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Maqsood R, Ullah S, Khan F, Waqas M, Halim SA, Khan A, Hussain J, Qayum U, Gibbons S, Rehman NU, Hussain A, Al-Harrasi A. Bioassay-guided isolation of a new cytotoxic compound targeting carbonic anhydrase-II: in-vitro structure-activity relationships and dynamics studies. J Biomol Struct Dyn 2025:1-17. [PMID: 40351225 DOI: 10.1080/07391102.2025.2500680] [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: 03/06/2024] [Accepted: 06/01/2024] [Indexed: 05/14/2025]
Abstract
Bioassay-guided isolation of Anogeissus dhofarica A.J. Scott afforded one new natural product (lupeol butyl ether, 1), along with sixteen known metabolites (2-17) reported from this source for the first time. Structural elucidation of the isolates was performed by NMR and mass spectrometry. An in vitro carbonic anhydrase-II (CA-II) inhibition assay was performed on the crude extract, the fractions, and the resulting pure constituents. The activity against CA-II of the crude extract and fractions was in the range of IC50 45.10-102.56 µg/mL. Among the isolates, 14 was the most active with an IC50 of 7.19 ± 0.20 µM followed by 10 (IC50 = 13.61 ± 0.30 µM), 12 (IC50 = 17.30 ± 0.58 µM) and 1 (21.63 ± 0.48 µM), with the remaining compounds having moderate to low inhibition. Fourteen compounds were evaluated against breast cancer (MDA-MB-231) and normal cell (3T3-L1) lines in an MTT assay, with most natural products exhibiting moderate activity against MDA-MB-231 cells (1, IC50 = 34.5 ± 0.8 μM/mL), and less active to the normal cell line. Additionally, the molecular binding of the active hits was predicted through an in-silico approach, specifically docking molecular dynamic (MD) simulations, which revealed that acetate and carboxyl moieties play an important role in ligand binding with the Zn2+ ion of the CA-II active site. The MD simulation of the structure dynamics revealed that the most active inhibitors (10 and 14) had strong affinity with the CA-II active site and brought structural conformational changes to the protein.
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Affiliation(s)
- Rabia Maqsood
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, Oman
- Department of Chemistry, University of Okara, Okara, Punjab, Pakistan
| | - Saeed Ullah
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, Oman
| | - Faizullah Khan
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, Oman
| | - Muhammad Waqas
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, Oman
| | - Sobia Ahsan Halim
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, Oman
| | - Ajmal Khan
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, Oman
| | - Javid Hussain
- Department of Biological Sciences and Chemistry, College of Arts and Sciences, University of Nizwa, Nizwa, Oman
| | - Usama Qayum
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, Oman
| | - Simon Gibbons
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, Oman
| | - Najeeb Ur Rehman
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, Oman
| | - Amjad Hussain
- Department of Chemistry, University of Okara, Okara, Punjab, Pakistan
| | - Ahmed Al-Harrasi
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, Oman
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El Haddad G, Diab E, Hajjar M, Aoun M, Mallat F, Zalaquett Z, Kourie HR. Insights Into the Emerging Entity of HER2-Low Breast Cancer. Int J Breast Cancer 2024; 2024:2853007. [PMID: 38962672 PMCID: PMC11221987 DOI: 10.1155/2024/2853007] [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: 02/22/2024] [Revised: 04/25/2024] [Accepted: 05/10/2024] [Indexed: 07/05/2024] Open
Abstract
Human epidermal growth factor receptor 2 (HER2)-low breast cancer (BC) is a subtype of BC that has been recently recognized as a separate clinical entity with distinct clinical and molecular characteristics. It is defined by a low level of HER2 protein expression, which distinguishes it from other more aggressive BC subtypes. Early studies suggest that it may have a more favorable prognosis than HER2-positive BC, as it is less likely to spread to other parts of the body and may be more responsive to standard BC treatments such as chemotherapy, radiation therapy, and hormone therapy. Given the relative new emergence of HER2-low BC, there is still much to be learned about this subtype; ongoing research is focused on identifying the underlying genetic mutations that contribute to HER2-low BC as well as developing targeted therapies that can improve outcomes for patients with this disease. This review is aimed at summarizing the current clinical knowledge on HER2-low BC, with the aim of creating a better understanding of this entity and paving the way for potential interventions and a new standard of care.
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Affiliation(s)
- Georges El Haddad
- Hematology-Oncology DepartmentHôtel-Dieu de France University HospitalSaint Joseph University of Beirut, Beirut, Lebanon
| | - Ernest Diab
- Hematology-Oncology DepartmentHôtel-Dieu de France University HospitalSaint Joseph University of Beirut, Beirut, Lebanon
| | - Michel Hajjar
- Hematology-Oncology DepartmentHôtel-Dieu de France University HospitalSaint Joseph University of Beirut, Beirut, Lebanon
| | - Maroun Aoun
- Hematology-Oncology DepartmentHôtel-Dieu de France University HospitalSaint Joseph University of Beirut, Beirut, Lebanon
| | - Farid Mallat
- Hematology-Oncology DepartmentHôtel-Dieu de France University HospitalSaint Joseph University of Beirut, Beirut, Lebanon
| | - Ziad Zalaquett
- Hematology-Oncology DepartmentHôtel-Dieu de France University HospitalSaint Joseph University of Beirut, Beirut, Lebanon
| | - Hampig-Raphael Kourie
- Hematology-Oncology DepartmentHôtel-Dieu de France University HospitalSaint Joseph University of Beirut, Beirut, Lebanon
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Ong C, Blue CM, Khan J, Deng X, Bandyopadhyay D, Louie RJ, McGuire KP. Luminal A Versus B After Choosing Wisely: Does Lymph Node Surgery Affect Oncologic Outcomes? Ann Surg Oncol 2024; 31:335-343. [PMID: 37831277 DOI: 10.1245/s10434-023-14407-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 09/17/2023] [Indexed: 10/14/2023]
Abstract
BACKGROUND In 2016, the Choosing Wisely campaign recommended against routine sentinel lymph node biopsy (SLNB) in women ≥ 70 years old diagnosed with early-stage hormone receptor positive (HR+), HER2 negative (HER2-) breast cancer. No distinction is made between luminal A and luminal B phenotypes, despite luminal B being considered more aggressive. This study evaluates the effect of SLNB on oncologic outcomes in HER2- luminal B versus luminal A breast cancer. PATIENTS AND METHODS We performed an IRB-approved, single institution, retrospective cohort study from 2010 to 2020 of women aged ≥ 70 years with clinically node negative, HR+ breast cancer undergoing definitive surgical treatment. Luminal status was defined by gene expression panel testing, Ki67%, and/or pathologic grading. Primary endpoints included locoregional recurrence (LRR), disease free survival (DFS), and overall survival (OS). RESULTS SLNB did not correlate with significant differences in LRR in luminal A (p = 0.92) or luminal B (p = 0.96) disease. SLNB correlated with improved DFS (p < 0.01) and OS (p < 0.001) in luminal A disease, but not in luminal B disease (DFS p = 0.73; OS p = 0.36). On multivariate analysis, age (HR = 1.17; p < 0.01) and tumor size (HR = 1.03; p < 0.05) were associated with DFS, while SLNB was not (p = 0.71). Luminal status (HR = 0.52, p < 0.05), age (HR = 1.15, p < 0.01), and comorbidities (HR = 1.35, p < 0.05) were associated with OS, but not SLNB (p = 0.71). CONCLUSIONS Our results suggest that SLNB may be safely omitted in patients aged ≥ 70 years with luminal B disease given similar LRR in luminal A disease. Our findings suggest that DFS and OS are driven by tumor biology, patient age, and comorbidities rather than receipt of SLNB.
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Affiliation(s)
- Cynthia Ong
- School of Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Christian M Blue
- School of Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Jamal Khan
- School of Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Xiaoyan Deng
- Department of Biostatistics, Virginia Commonwealth University, Richmond, VA, USA
| | | | - Raphael J Louie
- Department of Surgery, Virginia Commonwealth University Health, Richmond, VA, USA
| | - Kandace P McGuire
- Department of Surgery, Virginia Commonwealth University Health, Richmond, VA, USA.
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Ahmed R, Samanta S, Banerjee J, Kar SS, Dash SK. Modulatory role of miRNAs in thyroid and breast cancer progression and insights into their therapeutic manipulation. CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2022; 3:100131. [PMID: 36568259 PMCID: PMC9780070 DOI: 10.1016/j.crphar.2022.100131] [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: 07/06/2022] [Revised: 08/22/2022] [Accepted: 09/25/2022] [Indexed: 11/07/2022] Open
Abstract
Over the past few decades, thyroid cancer has become one of the most common types of endocrine cancer, contributing to an increase in prevalence. In the year 2020, there were 586,202 newly diagnosed cases of thyroid cancer around the world. This constituted approximately 3.0% of all patients diagnosed with cancer. The World Health Organization reported that there will be 2.3 million women receiving treatment for breast cancer in 2020, with 685,000. Despite the fact that carcinoma is one of the world's leading causes of death, there is still a paucity of information about its biology. MicroRNAs (miRNAs; miRs) are non-coding RNAs that can reduce gene expression by cleaving the 3' untranslated regions of mRNA. These factors make them a potential protein translation inhibitor. Diverse biological mechanisms implicated in the genesis of cancer are modulated by miRNA. The investigation of global miRNA expression in cancer showed regulatory activity through up regulation and down-regulation in several cancers, including thyroid cancer and breast cancer. In thyroid cancer, miRNA influences several cancers related signaling pathways through modulating MAPK, PI3K, and the RAS pathway. In breast cancer, the regulatory activity of miRNA was played through the cyclin protein family, protein kinases and their inhibitors, and other growth promoters or suppressors, which modulated cell proliferation and cell cycle progression. This article's goal is to discuss key miRNA expressions that are involved in the development of thyroid and breast cancer as well as their therapeutic manipulation for these two specific cancer types.
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Affiliation(s)
- Rubai Ahmed
- Department of Physiology, University of Gour Banga, Malda, 732103, West Bengal, India
| | - Sovan Samanta
- Department of Physiology, University of Gour Banga, Malda, 732103, West Bengal, India
| | - Jhimli Banerjee
- Department of Physiology, University of Gour Banga, Malda, 732103, West Bengal, India
| | - Suvrendu Sankar Kar
- Department of Medicine, R.G.Kar Medical College and Hospital, Kolkata, 700004, West Bengal, India
| | - Sandeep Kumar Dash
- Department of Physiology, University of Gour Banga, Malda, 732103, West Bengal, India,Corresponding author.
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The crosstalk of the human microbiome in breast and colon cancer: A metabolomics analysis. Crit Rev Oncol Hematol 2022; 176:103757. [PMID: 35809795 DOI: 10.1016/j.critrevonc.2022.103757] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 06/28/2022] [Accepted: 07/04/2022] [Indexed: 11/20/2022] Open
Abstract
The human microbiome's role in colon and breast cancer is described in this review. Understanding how the human microbiome and metabolomics interact with breast and colon cancer is the chief area of this study. First, the role of the gut and distal microbiome in breast and colon cancer is investigated, and the direct relationship between microbial dysbiosis and breast and colon cancer is highlighted. This work also focuses on the many metabolomic techniques used to locate prospective biomarkers, make an accurate diagnosis, and research new therapeutic targets for cancer treatment. This review clarifies the influence of anti-tumor medications on the microbiota and the proactive measures that can be taken to treat cancer using a variety of therapies, including radiotherapy, chemotherapy, next-generation biotherapeutics, gene-based therapy, integrated omics technology, and machine learning.
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Shrihastini V, Muthuramalingam P, Adarshan S, Sujitha M, Chen JT, Shin H, Ramesh M. Plant Derived Bioactive Compounds, Their Anti-Cancer Effects and In Silico Approaches as an Alternative Target Treatment Strategy for Breast Cancer: An Updated Overview. Cancers (Basel) 2021; 13:cancers13246222. [PMID: 34944840 PMCID: PMC8699774 DOI: 10.3390/cancers13246222] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 12/08/2021] [Accepted: 12/09/2021] [Indexed: 12/13/2022] Open
Abstract
Cancer is one of the most common malignant diseases that occur worldwide, among which breast cancer is the second leading cause of death in women. The subtypes are associated with differences in the outcome and were selected for treatments according to the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor. Triple-negative breast cancer, one of the subtypes of breast cancer, is difficult to treat and can even lead to death. If breast cancer is not treated during the initial stages, it may spread to nearby organs, a process called metastasis, through the blood or lymph system. For in vitro studies, MCF-7, MDA-MB-231, MDA-MB-468, and T47B are the most commonly used breast cancer cell lines. Clinically, chemotherapy and radiotherapy are usually expensive and can also cause side effects. To overcome these issues, medicinal plants could be the best alternative for chemotherapeutic drugs with fewer side effects and cost-effectiveness. Furthermore, the genes involved in breast cancer can be regulated and synergized with signaling molecules to suppress the proliferation of breast cancer cells. In addition, nanoparticles encapsulating (nano-encapsulation) medicinal plant extracts showed a significant reduction in the apoptotic and cytotoxic activities of breast cancer cells. This present review mainly speculates an overview of the native medicinal plant derived anti-cancerous compounds with its efficiency, types and pathways involved in breast cancer along with its genes, the mechanism of breast cancer brain metastasis, chemoresistivity and its mechanism, bioinformatics approaches which could be an effective alternative for drug discovery.
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Affiliation(s)
- Vijayakumar Shrihastini
- Department of Biotechnology, Sri Shakthi Institute of Engineering and Technology, Coimbatore 641062, Tamil Nadu, India; (V.S.); (M.S.)
| | - Pandiyan Muthuramalingam
- Department of Biotechnology, Sri Shakthi Institute of Engineering and Technology, Coimbatore 641062, Tamil Nadu, India; (V.S.); (M.S.)
- Correspondence: (P.M.); (J.-T.C.)
| | - Sivakumar Adarshan
- Department of Biotechnology, Science Campus, Alagappa University, Karaikudi 630003, Tamil Nadu, India; (S.A.); (M.R.)
| | - Mariappan Sujitha
- Department of Biotechnology, Sri Shakthi Institute of Engineering and Technology, Coimbatore 641062, Tamil Nadu, India; (V.S.); (M.S.)
| | - Jen-Tsung Chen
- Department of Life Sciences, National University of Kaohsiung, Kaohsiung 811, Taiwan
- Correspondence: (P.M.); (J.-T.C.)
| | - Hyunsuk Shin
- Department of Horticultural Sciences, Gyeongsang National University, Jinju 52725, Korea;
| | - Manikandan Ramesh
- Department of Biotechnology, Science Campus, Alagappa University, Karaikudi 630003, Tamil Nadu, India; (S.A.); (M.R.)
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Lien TG, Ohnstad HO, Lingjærde OC, Vallon-Christersson J, Aaserud M, Sveli MAT, Borg Å, OSBREAC OBO, Garred Ø, Borgen E, Naume B, Russnes H, Sørlie T. Sample Preparation Approach Influences PAM50 Risk of Recurrence Score in Early Breast Cancer. Cancers (Basel) 2021; 13:6118. [PMID: 34885228 PMCID: PMC8657125 DOI: 10.3390/cancers13236118] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 11/25/2021] [Accepted: 11/30/2021] [Indexed: 11/19/2022] Open
Abstract
The PAM50 gene expression subtypes and the associated risk of recurrence (ROR) score are used to predict the risk of recurrence and the benefits of adjuvant therapy in early-stage breast cancer. The Prosigna assay includes the PAM50 subtypes along with their clinicopathological features, and is approved for treatment recommendations for adjuvant hormonal therapy and chemotherapy in hormone-receptor-positive early breast cancer. The Prosigna test utilizes RNA extracted from macrodissected tumor cells obtained from formalin-fixed, paraffin-embedded (FFPE) tissue sections. However, RNA extracted from fresh-frozen (FF) bulk tissue without macrodissection is widely used for research purposes, and yields high-quality RNA for downstream analyses. To investigate the impact of the sample preparation approach on ROR scores, we analyzed 94 breast carcinomas included in an observational study that had available gene expression data from macrodissected FFPE tissue and FF bulk tumor tissue, along with the clinically approved Prosigna scores for the node-negative, hormone-receptor-positive, HER2-negative cases (n = 54). ROR scores were calculated in R; the resulting two sets of scores from FFPE and FF samples were compared, and treatment recommendations were evaluated. Overall, ROR scores calculated based on the macrodissected FFPE tissue were consistent with the Prosigna scores. However, analyses from bulk tissue yielded a higher proportion of cases classified as normal-like; these were samples with relatively low tumor cellularity, leading to lower ROR scores. When comparing ROR scores (low, intermediate, and high), discordant cases between the two preparation approaches were revealed among the luminal tumors; the recommended treatment would have changed in a minority of cases.
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Affiliation(s)
- Tonje G. Lien
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, P.O. Box 4953 Nydalen, N-0424 Oslo, Norway; (T.G.L.); (O.C.L.); (H.R.)
| | - Hege Oma Ohnstad
- Department of Oncology, Division of Cancer Medicine, Oslo University Hospital, P.O. Box 4953 Nydalen, N-0424 Oslo, Norway; (H.O.O.); (B.N.)
| | - Ole Christian Lingjærde
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, P.O. Box 4953 Nydalen, N-0424 Oslo, Norway; (T.G.L.); (O.C.L.); (H.R.)
- Centre for Bioinformatics, Department of Informatics, University of Oslo, Gaustadalléen 23 B, N-0373 Oslo, Norway
| | - Johan Vallon-Christersson
- Division of Oncology, Department of Clinical Sciences Lund, Lund University, Medicon Village, SE-22381 Lund, Sweden; (J.V.-C.); (Å.B.)
| | - Marit Aaserud
- Department of Pathology, Oslo University Hospital, P.O. Box 4953 Nydalen, N-0424 Oslo, Norway; (M.A.); (M.A.T.S.); (Ø.G.); (E.B.)
| | - My Anh Tu Sveli
- Department of Pathology, Oslo University Hospital, P.O. Box 4953 Nydalen, N-0424 Oslo, Norway; (M.A.); (M.A.T.S.); (Ø.G.); (E.B.)
| | - Åke Borg
- Division of Oncology, Department of Clinical Sciences Lund, Lund University, Medicon Village, SE-22381 Lund, Sweden; (J.V.-C.); (Å.B.)
| | | | - Øystein Garred
- Department of Pathology, Oslo University Hospital, P.O. Box 4953 Nydalen, N-0424 Oslo, Norway; (M.A.); (M.A.T.S.); (Ø.G.); (E.B.)
| | - Elin Borgen
- Department of Pathology, Oslo University Hospital, P.O. Box 4953 Nydalen, N-0424 Oslo, Norway; (M.A.); (M.A.T.S.); (Ø.G.); (E.B.)
| | - Bjørn Naume
- Department of Oncology, Division of Cancer Medicine, Oslo University Hospital, P.O. Box 4953 Nydalen, N-0424 Oslo, Norway; (H.O.O.); (B.N.)
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, P.O. Box 1171 Blindern, N-0318 Oslo, Norway
| | - Hege Russnes
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, P.O. Box 4953 Nydalen, N-0424 Oslo, Norway; (T.G.L.); (O.C.L.); (H.R.)
- Department of Pathology, Oslo University Hospital, P.O. Box 4953 Nydalen, N-0424 Oslo, Norway; (M.A.); (M.A.T.S.); (Ø.G.); (E.B.)
| | - Therese Sørlie
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, P.O. Box 4953 Nydalen, N-0424 Oslo, Norway; (T.G.L.); (O.C.L.); (H.R.)
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, P.O. Box 1171 Blindern, N-0318 Oslo, Norway
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Subramaiam H, Chu WL, Radhakrishnan AK, Chakravarthi S, Selvaduray KR, Kok YY. Evaluating Anticancer and Immunomodulatory Effects of Spirulina (Arthrospira) platensis and Gamma-Tocotrienol Supplementation in a Syngeneic Mouse Model of Breast Cancer. Nutrients 2021; 13:2320. [PMID: 34371830 PMCID: PMC8308567 DOI: 10.3390/nu13072320] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 06/18/2021] [Accepted: 06/23/2021] [Indexed: 12/13/2022] Open
Abstract
Nutrition can modulate host immune responses as well as promote anticancer effects. In this study, two nutritional supplements, namely gamma-tocotrienol (γT3) and Spirulina, were evaluated for their immune-enhancing and anticancer effects in a syngeneic mouse model of breast cancer (BC). Five-week-old female BALB/c mice were fed Spirulina, γT3, or a combination of Spirulina and γT3 (Spirulina + γT3) for 56 days. The mice were inoculated with 4T1 cells into their mammary fat pad on day 28 to induce BC. The animals were culled on day 56 for various analyses. A significant reduction (p < 0.05) in tumor volume was only observed on day 37 and 49 in animals fed with the combination of γT3 + Spirulina. There was a marked increase (p < 0.05) of CD4/CD127+ T-cells and decrease (p < 0.05) of T-regulatory cells in peripheral blood from mice fed with either γT3 or Spirulina. The breast tissue of the combined group showed abundant areas of necrosis, but did not prevent metastasis to the liver. Although there was a significant increase (p < 0.05) of MIG-6 and Cadherin 13 expression in tumors from γT3-fed animals, there were no significant (p > 0.05) differences in the expression of MIG-6, Cadherin 13, BIRC5, and Serpine1 upon combined feeding. This showed that combined γT3 + Spirulina treatment did not show any synergistic anticancer effects in this study model.
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Affiliation(s)
- Hemavathy Subramaiam
- School of Medicine, International Medical University, Kuala Lumpur 57000, Malaysia
| | - Wan-Loy Chu
- School of Postgraduate Studies, International Medical University, Kuala Lumpur 57000, Malaysia
| | - Ammu Kutty Radhakrishnan
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway 47500, Malaysia
| | - Srikumar Chakravarthi
- Faculty of Medicine, Bioscience and Nursing, MAHSA University, Bandar Saujana Putra 42610, Malaysia
| | - Kanga Rani Selvaduray
- Product Development and Advisory Services Division, Malaysian Palm Oil Board, Bandar Baru Bangi 43000, Malaysia
| | - Yih-Yih Kok
- School of Health Sciences, International Medical University, Kuala Lumpur 57000, Malaysia
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RNA-Seq-Based Breast Cancer Subtypes Classification Using Machine Learning Approaches. COMPUTATIONAL INTELLIGENCE AND NEUROSCIENCE 2020; 2020:4737969. [PMID: 33178256 PMCID: PMC7644310 DOI: 10.1155/2020/4737969] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 05/31/2020] [Accepted: 10/09/2020] [Indexed: 12/20/2022]
Abstract
Background Breast invasive carcinoma (BRCA) is not a single disease as each subtype has a distinct morphology structure. Although several computational methods have been proposed to conduct breast cancer subtype identification, the specific interaction mechanisms of genes involved in the subtypes are still incomplete. To identify and explore the corresponding interaction mechanisms of genes for each subtype of breast cancer can impose an important impact on the personalized treatment for different patients. Methods We integrate the biological importance of genes from the gene regulatory networks to the differential expression analysis and then obtain the weighted differentially expressed genes (weighted DEGs). A gene with a high weight means it regulates more target genes and thus holds more biological importance. Besides, we constructed gene coexpression networks for control and experiment groups, and the significantly differentially interacting structures encouraged us to design the corresponding Gene Ontology (GO) enrichment based on gene coexpression networks (GOEGCN). The GOEGCN considers the two-side distinction analysis between gene coexpression networks for control and experiment groups. The method allows us to study how the modulated coexpressed gene couples impact biological functions at a GO level. Results We modeled the binary classification with weighted DEGs for each subtype. The binary classifier could make a good prediction for an unseen sample, and the experimental results validated the effectiveness of our proposed approaches. The novel enriched GO terms based on GOEGCN for control and experiment groups of each subtype explain the specific biological function changes according to the two-side distinction of coexpression network structures to some extent. Conclusion The weighted DEGs contain biological importance derived from the gene regulatory network. Based on the weighted DEGs, five binary classifiers were learned and showed good performance concerning the “Sensitivity,” “Specificity,” “Accuracy,” “F1,” and “AUC” metrics. The GOEGCN with weighted DEGs for control and experiment groups presented a novel GO enrichment analysis results and the novel enriched GO terms would further unveil the changes of specific biological functions among all the BRCA subtypes to some extent. The R code in this research is available at https://github.com/yxchspring/GOEGCN_BRCA_Subtypes.
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Rahmawati Y, Setyawati Y, Widodo I, Ghozali A, Purnomosari D. Molecular Subtypes of Indonesian Breast Carcinomas - Lack of Association with Patient Age and Tumor Size. Asian Pac J Cancer Prev 2018; 19:161-166. [PMID: 29373908 PMCID: PMC5844611 DOI: 10.22034/apjcp.2018.19.1.161] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/09/2017] [Indexed: 01/16/2023] Open
Abstract
Objective: Breast carcinoma (BC) is a heterogeneous disease that exhibits variation in biological behaviour, prognosis and response to therapy. Molecular classification is generally into Luminal A, Luminal B, HER2+ and triple negative/basal-like, depending on receptor characteristics. Clinical factors that determined the BC prognosis are age and tumor size. Since information on molecular subtypes of Indonesian BCs is limited, the present study was conducted, with attention to subtypes in relation to age and tumor size. Methods: A retrospective cross-sectional study of 247 paraffin-embedded samples of invasive BC from Dr. Sardjito General Hospital Yogyakarta in the year 2012- 2015 was performed. Immunohistochemical staining using anti- ER, PR, HER2, Ki-67 and CK 5/6 antibodies was applied to classify molecular subtypes. Associations with age and tumor size were analyzed using the Chi Square Test. Results: The Luminal A was the most common subtype of Indonesian BC (41.3%), followed by triple negative (25.5%), HER2 (19.4%) and luminal B (13.8%). Among the triple negative lesions, the basal-like subtype was more frequent than the non basal-like (58.8 % vs 41.2%). Luminal B accounted for the highest percentage of younger age cases (< 40 years old) while HER2+ was most common in older age (> 50 years old) patients. Triple negative/basal-like were commonly large in size. Age (p = 0.080) and tumor size (p = 0.462) were not significantly associated with molecular subtypes of BC. Conclusion: The most common molecular subtype of Indonesian BC is luminal A, followed by triple-negative, HER2+ and luminal B. The majority of triple-negative lesions are basal-like. There are no association between age and tumor size with molecular subtypes of Indonesian BCs.
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Affiliation(s)
- Yeni Rahmawati
- Department of Histology and Cell Biology, Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia.
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Angahar LT. An Overview of Breast Cancer Epidemiology, Risk Factors, Pathophysiology, and Cancer Risks Reduction. ACTA ACUST UNITED AC 2017. [DOI: 10.15406/mojbm.2017.01.00019] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Bernhardt SM, Dasari P, Walsh D, Townsend AR, Price TJ, Ingman WV. Hormonal Modulation of Breast Cancer Gene Expression: Implications for Intrinsic Subtyping in Premenopausal Women. Front Oncol 2016; 6:241. [PMID: 27896218 PMCID: PMC5107819 DOI: 10.3389/fonc.2016.00241] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Accepted: 10/27/2016] [Indexed: 12/12/2022] Open
Abstract
Clinics are increasingly adopting gene-expression profiling to diagnose breast cancer subtype, providing an intrinsic, molecular portrait of the tumor. For example, the PAM50-based Prosigna test quantifies expression of 50 key genes to classify breast cancer subtype, and this method of classification has been demonstrated to be superior over traditional immunohistochemical methods that detect proteins, to predict risk of disease recurrence. However, these tests were largely developed and validated using breast cancer samples from postmenopausal women. Thus, the accuracy of such tests has not been explored in the context of the hormonal fluctuations in estrogen and progesterone that occur during the menstrual cycle in premenopausal women. Concordance between traditional methods of subtyping and the new tests in premenopausal women is likely to depend on the stage of the menstrual cycle at which the tissue sample is taken and the relative effect of hormones on expression of genes versus proteins. The lack of knowledge around the effect of fluctuating estrogen and progesterone on gene expression in breast cancer patients raises serious concerns for intrinsic subtyping in premenopausal women, which comprise about 25% of breast cancer diagnoses. Further research on the impact of the menstrual cycle on intrinsic breast cancer profiling is required if premenopausal women are to benefit from the new technology of intrinsic subtyping.
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Affiliation(s)
- Sarah M Bernhardt
- Discipline of Surgery, School of Medicine, The Queen Elizabeth Hospital, University of Adelaide, Woodville, SA, Australia; The Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia
| | - Pallave Dasari
- Discipline of Surgery, School of Medicine, The Queen Elizabeth Hospital, University of Adelaide, Woodville, SA, Australia; The Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia
| | - David Walsh
- Discipline of Surgery, School of Medicine, The Queen Elizabeth Hospital, University of Adelaide , Woodville, SA , Australia
| | - Amanda R Townsend
- Discipline of Surgery, School of Medicine, The Queen Elizabeth Hospital, University of Adelaide, Woodville, SA, Australia; Department of Medical Oncology, The Queen Elizabeth Hospital, Woodville, SA, Australia
| | - Timothy J Price
- Discipline of Surgery, School of Medicine, The Queen Elizabeth Hospital, University of Adelaide, Woodville, SA, Australia; Department of Medical Oncology, The Queen Elizabeth Hospital, Woodville, SA, Australia
| | - Wendy V Ingman
- Discipline of Surgery, School of Medicine, The Queen Elizabeth Hospital, University of Adelaide, Woodville, SA, Australia; The Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia
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13
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Shenker NS, Flower KJ, Wilhelm-Benartzi CS, Dai W, Bell E, Gore E, El Bahrawy M, Weaver G, Brown R, Flanagan JM. Transcriptional implications of intragenic DNA methylation in the oestrogen receptor alpha gene in breast cancer cells and tissues. BMC Cancer 2015; 15:337. [PMID: 25927974 PMCID: PMC4424887 DOI: 10.1186/s12885-015-1335-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Accepted: 04/22/2015] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND DNA methylation variability regions (MVRs) across the oestrogen receptor alpha (ESR1) gene have been identified in peripheral blood cells from breast cancer patients and healthy individuals. In contrast to promoter methylation, gene body methylation may be important in maintaining active transcription. This study aimed to assess MVRs in ESR1 in breast cancer cell lines, tumour biopsies and exfoliated epithelial cells from expressed breast milk (EBM), to determine their significance for ESR1 transcription. METHODS DNA methylation levels in eight MVRs across ESR1 were assessed by pyrosequencing bisulphite-converted DNA from three oestrogen receptor (ER)-positive and three ER-negative breast cancer cell lines. DNA methylation and expression were assessed following treatment with DAC (1 μM), or DMSO (controls). ESR1 methylation levels were also assayed in DNA from 155 invasive ductal carcinoma biopsies provided by the Breast Cancer Campaign Tissue Bank, and validated with DNA methylation profiles from the TCGA breast tumours (n = 356 ER-pos, n = 109 ER-neg). DNA methylation was profiled in exfoliated breast epithelial cells from EBM using the Illumina 450 K (n = 36) and pyrosequencing in a further 53 donor samples. ESR1 mRNA levels were measured by qRT-PCR. RESULTS We show that ER-positive cell lines had unmethylated ESR1 promoter regions and highly methylated intragenic regions (median, 80.45%) while ER-negative cells had methylated promoters and lower intragenic methylation levels (median, 38.62%). DAC treatment increased ESR1 expression in ER-negative cells, but significantly reduced methylation and expression of ESR1 in ER-positive cells. The ESR1 promoter was unmethylated in breast tumour biopsies with high levels of intragenic methylation, independent of ER status. However, ESR1 methylation in the strongly ER-positive EBM DNA samples were very similar to ER-positive tumour cell lines. CONCLUSION DAC treatment inhibited ESR1 transcription in cells with an unmethylated ESR1 promoter and reduced intragenic DNA methylation. Intragenic methylation levels correlated with ESR1 expression in homogenous cell populations (cell lines and exfoliated primary breast epithelial cells), but not in heterogeneous tumour biopsies, highlighting the significant differences between the in vivo tumour microenvironment and individual homogenous cell types. These findings emphasise the need for care when choosing material for epigenetic research and highlights the presence of aberrant intragenic methylation levels in tumour tissue.
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MESH Headings
- Breast Neoplasms/genetics
- Breast Neoplasms/metabolism
- Carcinoma, Ductal, Breast/genetics
- Carcinoma, Ductal, Breast/metabolism
- Cell Line, Tumor
- DNA Methylation
- Epigenesis, Genetic
- Estrogen Receptor alpha/genetics
- Estrogen Receptor alpha/metabolism
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Mammary Glands, Human/metabolism
- Milk, Human/cytology
- Promoter Regions, Genetic
- Sequence Analysis, DNA
- Transcription, Genetic
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Affiliation(s)
- Natalie S Shenker
- Department of Surgery and Cancer, Epigenetics Unit, Division of Cancer, Faculty of Medicine, Imperial College London, 4th Floor IRDB, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK.
| | - Kirsty J Flower
- Department of Surgery and Cancer, Epigenetics Unit, Division of Cancer, Faculty of Medicine, Imperial College London, 4th Floor IRDB, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK.
| | - Charlotte S Wilhelm-Benartzi
- Department of Surgery and Cancer, Epigenetics Unit, Division of Cancer, Faculty of Medicine, Imperial College London, 4th Floor IRDB, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK.
| | - Wei Dai
- Department of Surgery and Cancer, Epigenetics Unit, Division of Cancer, Faculty of Medicine, Imperial College London, 4th Floor IRDB, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK.
- Current Address: The University of Hong Kong, Pokfulam, Hong Kong, P. R. China.
| | - Emma Bell
- Department of Surgery and Cancer, Epigenetics Unit, Division of Cancer, Faculty of Medicine, Imperial College London, 4th Floor IRDB, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK.
| | - Edmund Gore
- Department of Surgery and Cancer, Epigenetics Unit, Division of Cancer, Faculty of Medicine, Imperial College London, 4th Floor IRDB, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK.
| | - Mona El Bahrawy
- Department of Surgery and Cancer, Epigenetics Unit, Division of Cancer, Faculty of Medicine, Imperial College London, 4th Floor IRDB, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK.
| | - Gillian Weaver
- Queen Charlotte and Chelsea Hospital Milk Bank, Du Cane Road, London, UK.
| | - Robert Brown
- Department of Surgery and Cancer, Epigenetics Unit, Division of Cancer, Faculty of Medicine, Imperial College London, 4th Floor IRDB, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK.
| | - James M Flanagan
- Department of Surgery and Cancer, Epigenetics Unit, Division of Cancer, Faculty of Medicine, Imperial College London, 4th Floor IRDB, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK.
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14
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Vellakkaran M, Lingayya R, Naveen Kumar B, Nagaiah K, Poornachandra Y, Ganesh Kumar C. Palladium(0)-catalyzed direct C–H hetero-arylation of 2-arylimidazo [1,2-a]pyridines with (E)-1-(5-bromothiophen-2-yl)-3-arylprop-2-en-1-ones and their anticancer activity. RSC Adv 2015. [DOI: 10.1039/c5ra15078g] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
An efficient palladium(0)-catalyzed direct hetero-arylation of imidazo[1,2-a]pyridines at the C-3 position of the imidazole ring has been described.
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Affiliation(s)
- Mari Vellakkaran
- Organic and Biomolecular Chemistry Division
- CSIR-Indian Institute of Chemical Technology
- Hyderabad 500 007
- India
| | - Rajaka Lingayya
- Organic and Biomolecular Chemistry Division
- CSIR-Indian Institute of Chemical Technology
- Hyderabad 500 007
- India
- Academy of Scientific and Innovative Research (AcSIR)
| | - Bejjanki Naveen Kumar
- Organic and Biomolecular Chemistry Division
- CSIR-Indian Institute of Chemical Technology
- Hyderabad 500 007
- India
| | - Kommu Nagaiah
- Organic and Biomolecular Chemistry Division
- CSIR-Indian Institute of Chemical Technology
- Hyderabad 500 007
- India
- Academy of Scientific and Innovative Research (AcSIR)
| | - Y. Poornachandra
- Medicinal Chemistry and Pharmacology Division
- CSIR-Indian Institute of Chemical Technology
- Hyderabad 500 007
- India
| | - C. Ganesh Kumar
- Medicinal Chemistry and Pharmacology Division
- CSIR-Indian Institute of Chemical Technology
- Hyderabad 500 007
- India
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15
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Neural networks and Fuzzy clustering methods for assessing the efficacy of microarray based intrinsic gene signatures in breast cancer classification and the character and relations of identified subtypes. Methods Mol Biol 2014. [PMID: 25502389 DOI: 10.1007/978-1-4939-2239-0_18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register]
Abstract
In the classification of breast cancer subtypes using microarray data, hierarchical clustering is commonly used. Although this form of clustering shows basic cluster patterns, more needs to be done to investigate the accuracy of clusters as well as to extract meaningful cluster characteristics and their relations to increase our confidence in their use in a clinical setting. In this study, an in-depth investigation of the efficacy of three reported gene subsets in distinguishing breast cancer subtypes was performed using four advanced computational intelligence methods-Self-Organizing Maps (SOM), Emergent Self-Organizing Maps (ESOM), Fuzzy Clustering by Local Approximation of Memberships (FLAME), and Fuzzy C-means (FCM)-each differing in the way they view data in terms of distance measures and fuzzy or crisp clustering. The gene subsets consisted of 71, 93, and 71 genes reported in the literature from three comprehensive experimental studies for distinguishing Luminal (A and B), Basal, Normal breast-like, and HER2 subtypes. Given the costly procedures involved in clinical studies, the proposed 93-gene set can be used for preliminary classification of breast cancer. Then, as a decision aid, SOM can be used to map the gene signature of a new patient to locate them with respect to all subtypes to get a comprehensive view of the classification. These can be followed by a deeper investigation in the light of the observations made in this study regarding overlapping subtypes. Results from the study could be used as the base for further refining the gene signatures from later experiments and from new experiments designed to separate overlapping clusters as well as to maximally separate all clusters.
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16
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Yersal O, Barutca S. Biological subtypes of breast cancer: Prognostic and therapeutic implications. World J Clin Oncol 2014; 5:412-424. [PMID: 25114856 PMCID: PMC4127612 DOI: 10.5306/wjco.v5.i3.412] [Citation(s) in RCA: 695] [Impact Index Per Article: 63.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2013] [Revised: 03/11/2014] [Accepted: 05/16/2014] [Indexed: 02/06/2023] Open
Abstract
Breast cancer is a heterogeneous complex of diseases, a spectrum of many subtypes with distinct biological features that lead to differences in response patterns to various treatment modalities and clinical outcomes. Traditional classification systems regarding biological characteristics may have limitations for patient-tailored treatment strategies. Tumors with similar clinical and pathological presentations may have different behaviors. Analyses of breast cancer with new molecular techniques now hold promise for the development of more accurate tests for the prediction of recurrence. Gene signatures have been developed as predictors of response to therapy and protein gene products that have direct roles in driving the biology and clinical behavior of cancer cells are potential targets for the development of novel therapeutics. The present review summarizes current knowledge in breast cancer molecular biology, focusing on novel prognostic and predictive factors.
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17
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Jørgensen CLT, Nielsen TO, Bjerre KD, Liu S, Wallden B, Balslev E, Nielsen DL, Ejlertsen B. PAM50 breast cancer intrinsic subtypes and effect of gemcitabine in advanced breast cancer patients. Acta Oncol 2014; 53:776-87. [PMID: 24359601 DOI: 10.3109/0284186x.2013.865076] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND In vitro studies suggest basal breast cancers are more sensitive to gemcitabine relative to other intrinsic subtypes. The main objective of this study was to use specimens from a randomized clinical trial to evaluate whether the basal-like subtype identifies patients with advanced breast cancer who benefit from gemcitabine plus docetaxel (GD) compared to single agent docetaxel (D). MATERIAL AND METHODS From patients randomly assigned to GD or D, RNA was isolated from archival formalin-fixed, paraffin-embedded primary breast tumor tissue and used for PAM50 intrinsic subtyping by NanoString nCounter. Statistical analyses were prespecified as a formal prospective-retrospective clinical trial correlative study. Using time to progression (TTP) as primary endpoint, overall survival (OS) and response rate as secondary endpoints, relationships between subtypes and outcome after chemotherapy were analyzed by the Kaplan-Meier method, and Cox proportional hazards regression models. Data analysis was performed independently by the Danish Breast Cancer Cooperative Group (DBCG) statistical core and all statistical tests were two-sided. RESULTS RNA from 270 patients was evaluable; 84 patients (31%) were classified as luminal A, 97 (36%) luminal B, 43 (16%) basal-like, and 46 (17%) as HER2-enriched. PAM50 intrinsic subtype was a significant independent prognostic factor for both TTP (p=0.014) and OS (p=0.0003). Response rate was not different by subtype, and PAM50 was not a predictor of TTP by treatment arm. PAM50 was however a highly significant predictor of OS following GD compared to D (pinteraction=0.0016). Patients with a basal-like subtype had a significant reduction in OS events [hazard ratio (HR)=0.29, 95% confidence interval (CI)=0.15-0.57; pinteraction=0.0006]. CONCLUSION A significantly improved and clinically important prolongation of survival was seen from the addition of gemcitabine to docetaxel in advanced basal-like breast cancer patients.
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18
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Shamir ER, Pappalardo E, Jorgens DM, Coutinho K, Tsai WT, Aziz K, Auer M, Tran PT, Bader JS, Ewald AJ. Twist1-induced dissemination preserves epithelial identity and requires E-cadherin. J Cell Biol 2014; 204:839-56. [PMID: 24590176 PMCID: PMC3941052 DOI: 10.1083/jcb.201306088] [Citation(s) in RCA: 155] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2013] [Accepted: 01/27/2014] [Indexed: 01/06/2023] Open
Abstract
Dissemination of epithelial cells is a critical step in metastatic spread. Molecular models of dissemination focus on loss of E-cadherin or repression of cell adhesion through an epithelial to mesenchymal transition (EMT). We sought to define the minimum molecular events necessary to induce dissemination of cells out of primary murine mammary epithelium. Deletion of E-cadherin disrupted epithelial architecture and morphogenesis but only rarely resulted in dissemination. In contrast, expression of the EMT transcription factor Twist1 induced rapid dissemination of cytokeratin-positive epithelial cells. Twist1 induced dramatic transcriptional changes in extracellular compartment and cell-matrix adhesion genes but not in cell-cell adhesion genes. Surprisingly, we observed disseminating cells with membrane-localized E-cadherin and β-catenin, and E-cadherin knockdown strongly inhibited Twist1-induced single cell dissemination. Dissemination can therefore occur with retention of epithelial cell identity. The spread of cancer cells during metastasis could similarly involve activation of an epithelial motility program without requiring a transition from epithelial to mesenchymal character.
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Affiliation(s)
- Eliah R. Shamir
- Department of Cell Biology and Department of Oncology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, MD 21205
| | - Elisa Pappalardo
- Department of Biomedical Engineering, High-Throughput Biology Center, Johns Hopkins University, Baltimore, MD 21218
| | - Danielle M. Jorgens
- Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720
| | - Kester Coutinho
- Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720
| | - Wen-Ting Tsai
- Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720
| | - Khaled Aziz
- Department of Radiation Oncology and Department of Molecular Radiation Sciences, Oncology, and Urology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231
| | - Manfred Auer
- Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720
| | - Phuoc T. Tran
- Department of Radiation Oncology and Department of Molecular Radiation Sciences, Oncology, and Urology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231
| | - Joel S. Bader
- Department of Biomedical Engineering, High-Throughput Biology Center, Johns Hopkins University, Baltimore, MD 21218
| | - Andrew J. Ewald
- Department of Cell Biology and Department of Oncology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, MD 21205
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19
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Soung YH, Pruitt K, Chung J. Epigenetic silencing of ARRDC3 expression in basal-like breast cancer cells. Sci Rep 2014; 4:3846. [PMID: 24457910 PMCID: PMC3900932 DOI: 10.1038/srep03846] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Accepted: 12/27/2013] [Indexed: 12/13/2022] Open
Abstract
Arrestin domain-containing 3 (ARRDC3) is a tumor suppressor whose expression is either lost or suppressed in basal-like breast cancer (BLBC). However, the mechanism by which BLBC suppresses ARRDC3 expression is not established. Here, we show that expression of ARRDC3 in BLBC cells is suppressed at the transcriptional level. Suppression of ARRDC3 expression in BLBC cells involves epigenetic silencing as inhibitors of class III histone deacetylases (HDACs) significantly restores ARRDC3 levels in BLBC cells. SIRT2, among class III HDACs, plays a major role in epigenetic silencing of ARRDC3 in MDA-MB-231 cells. Acetylation levels of the ARRDC3 promoter in BLBC cells is significantly lower than that of other sub-types of BC cells. Chromatin immunopreciptitation analysis established SIRT2 binding at ARRDC3 promoter in BLBC cells. Our studies indicate that SIRT2 dependent epigenetic silencing of ARRDC3 is one of the important events that may contribute to the aggressive nature of BLBC cells.
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Affiliation(s)
- Young Hwa Soung
- Department of Physiology and Stephenson cancer center, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104
| | - Kevin Pruitt
- Department of Molecular and Cellular Physiology Louisiana State University Health Science Center Shreveport, Louisiana 71130
| | - Jun Chung
- Department of Physiology and Stephenson cancer center, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104
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20
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Won JR, Gao D, Chow C, Cheng J, Lau SYH, Ellis MJ, Perou CM, Bernard PS, Nielsen TO. A survey of immunohistochemical biomarkers for basal-like breast cancer against a gene expression profile gold standard. Mod Pathol 2013; 26:1438-50. [PMID: 23702728 DOI: 10.1038/modpathol.2013.97] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2013] [Revised: 05/01/2013] [Accepted: 05/02/2013] [Indexed: 12/16/2022]
Abstract
Gene expression profiling of breast cancer delineates a particularly aggressive subtype referred to as 'basal-like', which comprises ∼15% of all breast cancers, afflicts younger women and is refractory to endocrine and anti-HER2 therapies. Immunohistochemical surrogate definitions for basal-like breast cancer, such as the clinical ER/PR/HER2 triple-negative phenotype and models incorporating positive expression for CK5 (CK5/6) and/or EGFR are heavily cited. However, many additional biomarkers for basal-like breast cancer have been described in the literature. A parallel comparison of 46 proposed immunohistochemical biomarkers of basal-like breast cancer was performed against a gene expression profile gold standard on a tissue microarray containing 42 basal-like and 80 non-basal-like breast cancer cases. Ki67 and PPH3 were the most sensitive biomarkers (both 92%) positively expressed in the basal-like subtype, whereas CK14, IMP3 and NGFR were the most specific (100%). Among biomarkers surveyed, loss of INPP4B (a negative regulator of phosphatidylinositol signaling) was 61% sensitive and 99% specific with the highest odds ratio (OR) at 108, indicating the strongest association with basal-like breast cancer. Expression of nestin, a common marker of neural progenitor cells that is also associated with the triple-negative/basal-like phenotype and poor breast cancer prognosis, possessed the second highest OR at 29 among the 46 biomarkers surveyed, as well as 54% sensitivity and 96% specificity. As a positively expressed biomarker, nestin possesses technical advantages over INPP4B that make it a more ideal biomarker for identification of basal-like breast cancer. The comprehensive immunohistochemical biomarker survey presented in this study is a necessary step for determining an optimized surrogate immunopanel that best defines basal-like breast cancer in a practical and clinically accessible way.
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Affiliation(s)
- Jennifer R Won
- 1] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada [2] Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, British Columbia, Canada
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O'Brien K, Rani S, Corcoran C, Wallace R, Hughes L, Friel AM, McDonnell S, Crown J, Radomski MW, O'Driscoll L. Exosomes from triple-negative breast cancer cells can transfer phenotypic traits representing their cells of origin to secondary cells. Eur J Cancer 2013; 49:1845-59. [PMID: 23453937 DOI: 10.1016/j.ejca.2013.01.017] [Citation(s) in RCA: 179] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2012] [Revised: 01/04/2013] [Accepted: 01/18/2013] [Indexed: 12/22/2022]
Abstract
BACKGROUND Triple-negative breast cancer (TNBC) accounts for 15-20% of breast cancers but is responsible for a disproportionate number of deaths. We investigated the relevance, in TNBC, of nano-sized exosomes expelled from cells. Specifically, we compared effects of exosomes derived from the claudin-low TNBC cell line Hs578T and its more invasive Hs578Ts(i)8 variant, as well as exosomes from TNBC patient sera compared to normal sera. METHODS Exosomes were isolated from conditioned media (CM) of Hs578T and Hs578Ts(i)8 cells and from sera by filtration and ultracentrifugation. Successful isolation was confirmed by transmission electron microscopy and immunoblotting. Subsequent analysis, of secondary/recipient cells in response to exosomes, included proliferation; motility/migration; invasion; anoikis assays and endothelial tubule formation assays. RESULTS Hs578Ts(i)8-exosomes versus Hs578T-exosomes significantly increased the proliferation, migration and invasion capacity of all three recipient cell lines evaluated i.e. SKBR3, MDA-MB-231 and HCC1954. Exosomes from Hs578Ts(i)8 cells also conferred increased invasiveness to parent Hs578T cells. Hs578Ts(i)8-exosomes increased sensitivity of SKBR3, MDA-MB-231 and HCC1954 to anoikis when compared to the effects of Hs578T-exosomes reflecting the fact that Hs578Ts(i)8 cells are themselves innately more sensitive to anoikis. In relation to vasculogenesis and subsequent angiogenesis, Hs578Ts(i)8-exosomes versus Hs578T-exosomes stimulated significantly more endothelial tubules formation. Finally, our pilot translational study showed that exosomes from TNBC patients' sera significantly increased recipient cells' invasion when compared to those derived from age- and gender-matched healthy control sera. CONCLUSION This study supports the hypothesis that TNBC exosomes may be involved in cancer cell-to-cell communication, conferring phenotypic traits to secondary cells that reflect those of their cells of origin.
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Affiliation(s)
- Keith O'Brien
- School of Pharmacy and Pharmaceutical Sciences & Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
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22
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Lindqvist BM, Farkas SA, Wingren S, Nilsson TK. DNA methylation pattern of the SLC25A43 gene in breast cancer. Epigenetics 2012; 7:300-6. [PMID: 22430806 DOI: 10.4161/epi.7.3.19064] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Solute carrier family 25A member 43 (SLC25A43) gene is a putative tumor suppressor gene that undergoes loss of heterozygosity (LOH) in human epidermal growth factor receptor 2 (HER2) positive breast cancer. Also, knockdown of SLC25A43 in cell lines influences cell turnover and metabolism. Absence of mutations in this gene in breast cancers prompted us to study methylation as an alternate mechanism for gene inactivation of this X encoded gene. Quantification of CpG site methylation using pyrosequencing was performed upstream of the SLC25A43 gene and at its 5' end in a cohort of breast tumor tissues (n = 80, HER2 positive or negative) with different SLC25A43 gene deletion status. Compared with control tissue, cancer tissues had lower levels of methylation at the 5' and 3' shores of the gene. Cancer tissues with no deletion in the SLC25A43 gene (Del (-)) had higher methylation in the CpG island (CGI) of the gene than cancers carrying the deletion (Del (+)). Methylation in the CGI of the SLC25A43 gene was negatively correlated with age at diagnosis. In HER2 positive breast cancer, ER negativity and lymph node positivity was associated with higher methylation in the CGI and in the adjacent shores of this gene. Our results suggest that methylation in the CGI of the SLC25A43 gene could be an alternate mechanism of gene silencing in the absence of LOH. Also, associations between site-specific methylation and clinicopathological parameters suggest that epigenetic changes in SLC25A43 gene could be of importance in breast carcinogenesis.
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23
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Jeschke J, Van Neste L, Glöckner SC, Dhir M, Calmon MF, Deregowski V, Van Criekinge W, Vlassenbroeck I, Koch A, Chan TA, Cope L, Hooker CM, Schuebel KE, Gabrielson E, Winterpacht A, Baylin SB, Herman JG, Ahuja N. Biomarkers for detection and prognosis of breast cancer identified by a functional hypermethylome screen. Epigenetics 2012; 7:701-9. [PMID: 22647880 DOI: 10.4161/epi.20445] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Breast cancer (BC) is a disease with diverse tumor heterogeneity, which challenges conventional approaches to develop biomarkers for early detection and prognosis. To identify effective biomarkers, we performed a genome-wide screen for functional methylation changes in BC, i.e., genes silenced by promoter hypermethylation, using a functionally proven gene expression approach. A subset of candidate hypermethylated genes were validated in primary BCs and tested as markers for detection and prognosis prediction of BC. We identified 33 cancer specific methylated genes and, among these, two categories of genes: (1) highly frequent methylated genes that detect early stages of BC. Within that category, we have identified the combination of NDRG2 and HOXD1 as the most sensitive (94%) and specific (90%) gene combination for detection of BC; (2) genes that show stage dependent methylation frequency pattern, which are candidates to help delineate BC prognostic signatures. For this category, we found that methylation of CDO1, CKM, CRIP1, KL and TAC1 correlated with clinical prognostic variables and was a significant prognosticator for poor overall survival in BC patients. CKM [Hazard ratio (HR) = 2.68] and TAC1 (HR = 7.73) were the strongest single markers and the combination of both (TAC1 and CKM) was associated with poor overall survival independent of age and stage in our training (HR = 1.92) and validation cohort (HR = 2.87). Our study demonstrates an efficient method to utilize functional methylation changes in BC for the development of effective biomarkers for detection and prognosis prediction of BC.
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Affiliation(s)
- Jana Jeschke
- Department of Surgery, Johns Hopkins University, Baltimore, MD, USA
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Pan J, Sun LC, Tao YF, Zhou Z, Du XL, Peng L, Feng X, Wang J, Li YP, Liu L, Wu SY, Zhang YL, Hu SY, Zhao WL, Zhu XM, Lou GL, Ni J. ATP synthase ecto-α-subunit: a novel therapeutic target for breast cancer. J Transl Med 2011; 9:211. [PMID: 22152132 PMCID: PMC3254596 DOI: 10.1186/1479-5876-9-211] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2011] [Accepted: 12/08/2011] [Indexed: 11/10/2022] Open
Abstract
Background Treatment failure for breast cancer is frequently due to lymph node metastasis and invasion to neighboring organs. The aim of the present study was to investigate invasion- and metastasis-related genes in breast cancer cells in vitro and in vivo. Identification of new targets will facilitate the developmental pace of new techniques in screening and early diagnosis. Improved abilities to predict progression and metastasis, therapeutic response and toxicity will help to increase survival of breast cancer patients. Methods Differential protein expression in two breast cancer cell lines, one with high and the other with low metastatic potential, was analyzed using two-dimensional liquid phase chromatographic fractionation (Proteome Lab PF 2D system) followed by matrix-assisted laser desorption/time-of-flight mass spectrometry (MALDI-TOF/MS). Results Up regulation of α-subunit of ATP synthase was identified in high metastatic cells compared with low metastatic cells. Immunohistochemical analysis of 168 human breast cancer specimens on tissue microarrays revealed a high frequency of ATP synthase α-subunit expression in breast cancer (94.6%) compared to normal (21.2%) and atypical hyperplasia (23%) breast tissues. Levels of ATP synthase expression levels strongly correlated with large tumor size, poor tumor differentiation and advanced tumor stages (P < 0.05). ATP synthase α-subunit over-expression was detected on the surface of a highly invasive breast cancer cell line. An antibody against the ATP synthase α-subunit inhibited proliferation, migration and invasion in these breast cancer cells but not that of a non-tumor derived breast cell line. Conclusions Over-expression of ATP synthase α-subunit may be involved in the progression and metastasis of breast cancer, perhaps representing a potential biomarker for diagnosis, prognosis and a therapeutic target for breast cancer. This finding of this study will help us to better understand the molecular mechanism of tumor metastasis and to improve the screening, diagnosis, as well as prognosis and/or prediction of responses to therapy for breast cancer.
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Affiliation(s)
- Jian Pan
- Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou 215003, China
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25
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Cerne JZ, Ferk P, Frkovic-Grazio S, Leskosek B, Gersak K. Risk factors for HR- and HER2-defined breast cancer in Slovenian postmenopausal women. Climacteric 2011; 15:68-74. [DOI: 10.3109/13697137.2011.609286] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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26
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Tumor grafts derived from women with breast cancer authentically reflect tumor pathology, growth, metastasis and disease outcomes. Nat Med 2011; 17:1514-20. [PMID: 22019887 DOI: 10.1038/nm.2454] [Citation(s) in RCA: 766] [Impact Index Per Article: 54.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2011] [Accepted: 07/27/2011] [Indexed: 11/09/2022]
Abstract
Development and preclinical testing of new cancer therapies is limited by the scarcity of in vivo models that authentically reproduce tumor growth and metastatic progression. We report new models for breast tumor growth and metastasis in the form of transplantable tumors derived directly from individuals undergoing treatment for breast cancer. These tumor grafts illustrate the diversity of human breast cancer and maintain essential features of the original tumors, including metastasis to specific sites. Co-engraftment of primary human mesenchymal stem cells maintains phenotypic stability of the grafts and increases tumor growth by promoting angiogenesis. We also report that tumor engraftment is a prognostic indicator of disease outcome for women with newly diagnosed breast cancer; orthotopic breast tumor grafting is a step toward individualized models for tumor growth, metastasis and prognosis. This bank of tumor grafts also serves as a publicly available resource for new models in which to study the biology of breast cancer.
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27
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Millar EKA, Graham PH, McNeil CM, Browne L, O'Toole SA, Boulghourjian A, Kearsley JH, Papadatos G, Delaney G, Fox C, Nasser E, Capp A, Sutherland RL. Prediction of outcome of early ER+ breast cancer is improved using a biomarker panel, which includes Ki-67 and p53. Br J Cancer 2011; 105:272-80. [PMID: 21712826 PMCID: PMC3142808 DOI: 10.1038/bjc.2011.228] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2011] [Revised: 05/20/2011] [Accepted: 05/25/2011] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND The aim of this study is to determine whether immunohistochemical (IHC) assessment of Ki67 and p53 improves prognostication of oestrogen receptor-positive (ER+) breast cancer after breast-conserving therapy (BCT). In all, 498 patients with invasive breast cancer from a randomised trial of BCT with or without tumour bed radiation boost were assessed using IHC. METHODS The ER+ tumours were classified as 'luminal A' (LA): ER+ and/or PR+, Ki-67 low, p53-, HER2- or 'luminal B' (LB): ER+ and/or PR+and/or Ki-67 high and/or p53+ and/or HER2+. Kaplan-Meier and Cox proportional hazards methodology were used to ascertain relationships to ispilateral breast tumour recurrence (IBTR), locoregional recurrence (LRR), distant metastasis-free survival (DMFS) and breast cancer-specific survival (BCSS). RESULTS In all, 73 patients previously LA were re-classified as LB: a greater than four-fold increase (4.6-19.3%) compared with ER, PR, HER2 alone. In multivariate analysis, the LB signature independently predicted LRR (hazard ratio (HR) 3.612, 95% CI 1.555-8.340, P=0.003), DMFS (HR 3.023, 95% CI 1.501-6.087, P=0.002) and BCSS (HR 3.617, 95% CI 1.629-8.031, P=0.002) but not IBTR. CONCLUSION The prognostic evaluation of ER+ breast cancer is improved using a marker panel, which includes Ki-67 and p53. This may help better define a group of poor prognosis ER+ patients with a greater probability of failure with endocrine therapy.
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Affiliation(s)
- E K A Millar
- Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia.
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Hood L, Friend SH. Predictive, personalized, preventive, participatory (P4) cancer medicine. Nat Rev Clin Oncol 2011; 8:184-7. [PMID: 21364692 DOI: 10.1038/nrclinonc.2010.227] [Citation(s) in RCA: 448] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Medicine will move from a reactive to a proactive discipline over the next decade--a discipline that is predictive, personalized, preventive and participatory (P4). P4 medicine will be fueled by systems approaches to disease, emerging technologies and analytical tools. There will be two major challenges to achieving P4 medicine--technical and societal barriers--and the societal barriers will prove the most challenging. How do we bring patients, physicians and members of the health-care community into alignment with the enormous opportunities of P4 medicine? In part, this will be done by the creation of new types of strategic partnerships--between patients, large clinical centers, consortia of clinical centers and patient-advocate groups. For some clinical trials it will necessary to recruit very large numbers of patients--and one powerful approach to this challenge is the crowd-sourced recruitment of patients by bringing large clinical centers together with patient-advocate groups.
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Affiliation(s)
- Leroy Hood
- Institute for Systems Biology, 1441 North 34th Street, Seattle, WA 98103, USA.
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Voss J, Goo YA, Cain K, Woods N, Jarrett M, Smith L, Shulman R, Heitkemper M. Searching for the noninvasive biomarker holy grail: are urine proteomics the answer? Biol Res Nurs 2011; 13:235-42. [PMID: 21586496 DOI: 10.1177/1099800411402056] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Recently, biobehavioral nursing scientists have focused their attention on the search for biomarkers or biological signatures to identify patients at risk for various health problems and poor disease outcomes. In response to the national impetus for biomarker discovery, the measurement of biological fluids and tissues has become increasingly sophisticated. Urine proteomics, in particular, may hold great promise for biobehavioral focused nursing scientists for examination of symptom-and syndrome-related research questions. Urine proteins are easily accessible secreted proteins that provide direct and indirect windows into bodily functions. Advances in proteomics and biomarker discovery provide new opportunities to conduct research studies with banked and fresh urine to benefit diagnosis, prognosis, and evaluation of outcomes in various disease populations. This article provides a review of proteomics and a rationale for utilizing urine proteomics in biobehavioral research. It addresses as well some of the challenges involved in data collection and sample preparation.
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Affiliation(s)
- Joachim Voss
- Department of Biobehavioral Nursing and Health Systems, University of Washington, Seattle, WA, USA
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30
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Affiliation(s)
- Lev M Berstein
- a Laboratory of Oncoendocrinology, N.N. Petrov Research Institute of Oncology, St Petersburg 197758, Russia.
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Rivera P, von Euler H. Molecular Biological Aspects on Canine and Human Mammary Tumors. Vet Pathol 2010; 48:132-46. [DOI: 10.1177/0300985810387939] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- P. Rivera
- Center of Clinical Comparative Oncology C3O, Department of Clinical Sciences, Division of Small Animals, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - H. von Euler
- Center of Clinical Comparative Oncology C3O, Department of Clinical Sciences, Division of Small Animals, Swedish University of Agricultural Sciences, Uppsala, Sweden
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Miller JA, Thompson PA, Hakim IA, Chow HHS, Thomson CA. d-Limonene: a bioactive food component from citrus and evidence for a potential role in breast cancer prevention and treatment. Oncol Rev 2010. [DOI: 10.1007/s12156-010-0066-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
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