|HOXA9 regulates BRCA1 expression to modulate human breast tumor phenotype.
|Year of Publication
|Gilbert PM, Mouw JK, Unger MA, Lakins JN, Gbegnon MK, Clemmer VB, Benezra M, Licht JD, Boudreau NJ, Tsai KKC, Welm AL, Feldman MD, Weber BL, Weaver VM
|J Clin Invest
|Adult, Animals, BRCA1 Protein, Breast Neoplasms, Female, Gene Expression Regulation, Neoplastic, Homeodomain Proteins, Humans, Mice, Middle Aged, Models, Genetic, Neoplasm Transplantation, Phenotype, Receptors, Estrogen, Receptors, Progesterone, Treatment Outcome
Breast cancer 1, early onset (BRCA1) expression is often reduced in sporadic breast tumors, even in the absence of BRCA1 genetic modifications, but the molecular basis for this is unknown. In this study, we identified homeobox A9 (HOXA9) as a gene frequently downregulated in human breast cancers and tumor cell lines and noted that reduced HOXA9 transcript levels associated with tumor aggression, metastasis, and patient mortality. Experiments revealed that loss of HOXA9 promoted mammary epithelial cell growth and survival and perturbed tissue morphogenesis. Restoring HOXA9 expression repressed growth and survival and inhibited the malignant phenotype of breast cancer cells in culture and in a xenograft mouse model. Molecular studies showed that HOXA9 restricted breast tumor behavior by directly modulating the expression of BRCA1. Indeed, ectopic expression of wild-type BRCA1 phenocopied the tumor suppressor function of HOXA9, and reducing BRCA1 levels or function inhibited the antitumor activity of HOXA9. Consistently, HOXA9 expression correlated with BRCA1 in clinical specimens and with tumor aggression in patients lacking estrogen receptor/progesterone receptor expression in their breast tissue. These findings indicate that HOXA9 restricts breast tumor aggression by modulating expression of the tumor suppressor gene BRCA1, which we believe provides an explanation for the loss of BRCA1 expression in sporadic breast tumors in the absence of BRCA1 genetic modifications.
|J. Clin. Invest.
|PubMed Central ID
|A107165 / / PHS HHS / United States
BC062562 / BC / NCI NIH HHS / United States
R01 CA138818 / CA / NCI NIH HHS / United States
R01-CA078731 / CA / NCI NIH HHS / United States
RS1-00449 / RS / DRS NIH HHS / United States
T32 CA009151 / CA / NCI NIH HHS / United States
U54CA143836 / CA / NCI NIH HHS / United States