Oncogenes and tumor suppressor genes in breast cancer: potential diagnostic and therapeutic applications.

Carcinogenesis is a multistep process characterized by genetic alterations that influence key cellular pathways involved in growth and development. Oncogenes refer to those genes whose alterations cause gain-of-function effects, while tumor suppressor genes cause loss-of-function effects that contribute to the malignant phenotype. The effects of these alterations are complex due to the high number of changes in a typical case of breast cancer and the interactions of the biological pathways involved. This review focuses on the more common abnormalities in oncogenes and tumor suppressor genes in human breast cancer and their known associations with clinical outcome in terms of tumor classification, prognosis, and response to specific therapies. A better understanding of these relationships has led to new therapeutic applications. Agents that target oncogenes and their associated pathways are now in clinical use, with many more undergoing preclinical and clinical testing. The availability of antibodies, small synthetic molecules, cyotokines, gene therapy techniques, and even natural compounds that are screened for specific biological properties has greatly increased the number of candidate drugs. Nevertheless, clinical successes have been limited because of the redundancy of many cancer-related pathways as well as the high degree of variability in genotype and phenotype among individual tumors. Likewise, strategies to replace tumor suppressor gene functions face numerous technical hurdles. This review summarizes the current achievements and future prospects for the therapeutic targeting of oncogenes and tumor suppressor genes and new technology to better classify tumors and accurately predict responses to standard and novel agents.

[1]  R. Tibshirani,et al.  Repeated observation of breast tumor subtypes in independent gene expression data sets , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[2]  J. O’Shaughnessy Gemcitabine and trastuzumab in metastatic breast cancer. , 2003, Seminars in oncology.

[3]  D. Easton,et al.  Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium. , 1993, American journal of human genetics.

[4]  E. Petricoin,et al.  Early detection: Proteomic applications for the early detection of cancer , 2003, Nature Reviews Cancer.

[5]  Adopted on March American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  Herman Yeger,et al.  Decreased levels of the cell-cycle inhibitor p27Kip1 protein: Prognostic implications in primary breast cancer , 1997, Nature Medicine.

[7]  M. Mita,et al.  Mammalian target of rapamycin: a new molecular target for breast cancer. , 2003, Clinical breast cancer.

[8]  Y. Yarden,et al.  Signal transduction: Molecular ticket to enter cells , 2002, Nature.

[9]  K. Bloom,et al.  The Her-2/neu gene and protein in breast cancer 2003: biomarker and target of therapy. , 2003, The oncologist.

[10]  J. Stec,et al.  Emerging science: Prospective validation of gene expression profiling-based prediction of complete pathologic response to neoadjuvant paclitaxel/FAC chemotherapy in breast cancer , 2003 .

[11]  E. Schmidt,et al.  Rate-limiting effects of Cyclin D1 in transformation by ErbB2 predicts synergy between herceptin and flavopiridol. , 2002, Cancer research.

[12]  Joel G. Pounds,et al.  Proteomic Characterization of Nipple Aspirate Fluid: Identification of Potential Biomarkers of Breast Cancer , 2003, Breast Cancer Research and Treatment.

[13]  B. Ponder,et al.  Mutation analysis of BRCA1 and BRCA2 in a male breast cancer population. , 1997, American journal of human genetics.

[14]  M. Dowsett,et al.  Phase II study of the efficacy and tolerability of two dosing regimens of the farnesyl transferase inhibitor, R115777, in advanced breast cancer. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  J W Gray,et al.  Positional cloning of ZNF217 and NABC1: genes amplified at 20q13.2 and overexpressed in breast carcinoma. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[16]  M. Loda,et al.  The cell cycle inhibitor p27 is an independent prognostic marker in small (T1a,b) invasive breast carcinomas. , 1997, Cancer research.

[17]  Steven E. Bayer,et al.  A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. , 1994, Science.

[18]  S. Grant,et al.  Cyclin-dependent kinase inhibitors. , 2003, Current opinion in pharmacology.

[19]  W. McGuire,et al.  Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. , 1987, Science.

[20]  M. Nelen,et al.  Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease. , 1997, Human molecular genetics.

[21]  C. Sartor,et al.  Epidermal growth factor family receptors and inhibitors: radiation response modulators. , 2003, Seminars in radiation oncology.

[22]  C. Perou,et al.  MYC Is Amplified in BRCA1-Associated Breast Cancers , 2004, Clinical Cancer Research.

[23]  S. Seal,et al.  Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. , 1994, Science.

[24]  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.

[25]  A. Garratt,et al.  Trastuzumab cardiotoxicity: Speculations regarding pathophysiology and targets for further study. , 2002, Seminars in oncology.

[26]  F. Khuri,et al.  Adenovirus-mediated p53 gene transfer in advanced non-small-cell lung cancer. , 1999, Journal of the National Cancer Institute.

[27]  B. Vogelstein,et al.  p53 mutations in human cancers. , 1991, Science.

[28]  M. Sliwkowski,et al.  Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers , 1999, Oncogene.

[29]  S. Edge,et al.  Prognostic factors in breast cancer , 2005 .

[30]  Philip D. Jeffrey,et al.  Crystal structure of the p27Kip1 cyclin-dependent-kinase inibitor bound to the cyclin A–Cdk2 complex , 1996, Nature.

[31]  W. Lee,et al.  Human retinoblastoma susceptibility gene: cloning, identification, and sequence , 1987, Science.

[32]  F. Collins,et al.  Mutations in the p53 gene occur in diverse human tumour types , 1989, Nature.

[33]  J. Eyfjörd,et al.  Study of a single BRCA2 mutation with high carrier frequency in a small population. , 1997, American journal of human genetics.

[34]  J Chang-Claude,et al.  Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. , 1998, American journal of human genetics.

[35]  K. Hruska,et al.  Expression of p27Kip1 in osteoblast-like cells during differentiation with parathyroid hormone. , 1997, Endocrinology.

[36]  Dieter Niederacher,et al.  Multistep carcinogenesis of breast cancer and tumour heterogeneity , 1997, Journal of Molecular Medicine.

[37]  Y. Yarden,et al.  Untangling the ErbB signalling network , 2001, Nature Reviews Molecular Cell Biology.

[38]  K. Phillips Immunophenotypic and pathologic differences between BRCA1 and BRCA2 hereditary breast cancers. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[39]  D. Lane,et al.  The role of the p53 protein in the apoptotic response. , 1994, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[40]  R. Gascoyne,et al.  Phase II Study of Oral Vinorelbine in First-Line Advanced Breast Cancer Chemotherapy , 2003 .

[41]  W. Kuo,et al.  High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays , 1998, Nature Genetics.

[42]  A. Levine p53, the Cellular Gatekeeper for Growth and Division , 1997, Cell.

[43]  P. Nowell The clonal evolution of tumor cell populations. , 1976, Science.

[44]  G. Hortobagyi,et al.  Growth factor receptors in breast cancer: potential for therapeutic intervention. , 2003, The oncologist.

[45]  L. Essioux,et al.  Loss of heterozygosity and linkage analysis in breast carcinoma: indication for a putative third susceptibility gene on the short arm of chromosome 8. , 1995, Oncogene.

[46]  J. Herman,et al.  Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. , 2000, Journal of the National Cancer Institute.

[47]  J. Nesland,et al.  Genetic alterations of the tumour suppressor gene regions 3p, 11p, 13q, 17p, and 17q in human breast carcinomas , 1992, Genes, chromosomes & cancer.

[48]  W. J. Brammar,et al.  Alterations to either c-erbB-2(neu) or c-myc proto-oncogenes in breast carcinomas correlate with poor short-term prognosis. , 1987, Oncogene.

[49]  L. Presta,et al.  Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets , 2000, Nature Medicine.

[50]  C. Marth,et al.  Why did p53 gene therapy fail in ovarian cancer? , 2003, The Lancet. Oncology.

[51]  Richard Simon,et al.  Initiating oncogenic event determines gene-expression patterns of human breast cancer models , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[52]  M. Stratton,et al.  The genetics of breast cancer susceptibility. , 1998, Annual review of genetics.

[53]  S. Nass,et al.  Defining a role for c-Myc in breast tumorigenesis , 1997, Breast Cancer Research and Treatment.

[54]  R. Lidereau,et al.  Molecular alterations in sporadic breast cancer. , 2002, Critical reviews in oncology/hematology.

[55]  M. King,et al.  Linkage of early-onset familial breast cancer to chromosome 17q21. , 1990, Science.

[56]  K. Miura,et al.  The expression of the KAI1 gene, a tumor metastasis suppressor, is directly activated by p53. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[57]  J. Minna,et al.  p53: a frequent target for genetic abnormalities in lung cancer. , 1989, Science.

[58]  E. Appella,et al.  p53 Regulates the Expression of the Tumor Suppressor Gene Maspin* , 2000, The Journal of Biological Chemistry.

[59]  Alfred A. Boyd,et al.  Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2 , 1996, Nature Genetics.

[60]  L. Presta,et al.  Humanization of an anti-p185HER2 antibody for human cancer therapy. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[61]  E. Thomson,et al.  Recommendations for follow-up care of individuals with an inherited predisposition to Cancer. II. BRCA1 and BRCA2 , 1997 .

[62]  Yudong D. He,et al.  A Gene-Expression Signature as a Predictor of Survival in Breast Cancer , 2002 .

[63]  E. Dougherty,et al.  Gene-expression profiles in hereditary breast cancer. , 2001, The New England journal of medicine.

[64]  P. Steeg,et al.  Cyclins and breast cancer , 2004, Breast Cancer Research and Treatment.

[65]  R. Kerbel,et al.  Impact of the cyclin–dependent kinase inhibitor p27Kip1 on resistance of tumor cells to anticancer agents , 1996, Nature Medicine.

[66]  A. Knudson Mutation and cancer: statistical study of retinoblastoma. , 1971, Proceedings of the National Academy of Sciences of the United States of America.

[67]  Y. Shiloh ATM and related protein kinases: safeguarding genome integrity , 2003, Nature Reviews Cancer.

[68]  Christian A. Rees,et al.  Molecular portraits of human breast tumours , 2000, Nature.

[69]  R. Elliott,et al.  Gene targets of antisense therapies in breast cancer , 2002, Expert opinion on therapeutic targets.

[70]  F. Li,et al.  Familial cancer syndromes and clusters. , 1990, Current problems in cancer.

[71]  K. Khanna Cancer risk and the ATM gene: a continuing debate. , 2000, Journal of the National Cancer Institute.

[72]  P. O’Connell,et al.  Analysis of loss of heterozygosity in 399 premalignant breast lesions at 15 genetic loci. , 1998, Journal of the National Cancer Institute.

[73]  G. Mills,et al.  The role of genetic abnormalities of PTEN and the phosphatidylinositol 3-kinase pathway in breast and ovarian tumorigenesis, prognosis, and therapy. , 2001, Seminars in oncology.

[74]  M. J. van de Vijver,et al.  Neu-protein overexpression in breast cancer. Association with comedo-type ductal carcinoma in situ and limited prognostic value in stage II breast cancer. , 1988, The New England journal of medicine.

[75]  Terry L. Smith,et al.  Phase II study of weekly docetaxel and trastuzumab for patients with HER-2-overexpressing metastatic breast cancer. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[76]  K Offit,et al.  Recommendations for follow-up care of individuals with an inherited predisposition to cancer. II. BRCA1 and BRCA2. Cancer Genetics Studies Consortium. , 1997, JAMA.

[77]  A. Ullrich,et al.  p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor , 1989, Molecular and cellular biology.

[78]  J. Baselga,et al.  Phase II and tumor pharmacodynamic study of gefitinib in patients with advanced breast cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[79]  Syed Mohsin,et al.  Gene expression profiling for the prediction of therapeutic response to docetaxel in patients with breast cancer , 2003, The Lancet.

[80]  Esposito,et al.  Prognostic role of the cyclin-dependent kinase inhibitor p27 in non-small cell lung cancer. , 1997, Cancer research.

[81]  M. Stratton Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases , 1997, The Lancet.

[82]  James M. Roberts,et al.  The cyclin-dependent kinase inhibitor p27Kip1 safeguards against inflammatory injury , 1998, Nature Medicine.

[83]  L. Belghiti,et al.  Prognostic factors in breast cancer , 2002 .

[84]  J. Holt,et al.  Ovarian cancer BRCA1 gene therapy: Phase I and II trial differences in immune response and vector stability. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[85]  T. Fleming,et al.  Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. , 2001, The New England journal of medicine.

[86]  D. F. Easton,et al.  Genetic linkage analysis in familial breast and ovarian cancer: Results from 214 families , 1993 .

[87]  S. Devries,et al.  Chromosomal alterations in ductal carcinomas in situ and their in situ recurrences. , 2000, Journal of the National Cancer Institute.

[88]  Zhao Rui,et al.  Use of serological proteomic methods to find biomarkers associated with breast cancer , 2003, Proteomics.

[89]  D. Birnbaum,et al.  Truncation at conserved terminal regions of BRCA1 protein is associated with highly proliferating hereditary breast cancers. , 1996, Cancer research.

[90]  A. deFazio,et al.  Antiestrogen inhibition of cell cycle progression in breast cancer cells in associated with inhibition of cyclin-dependent kinase activity and decreased retinoblastoma protein phosphorylation. , 1995, Molecular endocrinology.

[91]  K. Vermeulen,et al.  The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer , 2003, Cell proliferation.

[92]  D Tripathy,et al.  Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[93]  G. Landberg,et al.  The cyclin D1 high and cyclin E high subgroups of breast cancer: separate pathways in tumorogenesis based on pattern of genetic aberrations and inactivation of the pRb node , 2002, Oncogene.

[94]  O. Kallioniemi,et al.  A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. , 2002, American journal of human genetics.

[95]  E. Kawasaki,et al.  Accumulation of p53 tumor suppressor gene protein: an independent marker of prognosis in breast cancers. , 1992, Journal of the National Cancer Institute.

[96]  G. Nalepa,et al.  Therapeutic anti-cancer targets upstream of the proteasome. , 2003, Cancer treatment reviews.

[97]  D. Easton,et al.  Estimates of the gene frequency of BRCA1 and its contribution to breast and ovarian cancer incidence. , 1995, American journal of human genetics.

[98]  S. Shousha,et al.  High level expression of p27(kip1) and cyclin D1 in some human breast cancer cells: inverse correlation between the expression of p27(kip1) and degree of malignancy in human breast and colorectal cancers. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[99]  K. Isselbacher,et al.  Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. , 1999, Science.

[100]  Isabelle Bedrosian,et al.  Cyclin E and survival in patients with breast cancer. , 2002, The New England journal of medicine.

[101]  G. Colditz,et al.  HSD17B1 Gene Polymorphisms and Risk of Endometrial and Breast Cancer , 2004, Cancer Epidemiology Biomarkers & Prevention.

[102]  Ralph Scully,et al.  Dynamic Changes of BRCA1 Subnuclear Location and Phosphorylation State Are Initiated by DNA Damage , 1997, Cell.

[103]  W. Kuo,et al.  Quantitative mapping of amplicon structure by array CGH identifies CYP24 as a candidate oncogene , 2000, Nature Genetics.

[104]  N. Robert,et al.  Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[105]  J. Downward Targeting RAS signalling pathways in cancer therapy , 2003, Nature Reviews Cancer.

[106]  James M. Roberts,et al.  Expression of cell-cycle regulators p27Kip1 and cyclin E, alone and in combination, correlate with survival in young breast cancer patients , 1997, Nature Medicine.

[107]  J. R. Reeves,et al.  Expression of the HER1–4 family of receptor tyrosine kinases in breast cancer , 2003, The Journal of pathology.

[108]  J. Baselga,et al.  Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[109]  T. Darden,et al.  Molecular modeling of the amino-terminal zinc ring domain of BRCA1. , 1996, Cancer research.

[110]  M. Hjelm,et al.  Prevalence of mutations in the BRCA1 gene among Chinese patients with breast cancer. , 1999, Journal of the National Cancer Institute.

[111]  S. Formenti,et al.  Pharmacogenomics and breast cancer. , 2004, Pharmacogenomics.

[112]  S. Baylin,et al.  p53 activates expression of HIC-1, a new candidate tumour suppressor gene on 17p13.3 , 1995, Nature Genetics.

[113]  F. Couch,et al.  BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer. , 1997, The New England journal of medicine.

[114]  J. Holt,et al.  Gene therapy for carcinoma of the breast: Therapeutic genetic correction strategies , 1999, Breast Cancer Research.

[115]  S. Ramaswamy,et al.  Oncogenic role of the ubiquitin ligase subunit Skp2 in human breast cancer. , 2002, The Journal of clinical investigation.

[116]  D. Bentley,et al.  Identification of the breast cancer susceptibility gene BRCA2 , 1995, Nature.

[117]  S. Swain,et al.  Review of flavopiridol, a cyclin-dependent kinase inhibitor, as breast cancer therapy. , 2002, Seminars in oncology.

[118]  C. Markopoulos,et al.  p53 protein expression and oestrogen and progesterone receptor status in invasive ductal breast carcinomas , 2001, Cytopathology : official journal of the British Society for Clinical Cytology.

[119]  H. Koeffler,et al.  p27/Kip1 mutation found in breast cancer. , 1996, Cancer research.

[120]  Lyndsay N Harris,et al.  Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[121]  Brian Higgins,et al.  Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. , 2002, Cancer cell.

[122]  E. Winer,et al.  Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing metastatic breast cancer: multicenter phase II trial with clinical outcomes, analysis of serum tumor markers as predictive factors, and cardiac surveillance algorithm. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[123]  M. Loda,et al.  Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas , 1997, Nature Medicine.

[124]  J. Carroll,et al.  Mechanisms of growth arrest by c-myc antisense oligonucleotides in MCF-7 breast cancer cells: implications for the antiproliferative effects of antiestrogens. , 2002, Cancer research.

[125]  G. Hortobagyi,et al.  Cationic liposome-mediated E1A gene transfer to human breast and ovarian cancer cells and its biologic effects: a phase I clinical trial. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[126]  L. Strong,et al.  Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. , 1990, Science.

[127]  M. Dowsett,et al.  Integration of signal transduction inhibitors with endocrine therapy: an approach to overcoming hormone resistance in breast cancer. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[128]  J. Gray,et al.  The genetics and genomics of cancer , 2003, Nature Genetics.