title: HOXA9 regulates BRCA1 expression to modulate human breast tumor phenotype.
abstract: 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.
authors.affiliation: Department of Pathology, Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Penney M
authors.initials: PM
authors.lastname: Gilbert
authors.forename: Janna K
authors.initials: JK
authors.lastname: Mouw
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Unger
authors.forename: Johnathon N
authors.initials: JN
authors.lastname: Lakins
authors.forename: Mawuse K
authors.initials: MK
authors.lastname: Gbegnon
authors.forename: Virginia B
authors.initials: VB
authors.lastname: Clemmer
authors.forename: Miriam
authors.initials: M
authors.lastname: Benezra
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Licht
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Boudreau
authors.forename: Kelvin K C
authors.initials: KK
authors.lastname: Tsai
authors.forename: Alana L
authors.initials: AL
authors.lastname: Welm
authors.forename: Michael D
authors.initials: MD
authors.lastname: Feldman
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Weber
authors.forename: Valerie M
authors.initials: VM
authors.lastname: Weaver
mesh_terms: D000328:Adult; D000818:Animals; D019313:BRCA1 Protein / Q000096:biosynthesis*; D001943:Breast Neoplasms / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D051379:Mice; D008875:Middle Aged; D008957:Models, Genetic; D009368:Neoplasm Transplantation; D010641:Phenotype; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D018398:Homeodomain Proteins; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C097899:homeobox protein HOXA9
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