Molecular Basis of Triple Negative Breast Cancer and Implications for Therapy

Triple negative breast cancer is an aggressive form of breast cancer with limited treatment options and is without proven targeted therapy. Understanding the molecular basis of triple negative breast cancer is crucial for effective new drug development. Recent genomewide gene expression and DNA sequencing studies indicate that this cancer type is composed of a molecularly heterogeneous group of diseases that carry multiple somatic mutations and genomic structural changes. These findings have implications for therapeutic target identification and the design of future clinical trials for this aggressive group of breast cancer.

[1]  Joshua F. McMichael,et al.  Genome Remodeling in a Basal-like Breast Cancer Metastasis and Xenograft , 2010, Nature.

[2]  A. Nobel,et al.  Concordance among Gene-Expression – Based Predictors for Breast Cancer , 2011 .

[3]  W. Marsden I and J , 2012 .

[4]  M. Skolnick,et al.  BRCA1 mutations in primary breast and ovarian carcinomas. , 1994, Science.

[5]  R. Prentice,et al.  Reproductive history and oral contraceptive use in relation to risk of triple-negative breast cancer. , 2011, Journal of the National Cancer Institute.

[6]  John Quackenbush,et al.  Identification of Novel Kinase Targets for the Treatment of Estrogen Receptor–Negative Breast Cancer , 2009, Clinical Cancer Research.

[7]  A. Ashworth,et al.  Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. , 2009, The New England journal of medicine.

[8]  R. Kennedy,et al.  BRCA1 transcriptionally regulates genes associated with the basal-like phenotype in breast cancer , 2010, Breast Cancer Research and Treatment.

[9]  Jason I. Herschkowitz,et al.  Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer , 2010, Breast Cancer Research.

[10]  Zhi Hu,et al.  An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. , 2008, Cancer research.

[11]  J. Dering,et al.  Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/“triple-negative” breast cancer cell lines growing in vitro , 2007, Breast Cancer Research and Treatment.

[12]  Hanina Hibshoosh,et al.  PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. , 2005, Cancer research.

[13]  Emmanuel Barillot,et al.  Frequent PTEN genomic alterations and activated phosphatidylinositol 3-kinase pathway in basal-like breast cancer cells , 2008, Breast Cancer Research.

[14]  William D. Foulkes,et al.  Re: Germline BRCA1 Mutations and a Basal Epithelial Phenotype in Breast Cancer , 2004 .

[15]  Aaas News,et al.  Book Reviews , 1893, Buffalo Medical and Surgical Journal.

[16]  Shridar Ganesan,et al.  X chromosomal abnormalities in basal-like human breast cancer. , 2006, Cancer cell.

[17]  K Miller,et al.  A randomized phase III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin (G/C) in metastatic triple-negative breast cancer (TNBC). , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  A. Nobel,et al.  Supervised risk predictor of breast cancer based on intrinsic subtypes. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  A. Tutt,et al.  Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial , 2010, The Lancet.

[20]  S. Moulder Does the PI3K pathway play a role in basal breast cancer? , 2010, Clinical breast cancer.

[21]  G. G. Stokes "J." , 1890, The New Yale Book of Quotations.

[22]  S. Narod,et al.  Triple-Negative Breast Cancer: Clinical Features and Patterns of Recurrence , 2007, Clinical Cancer Research.

[23]  Susan G Hilsenbeck,et al.  Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. , 2008, Journal of the National Cancer Institute.

[24]  K. Hess,et al.  Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[25]  L. Bégin,et al.  Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. , 2004, Journal of the National Cancer Institute.

[26]  Zhiyuan Hu,et al.  Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors , 2007, Genome Biology.

[27]  R. Tibshirani,et al.  Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[28]  A. Lau,et al.  Selective Inhibition of BRCA2-Deficient Mammary Tumor Cell Growth by AZD2281 and Cisplatin , 2008, Clinical Cancer Research.

[29]  C. Perou,et al.  Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. , 2006, JAMA.

[30]  C. Perou,et al.  Evaluation of BRCA1 inactivation by promoter methylation as a marker of triple-negative and basal-like breast cancers. , 2010 .

[31]  X. Chen,et al.  Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. , 2011, The Journal of clinical investigation.

[32]  Robert L Sutherland,et al.  PI3K pathway activation in breast cancer is associated with the basal‐like phenotype and cancer‐specific mortality , 2010, International journal of cancer.

[33]  S. O'toole,et al.  PI3K Pathway Activation in Breast Cancer Is Associated with the Basal-Like Phenotype and Cancer-Specific Mortality. , 2009 .

[34]  C. Perou,et al.  TBCRC 001: EGFR inhibition with cetuximab added to carboplatin in metastatic triple-negative (basal-like) breast cancer , 2008 .

[35]  Chau Dang,et al.  Phase II trial of saracatinib (AZD0530), an oral SRC-inhibitor for the treatment of patients with hormone receptor-negative metastatic breast cancer. , 2011, Clinical breast cancer.

[36]  A. Lau,et al.  Selective Inhibition of BRCA 2-Deficient MammaryTumor Cell Growth byAZD 2281 and Cisplatin , 2008 .

[37]  Benjamin Haibe-Kains,et al.  Assessment of an RNA interference screen-derived mitotic and ceramide pathway metagene as a predictor of response to neoadjuvant paclitaxel for primary triple-negative breast cancer: a retrospective analysis of five clinical trials. , 2010, The Lancet. Oncology.

[38]  D. Sharma,et al.  Using epigenetic reprogramming to target triple-negative breast cancer. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[39]  Z. Szallasi,et al.  Efficacy of neoadjuvant Cisplatin in triple-negative breast cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[40]  A. Ashworth,et al.  Hallmarks of 'BRCAness' in sporadic cancers , 2004, Nature Reviews Cancer.

[41]  Mark Robson,et al.  Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial , 2010, The Lancet.

[42]  I. Ellis,et al.  Triple-Negative Breast Cancer: Distinguishing between Basal and Nonbasal Subtypes , 2009, Clinical Cancer Research.

[43]  C. Perou,et al.  Epidemiology of basal-like breast cancer , 2008, Breast Cancer Research and Treatment.

[44]  Daniel Birnbaum,et al.  How basal are triple‐negative breast cancers? , 2008, International journal of cancer.

[45]  Amy E. Hawkins,et al.  DNA sequencing of a cytogenetically normal acute myeloid leukemia genome , 2008, Nature.

[46]  Daniel Birnbaum,et al.  Gene expression profiling shows medullary breast cancer is a subgroup of basal breast cancers. , 2006, Cancer research.

[47]  A. Gown,et al.  Immunohistochemical and Clinical Characterization of the Basal-Like Subtype of Invasive Breast Carcinoma , 2004, Clinical Cancer Research.

[48]  Preclinical S Tudy BRCA1 transcriptionally regulates genes associated with the basal-like phenotype in breast cancer , 2010 .

[49]  Ken Chen,et al.  Recurring mutations found by sequencing an acute myeloid leukemia genome. , 2009, The New England journal of medicine.

[50]  Jeffrey M. Rosen,et al.  Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features , 2009, Proceedings of the National Academy of Sciences.

[51]  S. Narod,et al.  Pattern of metastatic spread in triple-negative breast cancer , 2009, Breast Cancer Research and Treatment.

[52]  G. Mills,et al.  Incidence and Outcome of BRCA Mutations in Unselected Patients with Triple Receptor-Negative Breast Cancer , 2011, Clinical Cancer Research.

[53]  W. Gerald,et al.  An estrogen receptor-negative breast cancer subset characterized by a hormonally regulated transcriptional program and response to androgen , 2006, Oncogene.

[54]  R. Prentice,et al.  Body Size, Physical Activity, and Risk of Triple-Negative and Estrogen Receptor–Positive Breast Cancer , 2011, Cancer Epidemiology, Biomarkers & Prevention.

[55]  Debra L Winkeljohn Triple-negative breast cancer. , 2008, Clinical journal of oncology nursing.

[56]  I. Gelman Src-family tyrosine kinases as therapeutic targets in advanced cancer. , 2011, Frontiers in bioscience.