c-Myc overexpression and endocrine resistance in breast cancer

• Published in: Journal of steroid biochemistry and molecular biology Vol. 102; no. 1; pp. 147 - 155
• Main Authors: McNeil, Catriona M., Sergio, C. Marcelo, Anderson, Luke R., Inman, Claire K., Eggleton, Sarah A., Murphy, Niamh C., Millar, Ewan K.A., Crea, Paul, Kench, James G., Alles, M. Chehani, Gardiner-Garden, Margaret, Ormandy, Christopher J., Butt, Alison J., Henshall, Susan M., Musgrove, Elizabeth A., Sutherland, Robert L.
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Oxford Elsevier Ltd 01.12.2006; Elsevier Science
• Subjects: Biological and medical sciences; Biomarkers, Tumor - metabolism; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; c-Myc; Drug Resistance, Neoplasm; Endocrine resistance; Estrogen Antagonists - pharmacology; Estrogens - pharmacology; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - drug effects; Gynecology. Andrology. Obstetrics; Humans; Mammary gland diseases; Medical sciences; Oligonucleotide Array Sequence Analysis; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Receptors, Estrogen - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Neoplasm - genetics; RNA, Neoplasm - metabolism; Tumor Cells, Cultured; Tumors; Vertebrates: endocrinology; c-Myc; Endocrine resistance; Breast cancer; Resistance; Mammary gland diseases; Gene overexpression; Malignant tumor; Protooncogene
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/j.jsbmb.2006.09.028

The oncoprotein c-Myc is frequently overexpressed in breast cancer and ectopic expression in breast cancer cell lines attenuates responses to antiestrogen treatment. Here, we review preliminary data aimed at further elucidating a potential role for c-Myc in clinical endocrine resistance in breast cancer. Immunohistochemical and semi-quantitative PCR revealed that c-Myc protein and c- myc mRNA were frequently overexpressed in both ER-positive and ER-negative breast carcinoma. Furthermore, both constitutive and inducible c-Myc overexpression in MCF-7 breast cancer cell lines markedly reduced their sensitivity to the growth inhibitory effects of the pure antiestrogen ICI 182,780. In order to identify potential downstream targets of c-Myc that mediate this effect, Affymetrix microarrays were employed to examine the patterns of gene expression shared by MCF-7 cells stimulated by estrogen, or by induction of c-Myc. Approximately 50% of estrogen target genes identified 6 h after treatment were also regulated by c-Myc. One novel target, EMU4, was transcriptionally regulated by c-Myc. In addition, there was a strong correlation between c- myc and EMU4 mRNA expression in a battery of breast cancer cell lines. These data confirm that c-Myc overexpression is a common event in breast cancer, and that this is associated with resistance to antiestrogens in vitro. Furthermore, the development of an experimental paradigm for the discovery of c-Myc and estrogen target genes associated with endocrine resistance provides a framework for the discovery and validation of genes involved in estrogen signalling, and c-Myc-mediated-antiestrogen resistance.