illinois 61801, United States
- Department of Chemical & Biochemical Engineering, University of Maryland-Baltimore County, Baltimore County, Maryland 21250, United States
- Huck Institutes of the Life Sciences, 101 Huck Life Sciences Building, University Park, Pennsylvania 16802, United States
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12
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Abdel-Mohsen MA, Badawy AM, Abu-Youssef MA, Yehia MA, Abou Shamaa LD, Mohamed SA. Influence of copper(I) nicotinate complex on the Notch1 signaling pathway in triple negative breast cancer cell lines. Sci Rep 2024; 14:2522. [PMID: 38291201 PMCID: PMC10827744 DOI: 10.1038/s41598-024-52952-1] [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: 07/07/2023] [Accepted: 01/25/2024] [Indexed: 02/01/2024] Open
Abstract
Triple negative breast cancer (TNBC) is a subtype of breast cancer which is characterized by its aggressiveness, poor and short overall survival. In this concept, there is a growing demand for metal-based compounds in TNBC therapy as copper complex that have a less toxic effect on normal cells and could stimulate apoptotic cell death. Additionally, Notch1 signaling pathway has received great attention as one of the most important potential targets for developing a novel therapeutic strategy. The present study is an attempt to assess the promising chemotherapeutic activities of copper(I) nicotinate (CNC) through its impact on the expression of downstream genes of Notch1 signaling pathway and the cell fate of TNBC. The co-treatment of TNBC cells with doxorubicin (Doxo) and CNC was also investigated. To approach the objective of the present study, TNBC cell lines; HCC1806 and MDAMB231, were utilized. MTT assay was used to determine the IC50 values of CNC and Doxo. After treatment, microtubule-associated protein light chain3 (LC3) were determined by flow cytometry. Additionally, qRT-PCR technique was used to detect the changes in genes levels that are involved Notch1 signaling pathway. Moreover, autophagosomes were monitored and imaged by Transmission electron microscopy. Treatment of TNBC cells with CNC modulated Notch1 signaling pathway in different manners with respect to the type of cells and the applied dose of CNC. The observed effects of CNC may reflect the possible anti-cancer activities of CNC in both types of TNBC. However, cell type and CNC dose should be considered.
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Affiliation(s)
- Mohamed A Abdel-Mohsen
- Applied Medical Chemistry Department, Medical Research Institute, Alexandria University, Alexandria, Egypt.
| | - Asmaa M Badawy
- Applied Medical Chemistry Department, Medical Research Institute, Alexandria University, Alexandria, Egypt.
| | - Morsy A Abu-Youssef
- Chemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt
| | - Mona A Yehia
- Histochemistry and Cell Biology Department, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Lobna D Abou Shamaa
- Immunology and Allergy Department, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Shymaa Abdullah Mohamed
- Molecular Biology Unit, Medical Technology Center and Applied Medical Chemistry Department, Medical Research Institute, Alexandria University, Alexandria, Egypt
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Avatefi M, HadavandSiri F, Nazari SSH, Akbari ME. Risk factors of developing contralateral breast cancer after first primary breast cancer treatment. Cancer Rep (Hoboken) 2024; 7:e1927. [PMID: 37919558 PMCID: PMC10809186 DOI: 10.1002/cnr2.1927] [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: 02/10/2023] [Revised: 10/11/2023] [Accepted: 10/16/2023] [Indexed: 11/04/2023] Open
Abstract
BACKGROUND Breast cancer (BC) is the most common cancer among women worldwide. Increased survival of primary BC (PBC) has increased contralateral breast cancer (CBC) and become a health problem. AIMS This study aimed to determine the effect of disease-free interval (DFI), risk factors and PBC characteristics on the progression of CBC within primary BC survivors. METHODS AND RESULTS This retrospective study identified 5003 women diagnosed with breast cancer between 2000 and 2020 in the cancer research center. The study included 145 CBC and 4858 PBC survivors, with CBC diagnosed at least 6 months after the detection of primary BC. ER+, PR+, and HER2+ were reported in 72.13%, 66.67%, and 30% of CBC patients. Invasive ductal carcinoma (IDC) BC was reported in 69.57% of patients, and 81.90% and 83.64% of the patients were treated with adjuvant chemotherapy and external radiotherapy. The Kaplan-Meier method indicated that the median time interval between PBC and CBC was 3.92 years, and the 5-year DFI was 97%. The Cox proportional hazard regression model indicated that although more than half of the participants had no family history of BC (69.57%), women 60 years and older were negatively associated with CBC. CONCLUSION This study provides the first investigation of CBC and DFI risk factors among PBC survivors in Iran. Age was found to be negatively associated with CBC development particularly after the age of 60, indicating the necessity of tracking CBC survivors carefully in this age group.
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Affiliation(s)
- Maryam Avatefi
- Cancer Research CenterShahid Beheshti University of Medical SciencesTehranIran
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14
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Abd ELhafeez AS, Ghanem HM, Swellam M, Taha AM. Involvement of FAM170B-AS1, hsa-miR-1202, and hsa-miR-146a-5p in breast cancer. Cancer Biomark 2024; 39:313-333. [PMID: 38250762 PMCID: PMC11091646 DOI: 10.3233/cbm-230396] [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: 09/09/2023] [Accepted: 12/01/2023] [Indexed: 01/23/2024]
Abstract
BACKGROUND FAM170B-AS1 is usually expressed low in all organs except for testicular tissues. No study was performed to explore its role in breast cancer (BC). Contradictory results were reported about hsa-miR-1202 and hsa-miR-146a-5p in BC. OBJECTIVE The present study aimed to explore the involvement of FAM170B-AS1 in BC using bioinformatics predictive tools, followed by a practical validation besides exploring the impact of hsa-miR-1202 and hsa-miR-146a-5p in BC. METHODS This study enrolled 96 female patients with BC, 30 patients with benign breast diseases (BBD), and 25 control subjects. The expressions of circulating FAM170B-AS1, hsa-miR-1202, and hsa-miR-146a-5p were quantified using qRT-PCR. These ncRNAs' associations, predictive, and diagnostic roles in BC were statistically tested. The underlying miRNA/mRNA targets of FAM170B-AS1 in BC were bioinformatically predicted followed by confirmation based on the GEPIA and TCGA databases. RESULTS The expression of FAM170B-AS1 was upregulated in sera of BC patients and hsa-miR-1202 was upregulated in sera of BBD and BC patients while that of hsa-miR-146a-5p was downregulated in BC. These FAM170B-AS1 was significantly associated with BC when compared to BBD. FAM170B-AS1 and hsa-miR-1202 were statistically associated with the BC's stage, grade, and LN metastasis. FAM170B-AS1 and hsa-miR-146a-5p gave the highest specificity and sensitivity for BC. KRAS and EGFR were predicted to be targeted by FAM170B-AS1 through interaction with hsa-miR-143-3p and hsa-miR-7-5p, respectively. Based on the TCGA database, cancer patients having mutations in FAM170B show good overall survival. CONCLUSIONS The present study reported that for the first time, FAM170B-AS1 may be a potential risk factor, predictive, and diagnostic marker for BC. In addition, FAM170B-AS1 might be involved in BC by interacting with hsa-miR-143-3p/KRAS and hsa-miR-7-5p/EGFR through enhancement or repression that may present a new therapeutic option for BC.
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Affiliation(s)
| | - Hala Mostafa Ghanem
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Menha Swellam
- Biochemistry Department, Biotechnology Research Institute, National Research Centre, Dokki, Giza, Egypt
- High Throughput Molecular and Genetic laboratory, Central Laboratories Network and the Centers of Excellence, National Research Centre, Dokki, Giza, Egypt
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15
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Dhanalakshmi B, Anil Kumar BM, Muddenahalli Srinivasa S, Vivek HK, Sennappan M, Rangappa S, Srinivasa Murthy V. Design and synthesis of 4-aminophenol-1,3,4-oxadiazole derivative potentiates apoptosis by targeting MAP kinase in triple negative breast cancer cells. J Biomol Struct Dyn 2023; 42:13114-13129. [PMID: 37948299 DOI: 10.1080/07391102.2023.2274973] [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: 02/08/2023] [Accepted: 10/18/2023] [Indexed: 11/12/2023]
Abstract
Women below 40 years greatly suffer from triple negative breast cancers (TNBCs). Compared to other breast cancer cases, the poor prognosis and lower survival rate of TNBC patients make it an alarming task to save the human era from this dreadful disease. Therefore, identifying potential novel leads is urgently required to combat the TNBC. To discover a novel anticancer agent, we synthesized a series of novel 4-aminophenolbenzamide-1,3,4 oxadiazole hybrid analogues (7a-l). The structure of the compounds was confirmed by spectral methods (1H & 13C NMR, IR and MS). All the compounds were subjected to their in-silico and in-vitro antiproliferative studies against the TNBC cell lines MDA-MB-468 and MDA-MB-231. The investigations revealed that 7i has significantly promoted apoptosis against MDA-MB-468 and MDA-MB-231 cells with IC50 values of 16.89 and 19.43 µM, respectively. Molecular docking of 7i, with MAPK has exhibited the highest binding score of -7.10 kcal/mol by interacting with crucial amino acids present at the active sites. Molecular docking is further validated with molecular dynamic studies with simulation for 100 ns, depicting various stable interactions with MAPK. Compound 7i, forms stable H-bonds and π-π stacking with amino acid residues. Molecular dynamic simulation (MDS) reveals that hydrophobic and water bridges were very prominent for 7i to bind, with the amino acid residues in close proximity to the active site of p38 MAPK. The investigations show that the In-vitro antiproliferative study of 7i agreed with the in-silico studies. Collectively, our investigations depict 7i as a potent novel lead for the inhibition of TNBCs by targeting p38 MAPK.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Boregowda Dhanalakshmi
- Department of Chemistry, School of Engineering, Dayananda Sagar University, Bengaluru, India
- Department of Chemistry, Rajeev Institute of Technology, Visvesvaraya Technological University, Hassan, India
| | - Belagal Motatis Anil Kumar
- Department of Molecular Biology, Adichunchanagiri School of Natural Sciences, ACU-CRI, Adichunchanagiri University, BGSIT, Nagamangala,India
- Adichunchanagiri Institute for Molecular Medicine, Adichunchanagiri Institute of Medical Sciences, Adichunchanagiri University, Nagamangala, India
| | - Sudhanva Muddenahalli Srinivasa
- Department of Molecular Biology, Adichunchanagiri School of Natural Sciences, ACU-CRI, Adichunchanagiri University, BGSIT, Nagamangala,India
- Adichunchanagiri Institute for Molecular Medicine, Adichunchanagiri Institute of Medical Sciences, Adichunchanagiri University, Nagamangala, India
| | - Hamse Kameshwar Vivek
- Department of Biotechnology, Adichunchanagiri School of Natural Sciences, ACU-CRI, Adichunchanagiri University, BGSIT, Nagamangala, India
- Department of Biochemistry, Adichunchanagiri Institute of Medical Sciences, Adichunchanagiri University, Nagamangala, India
| | - Madhappan Sennappan
- Department of Chemistry, Dayananda Sagar College of Engineering, Bengaluru, India
| | - Shobith Rangappa
- Department of Molecular Biology, Adichunchanagiri School of Natural Sciences, ACU-CRI, Adichunchanagiri University, BGSIT, Nagamangala,India
- Adichunchanagiri Institute for Molecular Medicine, Adichunchanagiri Institute of Medical Sciences, Adichunchanagiri University, Nagamangala, India
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16
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Wu L, Zhang Y, Zheng C, Zhao F, Lin Y. GEMIN4, a potential therapeutic targets for patients with basal-like subtype breast cancer. BMC Womens Health 2023; 23:396. [PMID: 37507701 PMCID: PMC10386636 DOI: 10.1186/s12905-023-02547-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 07/13/2023] [Indexed: 07/30/2023] Open
Abstract
BACKGROUND Basal-like breast cancer (BLBC) takes up about 10-20% of all breast cancer(BC), what's more, BLBC has the lowest survival rate among all BC subtypes because of lacks of efficient treatment methods. We aimed to explore the molecules that can be used as diagnostic maker for BLBC at early stage and provide optimized treatment strategies for BLBC patients in this study. METHODS Apply weighted gene co-expression network analysis (WGCNA) to identify gene modules related to BLBC;The functional enrichment of candidate genes related to BLBC in the red module of Go data package and KEGG analysis;Overlapping cross analysis of URGs and WGCNA to identify candidate genes in each BC subtype;Divide BCBL patients into high-risk and low-risk groups, and analyze the two groups of overall survival (OS) and relapse free survival (RFS);Screening of GEMIN4 dependent cell lines; QRT PCR was used to verify the expression of GEMIN4 transfected with siRNA; CCK8 was used to determine the effect of GEMIN4 on cell viability; Positive cell count detected by BrdU staining;GO and KEGG enrichment analysis of GEMIN4. RESULTS The "red module" has the highest correlation with BLBC, with 913 promising candidate genes identified from the red module;913 red module candidate genes related to BLBC participated in multiple GO terms, and KEGG enrichment analysis results mainly enriched in estrogen signaling pathways and pathways in cancer;There are 386 overlapping candidate genes among the 913 "red module" genes identified by 1893 common URG and WGCNA;In BLBC patients, 9 highly expressed genes are associated with OS. Five highly expressed genes are associated with RFS. Kaplan Meier survival analysis suggests that high GEMIN4 expression levels are associated with poor prognosis in BLBC patients;The GEMIN4 gene dependency score in HCC1143 and CAL120 cell lines is negative and low; Si-GEMIN4-1 can significantly reduce the mRNA expression of GEMIN4; Si-GEMIN4 can inhibit cell viability; Si-GEMIN4 can reduce the number of positive cells;GO enrichment analysis showed that GEMIN4 is associated with DNA metabolism processes and adenylate binding; KEGG pathway enrichment analysis shows that GEMIN4 is related to ribosome biogenesis in eukaryotes. CONCLUSION We hypothesized that GEMIN4 may be the potential target for the treatment of BLBC.
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Affiliation(s)
- Liang Wu
- Department of Emergency Surgery, The Second Affiliated Hospital of Qiqihar Medical University, Heilongjiang Province, Qiqihar, People's Republic of China
| | - Yue Zhang
- Department of International Education School, Qiqihar Medical University, Heilongjiang Province, Qiqihar, People's Republic of China
| | - Chunlei Zheng
- Department of Surgical Oncology, The Second Affiliated Hospital of Qiqihar Medical University, Heilongjiang Province, Qiqihar, People's Republic of China
| | - Fuqiang Zhao
- Department of Surgical Oncology, The Second Affiliated Hospital of Qiqihar Medical University, Heilongjiang Province, Qiqihar, People's Republic of China
| | - Yan Lin
- Department of School of Basic Medicine, Qiqihar Medical University, Heilongjiang Province, Qiqihar, People's Republic of China.
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Ahadi M, Moradi A, Rabiee E, Pourmotahari F. Evaluation of GATA3 and GCDFP15 Expression in Triple Negative Breast Cancers. IRANIAN JOURNAL OF PATHOLOGY 2023; 18:90-95. [PMID: 37383162 PMCID: PMC10293598 DOI: 10.30699/ijp.2023.561917.2969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 12/29/2022] [Indexed: 06/30/2023]
Abstract
Background & Objective Breast cancer is one of the most common cancers in the world. There are some different types of breast cancer and triple-negative breast cancer is the type in which no receptors for estrogen, progesterone, and human epidermal growth factor receptor-2 are expressed. Identifying factors that can facilitate the diagnosis of triple-negative breast cancer is important. In this study, we decided to investigate the expression of GATA3 and GCDFP15 genes in triple-negative breast cancers. Methods This is a retrospective descriptive-analytical study that was performed on 50 specimens of samples of triple-negative breast cancer. Data including age and sex, tumor grade, tumor size, types of invasion, GATA-3, and GCDFP-15 were assessed. Results The mean age of the patients was 48.3±14.17 years. Of the total specimens, 46% were positive for GCDFP15 and 90% were positive for GATA-3. The intensity of GATA3 was evaluated and it was observed that 33(73.3%) of the cells were strongly stained and 12(26.7%) were weakly stained. There were no relationships between GATA-3 and GCDFP-15 with tumor characteristics. Conclusion GATA-3 and GCDFP-15 may serve as diagnostic markers for triple-negative breast cancers and GATA-3 seems to be more reliable.
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Affiliation(s)
- Mahsa Ahadi
- Men’s Health and Reproductive Health Research Centre, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Afshin Moradi
- Men’s Health and Reproductive Health Research Centre, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Elham Rabiee
- Department of Pathology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Pourmotahari
- Clinical Research and Development Center, Shahid Modarres Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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18
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Systemically Identifying Triple-Negative Breast Cancer Subtype-Specific Prognosis Signatures, Based on Single-Cell RNA-Seq Data. Cells 2023; 12:cells12030367. [PMID: 36766710 PMCID: PMC9913740 DOI: 10.3390/cells12030367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 12/08/2022] [Accepted: 12/16/2022] [Indexed: 01/21/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is a highly heterogeneous disease with different molecular subtypes. Although progress has been made, the identification of TNBC subtype-associated biomarkers is still hindered by traditional RNA-seq or array technologies, since bulk data detected by them usually have some non-disease tissue samples, or they are confined to measure the averaged properties of whole tissues. To overcome these constraints and discover TNBC subtype-specific prognosis signatures (TSPSigs), we proposed a single-cell RNA-seq-based bioinformatics approach for identifying TSPSigs. Notably, the TSPSigs we developed mostly were found to be disease-related and involved in cancer development through investigating their enrichment analysis results. In addition, the prognostic power of TSPSigs was successfully confirmed in four independent validation datasets. The multivariate analysis results showed that TSPSigs in two TNBC subtypes-BL1 and LAR, were two independent prognostic factors. Further, analysis results of the TNBC cell lines revealed that the TSPSigs expressions and drug sensitivities had significant associations. Based on the preceding data, we concluded that TSPSigs could be exploited as novel candidate prognostic markers for TNBC patients and applied to individualized treatment in the future.
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19
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Wu M, Yuan K, Lyu S, Li Y. Screening potential immune signatures for early-stage basal-like/triple-negative breast cancer. World J Surg Oncol 2022; 20:214. [PMID: 35751103 PMCID: PMC9229513 DOI: 10.1186/s12957-022-02683-2] [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: 03/17/2022] [Accepted: 06/13/2022] [Indexed: 11/29/2022] Open
Abstract
Background Breast cancer (BC) is a highly heterogeneous disease. Among the BC molecular subtypes, basal-like/triple-negative BC (TNBC) is characterized by a high propensity for relatively early metastases and a lack of available endocrine and targeted therapies. Therefore, this study aimed to discover potential signatures for predicting the immune response in early-stage basal-like/triple-negative BC. Method A total of 86 cases of early-stage TNBC from the TCGA and 459 cases of normal breast tissue from GTEx were enrolled and analyzed to screen out differentially expressed genes (DEGs). Then, the prognostic effect and tumor immune cell infiltration relationship with the basal-like-specific DEGs were also evaluated. Results A total of 1556 DEGs, including 929 upregulated genes and 627 downregulated genes, were screened in early-stage basal-like BC. Two prognosis-associated DEGs, GAL and TTC36, were finally found to be basal-like BC specific. However, only GAL was significantly correlated with tumor immune-infiltrating cells, especially CD8+ T cells. The expressions of GAL and TTC36 were revalidated by using the GEO dataset. Conclusion GAL might be an immune signature for the response to immune checkpoint therapy in early basal-like/triple-negative BC. Supplementary Information The online version contains supplementary material available at 10.1186/s12957-022-02683-2.
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Affiliation(s)
- Min Wu
- Galactophore Department, Galactophore Center, Beijing Shijitan Hospital, Capital Medical University, Tieyi Road 10, Haidian District, Beijing, 100038, China
| | - Keyu Yuan
- Galactophore Department, Galactophore Center, Beijing Shijitan Hospital, Capital Medical University, Tieyi Road 10, Haidian District, Beijing, 100038, China
| | - Shuzhen Lyu
- Galactophore Department, Galactophore Center, Beijing Shijitan Hospital, Capital Medical University, Tieyi Road 10, Haidian District, Beijing, 100038, China
| | - Yanping Li
- Galactophore Department, Galactophore Center, Beijing Shijitan Hospital, Capital Medical University, Tieyi Road 10, Haidian District, Beijing, 100038, China.
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20
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Sun W, Wu W, Wang Q, Yao Q, Feng Q, Wang Y, Sun Y, Liu Y, Lai Q, Zhang G, Qi P, Sun Y, Qian C, Ren W, Luo Z, Chen J, Wang H, Xu Q, Zhou X, Sun W, Lin D. Clinical validation of a 90-gene expression test for tumor tissue of origin diagnosis: a large-scale multicenter study of 1417 patients. J Transl Med 2022; 20:114. [PMID: 35255924 PMCID: PMC8900384 DOI: 10.1186/s12967-022-03318-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 02/23/2022] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Once malignancy tumors were diagnosed, the determination of tissue origin and tumor type is critical for clinical management. Although the significant advance in imaging techniques and histopathological approaches, the diagnosis remains challenging in patients with metastatic and poorly differentiated or undifferentiated tumors. Gene expression profiling has been demonstrated the ability to classify multiple tumor types. The present study aims to assess the performance of a 90-gene expression test for tumor classification (i.e. the determination of tumor tissue of origin) in real clinical settings. METHODS Formalin-fixed paraffin-embedded samples and associated clinicopathologic information were collected from three cancer centers between January 2016 and January 2021. A total of 1417 specimens that met quality control criteria (RNA quality, tumor cell content ≥ 60% and so on) were analyzed by the 90-gene expression test to identify the tumor tissue of origin. The performance was evaluated by comparing the test results with histopathological diagnosis. RESULTS The 1417 samples represent 21 main tumor types classified by common tissue origins and anatomic sites. Overall, the 90-gene expression test reached an accuracy of 94.4% (1338/1417, 95% CI: 0.93 to 0.96). Among different tumor types, sensitivities were ranged from 74.2% (head&neck tumor) to 100% (adrenal carcinoma, mesothelioma, and prostate cancer). Sensitivities for the most prevalent cancers of lung, breast, colorectum, and gastroesophagus are 95.0%, 98.4%, 93.9%, and 90.6%, respectively. Moreover, specificities for all 21 tumor types are greater than 99%. CONCLUSIONS These findings showed robust performance of the 90-gene expression test for identifying the tumor tissue of origin and support the use of molecular testing as an adjunct to tumor classification, especially to those poorly differentiated or undifferentiated tumors in clinical practice.
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Affiliation(s)
- Wei Sun
- Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, No.52 Fucheng Road, Wu Ke Song, Haidian District, Beijing, China
| | - Wei Wu
- Department of Pathology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), No.1 East Road of Banshan, Hangzhou, Zhejiang, China
| | - Qifeng Wang
- Department of Pathology, Fudan University Shanghai Cancer Center, No.270 Dong'An Road, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
- The Cancer of Unknown Primary Group of Pathology Committee, Chinese Research Hospital Association, Shanghai, China
| | - Qian Yao
- Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, No.52 Fucheng Road, Wu Ke Song, Haidian District, Beijing, China
| | - Qin Feng
- Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, No.52 Fucheng Road, Wu Ke Song, Haidian District, Beijing, China
| | - Yue Wang
- Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, No.52 Fucheng Road, Wu Ke Song, Haidian District, Beijing, China
| | - Yu Sun
- Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, No.52 Fucheng Road, Wu Ke Song, Haidian District, Beijing, China
| | - Yunying Liu
- Department of Pathology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), No.1 East Road of Banshan, Hangzhou, Zhejiang, China
| | - Qian Lai
- Department of Pathology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), No.1 East Road of Banshan, Hangzhou, Zhejiang, China
| | - Gu Zhang
- Department of Pathology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), No.1 East Road of Banshan, Hangzhou, Zhejiang, China
| | - Peng Qi
- Department of Pathology, Fudan University Shanghai Cancer Center, No.270 Dong'An Road, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
- The Cancer of Unknown Primary Group of Pathology Committee, Chinese Research Hospital Association, Shanghai, China
| | - Yifeng Sun
- The Canhelp Genomics Research Center, Canhelp Genomics Co., Ltd., Hangzhou, China
| | - Chenhui Qian
- The Canhelp Genomics Research Center, Canhelp Genomics Co., Ltd., Hangzhou, China
| | - Wanli Ren
- The Canhelp Genomics Research Center, Canhelp Genomics Co., Ltd., Hangzhou, China
| | - Zhengzhi Luo
- The Canhelp Genomics Research Center, Canhelp Genomics Co., Ltd., Hangzhou, China
| | - Jinying Chen
- The Canhelp Genomics Research Center, Canhelp Genomics Co., Ltd., Hangzhou, China
| | - Hongying Wang
- The Canhelp Genomics Research Center, Canhelp Genomics Co., Ltd., Hangzhou, China
| | - Qinghua Xu
- The Cancer of Unknown Primary Group of Pathology Committee, Chinese Research Hospital Association, Shanghai, China
- The Canhelp Genomics Research Center, Canhelp Genomics Co., Ltd., Hangzhou, China
- The Institute of Machine Learning and Systems Biology, College of Electronics and Information Engineering, Tongji University, Shanghai, China
- Xuzhou Engineering Research Center of Medical Genetics and Transformation, Department of Genetics, Xuzhou Medical University, Xuzhou, China
| | - Xiaoyan Zhou
- Department of Pathology, Fudan University Shanghai Cancer Center, No.270 Dong'An Road, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
- Institute of Pathology, Fudan University, Shanghai, China.
- The Cancer of Unknown Primary Group of Pathology Committee, Chinese Research Hospital Association, Shanghai, China.
| | - Wenyong Sun
- Department of Pathology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), No.1 East Road of Banshan, Hangzhou, Zhejiang, China.
| | - Dongmei Lin
- Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, No.52 Fucheng Road, Wu Ke Song, Haidian District, Beijing, China.
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21
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Cravero K, Pantone MV, Shin DH, Bergman R, Cochran R, Chu D, Zabransky DJ, Karthikeyan S, Waters IG, Hunter N, Rosen DM, Kyker-Snowman K, Dalton WB, Button B, Shinn D, Wong HY, Donaldson J, Hurley PJ, Croessmann S, Park BH. NOTCH1 PEST domain variants are responsive to standard of care treatments despite distinct transformative properties in a breast cancer model. Oncotarget 2022; 13:373-386. [PMID: 35186194 PMCID: PMC8849273 DOI: 10.18632/oncotarget.28200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 02/07/2022] [Indexed: 12/01/2022] Open
Abstract
Activating variants in the PEST region of NOTCH1 have been associated with aggressive phenotypes in human cancers, including triple-negative breast cancer (TNBC). Previous studies suggested that PEST domain variants in TNBC patients resulted in increased cell proliferation, invasiveness, and decreased overall survival. In this study, we assess the phenotypic transformation of activating NOTCH1 variants and their response to standard of care therapies. AAV-mediated gene targeting was used to isogenically incorporate 3 NOTCH1 variants, including a novel TNBC frameshift variant, in two non-tumorigenic breast epithelial cell lines, MCF10A and hTERT-IMEC. Two different variants at the NOTCH1 A2241 site (A2441fs and A2441T) both demonstrated increased transformative properties when compared to a non-transformative PEST domain variant (S2523L). These phenotypic changes include proliferation, migration, anchorage-independent growth, and MAPK pathway activation. In contrast to previous studies, activating NOTCH1 variants did not display sensitivity to a gamma secretase inhibitor (GSI) or resistance to chemotherapies. This study demonstrates distinct transformative phenotypes are specific to a given variant within NOTCH1 and these phenotypes do not correlate with sensitivities or resistance to chemotherapies or GSIs. Although previous studies have suggested NOTCH1 variants may be prognostic for TNBC, our study does not demonstrate prognostic ability of these variants and suggests further characterization would be required for clinical applications.
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Affiliation(s)
- Karen Cravero
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
- These authors contributed equally to this work
| | - Morgan V. Pantone
- Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center and The Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
- These authors contributed equally to this work
| | - Dong Ho Shin
- Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center and The Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
- These authors contributed equally to this work
| | - Riley Bergman
- Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center and The Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
| | - Rory Cochran
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - David Chu
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Daniel J. Zabransky
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Swathi Karthikeyan
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ian G. Waters
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Natasha Hunter
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - D. Marc Rosen
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Kelly Kyker-Snowman
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - W. Brian Dalton
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Berry Button
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Dan Shinn
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Hong Yuen Wong
- Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center and The Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
| | - Joshua Donaldson
- Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center and The Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
| | - Paula J. Hurley
- Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center and The Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
| | - Sarah Croessmann
- Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center and The Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
| | - Ben Ho Park
- Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center and The Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
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22
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Baranova A, Krasnoselskyi M, Starikov V, Kartashov S, Zhulkevych I, Vlasenko V, Oleshko K, Bilodid O, Sadchikova M, Vinnyk Y. Triple-negative breast cancer: current treatment strategies and factors of negative prognosis. J Med Life 2022; 15:153-161. [PMID: 35419095 PMCID: PMC8999097 DOI: 10.25122/jml-2021-0108] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 10/28/2021] [Indexed: 12/26/2022] Open
Abstract
Breast cancer is the most common cancer in women and the most common cause of death in working-age women. According to the results of immunohistochemical studies, 10-20% of cases revealed a triple-negative type of breast cancer. This subtype is characterized by significant proliferative activity and growth rate, aggressive clinical course, and early metastasis. This leads to a suspicious prognosis and, accordingly, encourages an increase of surgical treatment radicalism and aggressive systemic treatment. This review briefly analyzes existing treatment strategies for triple-negative breast cancer with a focus on surgical treatment. Surgical treatment is an integral part of complex therapy. Currently, the attention of researchers is focused not only on the radicalism of the operation, ensuring long-term survival, but also on achieving a good cosmetic result that determines the quality of life of patients. In this aspect, organ-preserving and prosthetic methods of operations are promising, the feasibility and effectiveness of which are being discussed. The relevance of choosing the optimal method of operation is evidenced by the lack of generally accepted approaches based on informative markers for the prognosis of the course of the disease. Therefore, the choice of the optimal method of surgical treatment taking into account the individual characteristics of the patient and the tumor, indications for chemotherapy, and radiation therapy remains an unresolved issue and requires further research.
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Affiliation(s)
- Anna Baranova
- Department of Radiology and Oncology, Grigoriev Institute for Medical Radiology NAMS of Ukraine, Kharkiv, Ukraine.,Department of Oncology, Kharkiv National Medical University, Kharkiv, Ukraine
| | - Mykola Krasnoselskyi
- Department of Radiology and Oncology, Grigoriev Institute for Medical Radiology NAMS of Ukraine, Kharkiv, Ukraine.,Department of Oncology, Radiology and Radiation Medicine V. N. Karazin Kharkiv National University, Kharkiv, Ukraine
| | - Volodymyr Starikov
- Department of Oncology, Kharkiv National Medical University, Kharkiv, Ukraine
| | - Sergii Kartashov
- Department of Obstetrics, Gynecology and Oncogynecology, Kharkiv Medical Academy of Postgraduate Education, Kharkiv, Ukraine
| | - Igor Zhulkevych
- Department of Oncology, Radiology Diagnostics and Therapy and Radiation Medicine, I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine
| | - Vadym Vlasenko
- Department of Cancer Surgery, Medical Center Molecule, Kharkiv, Ukraine
| | - Kateryna Oleshko
- Department of Obstetrics, Gynecology and Oncogynecology, Kharkiv Medical Academy of Postgraduate Education, Kharkiv, Ukraine
| | - Olga Bilodid
- Department of Obstetrics, Gynecology and Oncogynecology, Kharkiv Medical Academy of Postgraduate Education, Kharkiv, Ukraine
| | - Marina Sadchikova
- Department of Cancer Surgery, Radiation Therapy and Palliative Care, Kharkiv Medical Academy of Postgraduate Education, Kharkiv, Ukraine
| | - Yurii Vinnyk
- Department of Cancer Surgery, Radiation Therapy and Palliative Care, Kharkiv Medical Academy of Postgraduate Education, Kharkiv, Ukraine
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23
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Comprehensive Transcriptome and Pathway Analyses Revealed Central Role for Fascin in Promoting Triple-Negative Breast Cancer Progression. Pharmaceuticals (Basel) 2021; 14:ph14121228. [PMID: 34959629 PMCID: PMC8708558 DOI: 10.3390/ph14121228] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 11/24/2021] [Accepted: 11/25/2021] [Indexed: 11/16/2022] Open
Abstract
Recent years have witnessed major progress in development of novel therapeutic agents such as chemotherapy, targeted therapy and immune checkpoint inhibitors for breast cancer. However, cancer-related death remains high especially in triple-negative breast cancer (TNBC) due limited therapeutic options. Development of targeted therapies for TNBC requires better understanding of biology and signaling networks that promote disease progression. Fascin, an actin bundling protein, was identified as a key regulator of many signaling pathways that contribute to breast cancer progression. Herein, fascin ShRNA was used to generate stable fascin knockdown (FSCN1KD) in the MDA-MB-231 TNBC cell line and then were subjected to comprehensive mRNA and miRNA transcriptome analysis. We identified 129 upregulated and 114 downregulated mRNA transcripts, while 14 miRNAs were differentially expressed in FSCN1KD. Ingenuity pathway analysis (IPA) was used to predict the impact of differentially expressed transcripts on signaling pathways and functional categories and to construct miRNA-mRNA regulatory networks in the context of FSCN1 knockdown. Compared to FSCN1KD, fascin-positive (FSCN1CON) breast cancer cells showed enrichment in genes promoting cellular proliferation, migration, survival, DNA replication and repair. Expression of FSCN1high (identified in BRCA dataset from TCGA) in conjunction with elevated expression of the top 10 upregulated or decreased expression of the top 10 downregulated genes (identified in our FSCN1CON vs. FSCN1KD) correlates with worst survival outcome. Taken together, these data confirmed fascin's role in promoting TNBC progression, and identified a novel opportunity for therapeutic interventions via targeting those FSCN1-related transcripts.
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24
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Wang Q, Li F, Jiang Q, Sun Y, Liao Q, An H, Li Y, Li Z, Fan L, Guo F, Xu Q, Wo Y, Ren W, Yue J, Meng B, Liu W, Zhou X. Gene Expression Profiling for Differential Diagnosis of Liver Metastases: A Multicenter, Retrospective Cohort Study. Front Oncol 2021; 11:725988. [PMID: 34631555 PMCID: PMC8493028 DOI: 10.3389/fonc.2021.725988] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 08/18/2021] [Indexed: 02/05/2023] Open
Abstract
Background Liver metastases (LM) are the most common tumors encountered in the liver and continue to be a significant cause of morbidity and mortality. Identification of the primary tumor of any LM is crucial for the implementation of effective and tailored treatment approaches, which still represents a difficult problem in clinical practice. Methods The resection or biopsy specimens and associated clinicopathologic data were archived from seven independent centers between January 2017 and December 2020. The primary tumor sites of liver tumors were verified through evaluation of available medical records, pathological and imaging information. The performance of a 90-gene expression assay for the determination of the site of tumor origin was assessed. Result A total of 130 LM covering 15 tumor types and 16 primary liver tumor specimens that met all quality control criteria were analyzed by the 90-gene expression assay. Among 130 LM cases, tumors were most frequently located in the colorectum, ovary and breast. Overall, the analysis of the 90-gene signature showed 93.1% and 100% agreement rates with the reference diagnosis in LM and primary liver tumor, respectively. For the common primary tumor types, the concordance rate was 100%, 95.7%, 100%, 93.8%, 87.5% for classifying the LM from the ovary, colorectum, breast, neuroendocrine, and pancreas, respectively. Conclusion The overall accuracy of 93.8% demonstrates encouraging performance of the 90-gene expression assay in identifying the primary sites of liver tumors. Future incorporation of the 90-gene expression assay in clinical diagnosis will aid oncologists in applying precise treatments, leading to improved care and outcomes for LM patients.
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Affiliation(s)
- Qifeng Wang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Institute of Pathology, Fudan University, Shanghai, China.,The Cancer of Unknown Primary Group of Pathology Committee, Chinese Research Hospital Association, Shanghai, China
| | - Fen Li
- Department of Pathology, Chengdu Second People's Hospital, Chengdu, China
| | - Qingming Jiang
- Department of Pathology, Chongqing University Cancer Hospital, Chongqing, China
| | - Yifeng Sun
- The Canhelp Genomics Research Center, Canhelp Genomics Co., Ltd., Hangzhou, China
| | - Qiong Liao
- The Cancer of Unknown Primary Group of Pathology Committee, Chinese Research Hospital Association, Shanghai, China.,Department of Pathology, Sichuan Cancer Hospital, Chengdu, China
| | - Huimin An
- The Cancer of Unknown Primary Group of Pathology Committee, Chinese Research Hospital Association, Shanghai, China.,Department of Pathology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yunzhu Li
- Department of Pathology, Sichuan Cancer Hospital, Chengdu, China
| | - Zhenyu Li
- Department of Pathology, Chongqing University Cancer Hospital, Chongqing, China
| | - Lifang Fan
- Department of Pathology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Fang Guo
- Department of Pathology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qinghua Xu
- The Cancer of Unknown Primary Group of Pathology Committee, Chinese Research Hospital Association, Shanghai, China.,The Canhelp Genomics Research Center, Canhelp Genomics Co., Ltd., Hangzhou, China.,The Institute of Machine Learning and Systems Biology, College of Electronics and Information Engineering, Tongji University, Shanghai, China.,Xuzhou Engineering Research Center of Medical Genetics and Transformation, Department of Genetics, Xuzhou Medical University, Xuzhou, China
| | - Yixin Wo
- The Canhelp Genomics Research Center, Canhelp Genomics Co., Ltd., Hangzhou, China
| | - Wanli Ren
- The Canhelp Genomics Research Center, Canhelp Genomics Co., Ltd., Hangzhou, China
| | - Junqiu Yue
- The Cancer of Unknown Primary Group of Pathology Committee, Chinese Research Hospital Association, Shanghai, China.,Department of Pathology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bin Meng
- The Cancer of Unknown Primary Group of Pathology Committee, Chinese Research Hospital Association, Shanghai, China.,Department of Pathology, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Weiping Liu
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaoyan Zhou
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Institute of Pathology, Fudan University, Shanghai, China.,The Cancer of Unknown Primary Group of Pathology Committee, Chinese Research Hospital Association, Shanghai, China
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25
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Smith J, Shi Y, Benedikt M, Nikolic M. Scalable analysis of multi-modal biomedical data. Gigascience 2021; 10:giab058. [PMID: 34508579 PMCID: PMC8434767 DOI: 10.1093/gigascience/giab058] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 05/31/2021] [Accepted: 08/18/2021] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND Targeted diagnosis and treatment options are dependent on insights drawn from multi-modal analysis of large-scale biomedical datasets. Advances in genomics sequencing, image processing, and medical data management have supported data collection and management within medical institutions. These efforts have produced large-scale datasets and have enabled integrative analyses that provide a more thorough look of the impact of a disease on the underlying system. The integration of large-scale biomedical data commonly involves several complex data transformation steps, such as combining datasets to build feature vectors for learning analysis. Thus, scalable data integration solutions play a key role in the future of targeted medicine. Though large-scale data processing frameworks have shown promising performance for many domains, they fail to support scalable processing of complex datatypes. SOLUTION To address these issues and achieve scalable processing of multi-modal biomedical data, we present TraNCE, a framework that automates the difficulties of designing distributed analyses with complex biomedical data types. PERFORMANCE We outline research and clinical applications for the platform, including data integration support for building feature sets for classification. We show that the system is capable of outperforming the common alternative, based on "flattening" complex data structures, and runs efficiently when alternative approaches are unable to perform at all.
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Affiliation(s)
- Jaclyn Smith
- University of Oxford, Computer Science, Wolfson Building, Parks Road, Oxford OX1 3QD, UK
| | - Yao Shi
- University of Oxford, Computer Science, Wolfson Building, Parks Road, Oxford OX1 3QD, UK
| | - Michael Benedikt
- University of Oxford, Computer Science, Wolfson Building, Parks Road, Oxford OX1 3QD, UK
| | - Milos Nikolic
- University of Edinburgh, School of Informatics, Informatics Forum, 10 Crichton St, Newington, Edinburgh EH8 9AB, Scotland
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26
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Manjunath M, Choudhary B. Triple-negative breast cancer: A run-through of features, classification and current therapies. Oncol Lett 2021; 22:512. [PMID: 33986872 PMCID: PMC8114477 DOI: 10.3892/ol.2021.12773] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Accepted: 03/01/2021] [Indexed: 02/06/2023] Open
Abstract
Breast cancer is the most prevalent cancer in women worldwide. Triple-negative breast cancer (TNBC) is characterized by the lack of expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. It is the most aggressive subtype of breast cancer and accounts for 12-20% of all breast cancer cases. TNBC is associated with younger age of onset, greater metastatic potential, higher incidence of relapse, and lower overall survival rates. Based on molecular phenotype, TNBC has been classified into six subtypes (BL1, BL2, M, MES, LAR, and IM). TNBC treatment is challenging due to its heterogeneity, highly invasive nature, and relatively poor therapeutics response. Chemotherapy and radiotherapy are conventional strategies for the treatment of TNBC. Recent research in TNBC and mechanistic understanding of disease pathogenesis using cutting-edge technologies has led to the unfolding of new lines of therapies that have been incorporated into clinical practice. Poly (ADP-ribose) polymerase and immune checkpoint inhibitors have made their way to the current TNBC treatment paradigm. This review focuses on the classification, features, and treatment progress in TNBC. Histological subtypes connected to recurrence, molecular classification of TNBC, targeted therapy for early and advanced TNBC, and advances in non-coding RNA in therapy are the key highlights in this review.
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Affiliation(s)
- Meghana Manjunath
- Department of Biotechnology, Institute of Bioinformatics and Applied Biotechnology, Bengaluru, Karnataka 560100, India
- Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Bibha Choudhary
- Department of Biotechnology, Institute of Bioinformatics and Applied Biotechnology, Bengaluru, Karnataka 560100, India
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27
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Zhou L, Guo Z, Wang B, Wu Y, Li Z, Yao H, Fang R, Yang H, Cao H, Cui Y. Risk Prediction in Patients With Heart Failure With Preserved Ejection Fraction Using Gene Expression Data and Machine Learning. Front Genet 2021; 12:652315. [PMID: 33828587 PMCID: PMC8019773 DOI: 10.3389/fgene.2021.652315] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 03/02/2021] [Indexed: 12/27/2022] Open
Abstract
Heart failure with preserved ejection fraction (HFpEF) has become a major health issue because of its high mortality, high heterogeneity, and poor prognosis. Using genomic data to classify patients into different risk groups is a promising method to facilitate the identification of high-risk groups for further precision treatment. Here, we applied six machine learning models, namely kernel partial least squares with the genetic algorithm (GA-KPLS), the least absolute shrinkage and selection operator (LASSO), random forest, ridge regression, support vector machine, and the conventional logistic regression model, to predict HFpEF risk and to identify subgroups at high risk of death based on gene expression data. The model performance was evaluated using various criteria. Our analysis was focused on 149 HFpEF patients from the Framingham Heart Study cohort who were classified into good-outcome and poor-outcome groups based on their 3-year survival outcome. The results showed that the GA-KPLS model exhibited the best performance in predicting patient risk. We further identified 116 differentially expressed genes (DEGs) between the two groups, thus providing novel therapeutic targets for HFpEF. Additionally, the DEGs were enriched in Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways related to HFpEF. The GA-KPLS-based HFpEF model is a powerful method for risk stratification of 3-year mortality in HFpEF patients.
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Affiliation(s)
- Liye Zhou
- Division of Health Management, School of Management, Shanxi Medical University, Taiyuan, China
| | - Zhifei Guo
- Division of Health Management, School of Management, Shanxi Medical University, Taiyuan, China
| | - Bijue Wang
- Division of Health Management, School of Management, Shanxi Medical University, Taiyuan, China
| | - Yongqing Wu
- Division of Health Statistics, School of Public Health, Shanxi Medical University, Taiyuan, China
| | - Zhi Li
- Department of Hematology, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, China
| | - Hongmei Yao
- Department of Cardiology, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Ruiling Fang
- Division of Health Statistics, School of Public Health, Shanxi Medical University, Taiyuan, China
| | - Haitao Yang
- Division of Health Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Hongyan Cao
- Division of Health Statistics, School of Public Health, Shanxi Medical University, Taiyuan, China.,Key Laboratory of Major Disease Risk Assessment, Shanxi Medical University, Taiyuan, China
| | - Yuehua Cui
- Department of Statistics and Probability, Michigan State University, East Lansing, MI, United States
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28
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Analysis of transient membrane protein interactions by single-molecule diffusional mobility shift assay. Exp Mol Med 2021; 53:291-299. [PMID: 33603128 PMCID: PMC8080847 DOI: 10.1038/s12276-021-00567-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 12/29/2020] [Accepted: 01/06/2021] [Indexed: 01/31/2023] Open
Abstract
Various repertoires of membrane protein interactions determine cellular responses to diverse environments around cells dynamically in space and time. Current assays, however, have limitations in unraveling these interactions in the physiological states in a living cell due to the lack of capability to probe the transient nature of these interactions on the crowded membrane. Here, we present a simple and robust assay that enables the investigation of transient protein interactions in living cells by using the single-molecule diffusional mobility shift assay (smDIMSA). Utilizing smDIMSA, we uncovered the interaction profile of EGFR with various membrane proteins and demonstrated the promiscuity of these interactions depending on the cancer cell line. The transient interaction profile obtained by smDIMSA will provide critical information to comprehend the crosstalk among various receptors on the plasma membrane.
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Li R, Liao B, Wang B, Dai C, Liang X, Tian G, Wu F. Identification of Tumor Tissue of Origin with RNA-Seq Data and Using Gradient Boosting Strategy. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6653793. [PMID: 33681364 PMCID: PMC7904362 DOI: 10.1155/2021/6653793] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 01/19/2021] [Accepted: 02/06/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND Cancer of unknown primary (CUP) is a type of malignant tumor, which is histologically diagnosed as a metastatic carcinoma while the tissue-of-origin cannot be identified. CUP accounts for roughly 5% of all cancers. Traditional treatment for CUP is primarily broad-spectrum chemotherapy; however, the prognosis is relatively poor. Thus, it is of clinical importance to accurately infer the tissue-of-origin of CUP. METHODS We developed a gradient boosting framework to trace tissue-of-origin of 20 types of solid tumors. Specifically, we downloaded the expression profiles of 20,501 genes for 7713 samples from The Cancer Genome Atlas (TCGA), which were used as the training data set. The RNA-seq data of 79 tumor samples from 6 cancer types with known origins were also downloaded from the Gene Expression Omnibus (GEO) for an independent data set. RESULTS 400 genes were selected to train a gradient boosting model for identification of the primary site of the tumor. The overall 10-fold cross-validation accuracy of our method was 96.1% across 20 types of cancer, while the accuracy for the independent data set reached 83.5%. CONCLUSION Our gradient boosting framework was proven to be accurate in identifying tumor tissue-of-origin on both training data and independent testing data, which might be of practical usage.
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Affiliation(s)
- Ruixi Li
- School of Mathematics and Statistics, Hainan Normal University, Haikou 570100, China
- Key Laboratory of Computational Science and Application of Hainan Province, Haikou 571158, China
- Key Laboratory of Data Science and Intelligence Education (Hainan Normal University), Ministry of Education, Haikou 571158, China
| | - Bo Liao
- School of Mathematics and Statistics, Hainan Normal University, Haikou 570100, China
- Key Laboratory of Computational Science and Application of Hainan Province, Haikou 571158, China
- Key Laboratory of Data Science and Intelligence Education (Hainan Normal University), Ministry of Education, Haikou 571158, China
| | - Bo Wang
- Qingdao Geneis Institute of Big Data Mining and Precision Medicine, Qingdao 266000, China
- Geneis (Beijing) Co., Ltd., Beijing 100102, China
| | - Chan Dai
- Qingdao Geneis Institute of Big Data Mining and Precision Medicine, Qingdao 266000, China
- Geneis (Beijing) Co., Ltd., Beijing 100102, China
| | - Xin Liang
- School of Mathematics and Statistics, Hainan Normal University, Haikou 570100, China
- Key Laboratory of Computational Science and Application of Hainan Province, Haikou 571158, China
- Key Laboratory of Data Science and Intelligence Education (Hainan Normal University), Ministry of Education, Haikou 571158, China
| | - Geng Tian
- Qingdao Geneis Institute of Big Data Mining and Precision Medicine, Qingdao 266000, China
- Geneis (Beijing) Co., Ltd., Beijing 100102, China
| | - Fangxiang Wu
- School of Mathematics and Statistics, Hainan Normal University, Haikou 570100, China
- Key Laboratory of Computational Science and Application of Hainan Province, Haikou 571158, China
- Key Laboratory of Data Science and Intelligence Education (Hainan Normal University), Ministry of Education, Haikou 571158, China
- Division of Biomedical Engineering, Department of Mechanical Engineering, University of Saskatchewan, Saskatoon, SK, S7N5A9, Canada
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30
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Gene expression profiling for the diagnosis of multiple primary malignant tumors. Cancer Cell Int 2021; 21:47. [PMID: 33514366 PMCID: PMC7846996 DOI: 10.1186/s12935-021-01748-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 01/02/2021] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND The incidence of multiple primary malignant tumors (MPMTs) is rising due to the development of screening technologies, significant treatment advances and increased aging of the population. For patients with a prior cancer history, identifying the tumor origin of the second malignant lesion has important prognostic and therapeutic implications and still represents a difficult problem in clinical practice. METHODS In this study, we evaluated the performance of a 90-gene expression assay and explored its potential diagnostic utility for MPMTs across a broad spectrum of tumor types. Thirty-five MPMT patients from Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University and Fudan University Shanghai Cancer Center were enrolled; 73 MPMT specimens met all quality control criteria and were analyzed by the 90-gene expression assay. RESULTS For each clinical specimen, the tumor type predicted by the 90-gene expression assay was compared with its pathological diagnosis, with an overall accuracy of 93.2% (68 of 73, 95% confidence interval 0.84-0.97). For histopathological subgroup analysis, the 90-gene expression assay achieved an overall accuracy of 95.0% (38 of 40; 95% CI 0.82-0.99) for well-moderately differentiated tumors and 92.0% (23 of 25; 95% CI 0.82-0.99) for poorly or undifferentiated tumors, with no statistically significant difference (p-value > 0.5). For squamous cell carcinoma specimens, the overall accuracy of gene expression assay also reached 87.5% (7 of 8; 95% CI 0.47-0.99) for identifying the tumor origins. CONCLUSIONS The 90-gene expression assay provides flexibility and accuracy in identifying the tumor origin of MPMTs. Future incorporation of the 90-gene expression assay in pathological diagnosis will assist oncologists in applying precise treatments, leading to improved care and outcomes for MPMT patients.
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31
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Liang Y, Wang H, Yang J, Li X, Dai C, Shao P, Tian G, Wang B, Wang Y. A Deep Learning Framework to Predict Tumor Tissue-of-Origin Based on Copy Number Alteration. Front Bioeng Biotechnol 2020; 8:701. [PMID: 32850687 PMCID: PMC7419421 DOI: 10.3389/fbioe.2020.00701] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Accepted: 06/04/2020] [Indexed: 12/18/2022] Open
Abstract
Cancer of unknown primary site (CUPS) is a type of metastatic tumor for which the sites of tumor origin cannot be determined. Precise diagnosis of the tissue origin for metastatic CUPS is crucial for developing treatment schemes to improve patient prognosis. Recently, there have been many studies using various cancer biomarkers to predict the tissue-of-origin (TOO) of CUPS. However, only a very few of them use copy number alteration (CNA) to trance TOO. In this paper, a two-step computational framework called CNA_origin is introduced to predict the tissue-of-origin of a tumor from its gene CNA levels. CNA_origin set up an intellectual deep-learning network mainly composed of an autoencoder and a convolution neural network (CNN). Based on real datasets released from the public database, CNA_origin had an overall accuracy of 83.81% on 10-fold cross-validation and 79% on independent datasets for predicting tumor origin, which improved the accuracy by 7.75 and 9.72% compared with the method published in a previous paper. Our results suggested that the autoencoder model can extract key characteristics of CNA and that the CNN classifier model developed in this study can predict the origin of tumors robustly and effectively. CNA_origin was written in Python and can be downloaded from https://github.com/YingLianghnu/CNA_origin.
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Affiliation(s)
- Ying Liang
- College of Computer and Information Engineering, Jiangxi Agricultural University, Nanchang, China
| | - Haifeng Wang
- Department of Urology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | | | - Xiong Li
- School of Software, East China Jiaotong University, Nanchang, China
| | - Chan Dai
- Geneis (Beijing) Co. Ltd., Beijing, China
| | - Peng Shao
- College of Computer and Information Engineering, Jiangxi Agricultural University, Nanchang, China
| | - Geng Tian
- Geneis (Beijing) Co. Ltd., Beijing, China
| | - Bo Wang
- Geneis (Beijing) Co. Ltd., Beijing, China
| | - Yinglong Wang
- College of Computer and Information Engineering, Jiangxi Agricultural University, Nanchang, China
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Qu N, Huang D, Xu Q, Wang J, Chen C, Ji Q, Wu W, Zhu Y, Xu M. Gene expression profiling of cells of origin of squamous cell carcinomas in head-and-neck, esophagus, and lung. Acta Biochim Biophys Sin (Shanghai) 2020; 52:211-214. [PMID: 31960064 DOI: 10.1093/abbs/gmz153] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- Ning Qu
- Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Dongzhe Huang
- Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Qinghua Xu
- Cancer of Unknown Primary Group of Pathology Committee of Chinese Research Hospital Association, Beijing 100081, China
- Canhelp Genomics, Hangzhou 311100, China
- Institute of Machine Learning and Systems Biology, College of Electronics and Information Engineering, Tongji University, Shanghai 200092 , China
| | - Jian Wang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Institute of Pathology, Fudan University, Shanghai 200032, China
| | | | - Qinghai Ji
- Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Weili Wu
- Department of Surgical Oncology, Third Affiliated Hospital of Wenzhou Medical University, Wenzhou 325200, China
| | - Yongxue Zhu
- Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Midie Xu
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Institute of Pathology, Fudan University, Shanghai 200032, China
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