HOXA9 regulates BRCA1 expression to modulate human breast tumor phenotype

Penney M. Gilbert, Janna K. Mouw, Meredith A. Unger, Johnathon N. Lakins, Mawuse K. Gbegnon, Virginia B. Clemmer, Miriam Benezra, Jonathan D. Licht, Nancy J. Boudreau, Kelvin K.C. Tsai, Alana L. Welm, Michael D. Feldman, Barbara L. Weber, Valerie M. Weaver

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)1535-1550
Number of pages16
JournalJournal of Clinical Investigation
Volume120
Issue number5
DOIs
Publication statusPublished - May 3 2010

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Homeobox Genes
Breast Neoplasms
Phenotype
Aggression
Breast
Neoplasms
Progesterone Receptors
Growth
Tumor Cell Line
Tumor Suppressor Genes
Morphogenesis
Heterografts
Estrogen Receptors

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Gilbert, P. M., Mouw, J. K., Unger, M. A., Lakins, J. N., Gbegnon, M. K., Clemmer, V. B., ... Weaver, V. M. (2010). HOXA9 regulates BRCA1 expression to modulate human breast tumor phenotype. Journal of Clinical Investigation, 120(5), 1535-1550. https://doi.org/10.1172/JCI39534

HOXA9 regulates BRCA1 expression to modulate human breast tumor phenotype. / Gilbert, Penney M.; Mouw, Janna K.; Unger, Meredith A.; Lakins, Johnathon N.; Gbegnon, Mawuse K.; Clemmer, Virginia B.; Benezra, Miriam; Licht, Jonathan D.; Boudreau, Nancy J.; Tsai, Kelvin K.C.; Welm, Alana L.; Feldman, Michael D.; Weber, Barbara L.; Weaver, Valerie M.

In: Journal of Clinical Investigation, Vol. 120, No. 5, 03.05.2010, p. 1535-1550.

Research output: Contribution to journalArticle

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 2010, 'HOXA9 regulates BRCA1 expression to modulate human breast tumor phenotype', Journal of Clinical Investigation, vol. 120, no. 5, pp. 1535-1550. https://doi.org/10.1172/JCI39534
Gilbert PM, Mouw JK, Unger MA, Lakins JN, Gbegnon MK, Clemmer VB et al. HOXA9 regulates BRCA1 expression to modulate human breast tumor phenotype. Journal of Clinical Investigation. 2010 May 3;120(5):1535-1550. https://doi.org/10.1172/JCI39534
Gilbert, Penney M. ; Mouw, Janna K. ; Unger, Meredith A. ; Lakins, Johnathon N. ; Gbegnon, Mawuse K. ; Clemmer, Virginia B. ; Benezra, Miriam ; Licht, Jonathan D. ; Boudreau, Nancy J. ; Tsai, Kelvin K.C. ; Welm, Alana L. ; Feldman, Michael D. ; Weber, Barbara L. ; Weaver, Valerie M. / HOXA9 regulates BRCA1 expression to modulate human breast tumor phenotype. In: Journal of Clinical Investigation. 2010 ; Vol. 120, No. 5. pp. 1535-1550.
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