Initiating oncogenic event determines gene-expression patterns of human breast cancer models

Molecular expression profiling of tumors initiated by transgenic overexpression of c-myc, c-neu, c-ha-ras, polyoma middle T antigen (PyMT) or simian virus 40 T/t antigen (T-ag) targeted to the mouse mammary gland have identified both common and oncogene-specific events associated with tumor formation and progression. The tumors shared great similarities in their gene-expression profiles as compared with the normal mammary gland with an induction of cell-cycle regulators, metabolic regulators, zinc finger proteins, and protein tyrosine phosphatases, along with the suppression of some protein tyrosine kinases. Selection and hierarchical clustering of the most variant genes, however, resulted in separating the mouse models into three groups with distinct oncogene-specific patterns of gene expression. Such an identification of targets specified by particular oncogenes may facilitate development of lesion-specific therapeutics and preclinical testing. Moreover, similarities in gene expression between human breast cancers and the mouse models have been identified, thus providing an important component for the validation of transgenic mammary cancer models.

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

[2]  T. Hoang,et al.  Transgenic mice carrying the mouse mammary tumor virus ras fusion gene: distinct effects in various tissues , 1989, Molecular and cellular biology.

[3]  R. Cardiff,et al.  Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease , 1992, Molecular and cellular biology.

[4]  G. Stark,et al.  Regulation of the G2/M transition by p53 , 2001, Oncogene.

[5]  G. Church,et al.  Genomic sequencing. , 1993, Methods in molecular biology.

[6]  Steve D. M. Brown,et al.  The murine polycomb-group genes Ezh1 and Ezh2 map close to Hox gene clusters on mouse Chromosomes 11 and 6 , 1999, Mammalian Genome.

[7]  M. White,et al.  Interaction in Vivo and in Vitro of the Metastasis-inducing S100 Protein, S100A4 (p9Ka) with S100A1* , 2000, The Journal of Biological Chemistry.

[8]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[9]  A. Graessmann,et al.  Breast cancer formation in transgenic animals induced by the whey acidic protein SV40 T antigen (WAP-SV-T) hybrid gene. , 1993, Oncogene.

[10]  R. Cardiff,et al.  The mammary pathology of genetically engineered mice: the consensus report and recommendations from the Annapolis meeting‡ , 2000, Oncogene.

[11]  E. Lander,et al.  Expression analysis with oligonucleotide microarrays reveals that MYC regulates genes involved in growth, cell cycle, signaling, and adhesion. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[12]  J. Green,et al.  Prostate and mammary adenocarcinoma in transgenic mice carrying a rat C3(1) simian virus 40 large tumor antigen fusion gene. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[13]  S. Atkin,et al.  Response of estrogen receptor containing tumour cells to pure antiestrogens and the calmodulin inhibitor, calmidzolium chloride , 2000, The Journal of Steroid Biochemistry and Molecular Biology.

[14]  A. Ullrich,et al.  Molecular targets for breast cancer therapy and prevention , 2001, Nature Medicine.

[15]  B Angus,et al.  Expression of c-erbB-2 oncoprotein: a prognostic indicator in human breast cancer. , 1989, Cancer research.

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

[17]  P. Jolicoeur,et al.  Stochastic appearance of mammary tumors in transgenic mice carrying the MMTV/c-neu oncogene , 1989, Cell.

[18]  P. Howley,et al.  The transcriptional transactivation function of wild‐type p53 is inhibited by SV40 large T‐antigen and by HPV‐16 E6 oncoprotein. , 1992, The EMBO journal.

[19]  E. Odintsova,et al.  Characterization of integrin-tetraspanin adhesion complexes: role of tetraspanins in integrin signaling. , 1999 .

[20]  R. Eisenman,et al.  The Myc/Max/Mad network and the transcriptional control of cell behavior. , 2000, Annual review of cell and developmental biology.

[21]  J. Robertson,et al.  New calmodulin antagonists inhibit in vitro growth of human breast cancer cell lines independent of their estrogen receptor status , 2000, Anti-cancer drugs.

[22]  Christian A. Rees,et al.  Distinctive gene expression patterns in human mammary epithelial cells and breast cancers. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[23]  D. Botstein,et al.  Cluster analysis and display of genome-wide expression patterns. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[24]  N. Lee,et al.  Identification of c-myc responsive genes using rat cDNA microarray. , 2000, Cancer research.

[25]  W. Muller,et al.  Signal transduction in mammary tumorigenesis: a transgenic perspective , 2000, Oncogene.

[26]  Manfred Gessler,et al.  Hey genes: a novel subfamily of hairy- and Enhancer of split related genes specifically expressed during mouse embryogenesis , 1999, Mechanisms of Development.

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

[28]  Y. Yarden,et al.  Cyclin D1 Is Required for Transformation by Activated Neu and Is Induced through an E2F-Dependent Signaling Pathway , 2000, Molecular and Cellular Biology.

[29]  J. Harbour,et al.  The Rb/E2F pathway: expanding roles and emerging paradigms. , 2000, Genes & development.

[30]  M. Baum,et al.  Alternative mechanisms of action of anti-oestrogens , 2004, Breast Cancer Research and Treatment.

[31]  K. Korach,et al.  Estrogen promotes mammary tumor development in C3(1)/SV40 large T-antigen transgenic mice: paradoxical loss of estrogen receptoralpha expression during tumor progression. , 2000, Cancer research.

[32]  A. Balmain,et al.  Integration of positive and negative growth signals during ras pathway activation in vivo. , 2000, Current opinion in genetics & development.

[33]  Wen-Hwa Lee,et al.  SV40 large tumor antigen forms a specific complex with the product of the retinoblastoma susceptibility gene , 1988, Cell.

[34]  E. Schröck,et al.  A recurring pattern of chromosomal aberrations in mammary gland tumors of MMTV‐cmyc transgenic mice , 1999, Genes, chromosomes & cancer.

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

[36]  G. Hortobagyi,et al.  Chemotherapy of metastatic breast cancer: what to expect in 2001 and beyond. , 2001, The oncologist.

[37]  N. Lee,et al.  A concise guide to cDNA microarray analysis. , 2000, BioTechniques.

[38]  R. Derynck,et al.  The Tetraspanin Cd9 Associates with Transmembrane TGF-α and Regulates TGF-α–Induced Egf Receptor Activation and Cell Proliferation , 2000, The Journal of cell biology.

[39]  M. Bittner,et al.  Gene expression profiling of alveolar rhabdomyosarcoma with cDNA microarrays. , 1998, Cancer research.

[40]  P. Leder,et al.  Consequences of widespread deregulation of the c-myc gene in transgenic mice: Multiple neoplasms and normal development , 1986, Cell.