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      Deconstructing the molecular portraits of breast cancer

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      Author(s): 1 , 2 , 3 , 1 , 2 , 3 ,
      Publication date (Electronic):
      Journal: Molecular Oncology
      Publisher: John Wiley and Sons Inc.
      Keywords: Breast cancer, Claudin-low, Gene expression, Subtypes, Stem cell

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          Abstract

          Breast cancer is a heterogeneous disease in terms of histology, therapeutic response, dissemination patterns to distant sites, and patient outcomes. Global gene expression analyses using high‐throughput technologies have helped to explain much of this heterogeneity and provided important new classifications of cancer patients. In the last decade, genomic studies have established five breast cancer intrinsic subtypes (Luminal A, Luminal B, HER2‐enriched, Claudin‐low, Basal‐like) and a Normal Breast‐like group. In this review, we dissect the most recent data on this genomic classification of breast cancer with a special focus on the Claudin‐low subtype, which appears enriched for mesenchymal and stem cell features. In addition, we discuss how the combination of standard clinical‐pathological markers with the information provided by these genomic entities might help further understand the biological complexity of this disease, increase the efficacy of current and novel therapies, and ultimately improve outcomes for breast cancer patients.

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          Identification of selective inhibitors of cancer stem cells by high-throughput screening.

          Piyush B Gupta, Tamer Onder, Guozhi Jiang … (2009)
          Screens for agents that specifically kill epithelial cancer stem cells (CSCs) have not been possible due to the rarity of these cells within tumor cell populations and their relative instability in culture. We describe here an approach to screening for agents with epithelial CSC-specific toxicity. We implemented this method in a chemical screen and discovered compounds showing selective toxicity for breast CSCs. One compound, salinomycin, reduces the proportion of CSCs by >100-fold relative to paclitaxel, a commonly used breast cancer chemotherapeutic drug. Treatment of mice with salinomycin inhibits mammary tumor growth in vivo and induces increased epithelial differentiation of tumor cells. In addition, global gene expression analyses show that salinomycin treatment results in the loss of expression of breast CSC genes previously identified by analyses of breast tissues isolated directly from patients. This study demonstrates the ability to identify agents with specific toxicity for epithelial CSCs.
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            Ki67 Index, HER2 Status, and Prognosis of Patients With Luminal B Breast Cancer

            Maggie C. U. Cheang, Stephen Chia, David Voduc … (2009)
            Background Gene expression profiling of breast cancer has identified two biologically distinct estrogen receptor (ER)-positive subtypes of breast cancer: luminal A and luminal B. Luminal B tumors have higher proliferation and poorer prognosis than luminal A tumors. In this study, we developed a clinically practical immunohistochemistry assay to distinguish luminal B from luminal A tumors and investigated its ability to separate tumors according to breast cancer recurrence-free and disease-specific survival. Methods Tumors from a cohort of 357 patients with invasive breast carcinomas were subtyped by gene expression profile. Hormone receptor status, HER2 status, and the Ki67 index (percentage of Ki67-positive cancer nuclei) were determined immunohistochemically. Receiver operating characteristic curves were used to determine the Ki67 cut point to distinguish luminal B from luminal A tumors. The prognostic value of the immunohistochemical assignment for breast cancer recurrence-free and disease-specific survival was investigated with an independent tissue microarray series of 4046 breast cancers by use of Kaplan–Meier curves and multivariable Cox regression. Results Gene expression profiling classified 101 (28%) of the 357 tumors as luminal A and 69 (19%) as luminal B. The best Ki67 index cut point to distinguish luminal B from luminal A tumors was 13.25%. In an independent cohort of 4046 patients with breast cancer, 2847 had hormone receptor–positive tumors. When HER2 immunohistochemistry and the Ki67 index were used to subtype these 2847 tumors, we classified 1530 (59%, 95% confidence interval [CI] = 57% to 61%) as luminal A, 846 (33%, 95% CI = 31% to 34%) as luminal B, and 222 (9%, 95% CI = 7% to 10%) as luminal–HER2 positive. Luminal B and luminal–HER2-positive breast cancers were statistically significantly associated with poor breast cancer recurrence-free and disease-specific survival in all adjuvant systemic treatment categories. Of particular relevance are women who received tamoxifen as their sole adjuvant systemic therapy, among whom the 10-year breast cancer–specific survival was 79% (95% CI = 76% to 83%) for luminal A, 64% (95% CI = 59% to 70%) for luminal B, and 57% (95% CI = 47% to 69%) for luminal–HER2 subtypes. Conclusion Expression of ER, progesterone receptor, and HER2 proteins and the Ki67 index appear to distinguish luminal A from luminal B breast cancer subtypes.
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              Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer.

              Soonmyung Paik, Gong Tang, Steven Shak … (2006)
              The 21-gene recurrence score (RS) assay quantifies the likelihood of distant recurrence in women with estrogen receptor-positive, lymph node-negative breast cancer treated with adjuvant tamoxifen. The relationship between the RS and chemotherapy benefit is not known. The RS was measured in tumors from the tamoxifen-treated and tamoxifen plus chemotherapy-treated patients in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B20 trial. Cox proportional hazards models were utilized to test for interaction between chemotherapy treatment and the RS. A total of 651 patients were assessable (227 randomly assigned to tamoxifen and 424 randomly assigned to tamoxifen plus chemotherapy). The test for interaction between chemotherapy treatment and RS was statistically significant (P = .038). Patients with high-RS (> or = 31) tumors (ie, high risk of recurrence) had a large benefit from chemotherapy (relative risk, 0.26; 95% CI, 0.13 to 0.53; absolute decrease in 10-year distant recurrence rate: mean, 27.6%; SE, 8.0%). Patients with low-RS (< 18) tumors derived minimal, if any, benefit from chemotherapy treatment (relative risk, 1.31; 95% CI, 0.46 to 3.78; absolute decrease in distant recurrence rate at 10 years: mean, -1.1%; SE, 2.2%). Patients with intermediate-RS tumors did not appear to have a large benefit, but the uncertainty in the estimate can not exclude a clinically important benefit. The RS assay not only quantifies the likelihood of breast cancer recurrence in women with node-negative, estrogen receptor-positive breast cancer, but also predicts the magnitude of chemotherapy benefit.
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                Author and article information

                Contributors
                Charles M. Perou: cperou@med.unc.edu
                Journal
                Journal ID (nlm-ta): Mol Oncol
                Journal ID (iso-abbrev): Mol Oncol
                Journal ID (doi): 10.1002/(ISSN)1878-0261
                Journal ID (publisher-id): MOL2
                Title: Molecular Oncology
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Print): 1574-7891
                ISSN (Electronic): 1878-0261
                Publication date (Electronic): 24 November 2010
                Publication date (Print): February 2011
                Volume: 5
                Issue: 1 ( doiID: 10.1002/mol2.2011.5.issue-1 )
                Pages: 5-23
                Affiliations
                [ 1 ]Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
                [ 2 ]Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
                [ 3 ]Department of Pathology & Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
                Author notes
                [*] [* ]Corresponding author. Lineberger Comprehensive Cancer Center, University of North Carolina, 450 West Drive, CB7295, Chapel Hill, NC 27599, USA. Tel.: +1 919 843 5740; fax: +1 919 843 5718.
                Article
                Publisher ID: MOL22011515
                DOI: 10.1016/j.molonc.2010.11.003
                PMC ID: 5528267
                PubMed ID: 21147047
                SO-VID: ff4e6e40-e47f-4444-ad85-4e6d676cc4fb
                Copyright © © 2011 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.
                License:

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                Date received : 12 October 2010
                Date revision received : 14 November 2010
                Date accepted : 15 November 2010
                Page count
                Figures: 7, Tables: 0, Equations: 0, References: 105, Pages: 19, Words: 17882
                Categories
                Subject: Review
                Subject: Review
                Custom metadata
                source-schema-version-number 2.0
                component-id mol22011515
                cover-date February 2011
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:5.1.4 mode:remove_FC converted:25.07.2017

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: breast cancer,claudin-low,gene expression,subtypes,stem cell
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: breast cancer, claudin-low, gene expression, subtypes, stem cell

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