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DAX-1, as an androgen-target gene, inhibits aromatase expression: a novel mechanism blocking estrogen-dependent breast cancer cell proliferation.

Abstract
Sexual hormones, estrogens and androgens, determine biological response in a tissue- and gender-specific manner and have a pivotal role in endocrine-mediated tumorigenesis. In situ estrogen production by aromatase is a critical determinant for breast cancer growth and progression. On the contrary, clinical and in vitro studies indicate that androgens have a protective role in mammary carcinogenesis. Here, we demonstrated, in hormone-dependent breast cancer cells, the existence of a functional interplay between the androgen receptor (AR), the orphan nuclear receptor DAX-1 and the aromatase enzyme involved in the inhibition of the estrogen-dependent breast cancer cell proliferation exerted by androgen signaling. Indeed, our results revealed, in MCF-7 cells, that ligand-activated AR induces the expression of the orphan nuclear receptor DAX-1 by direct binding to a newly identified androgen-response-element within the DAX-1 proximal promoter. In turn, androgen-induced DAX-1 is recruited, in association with the corepressor N-CoR, within the SF-1/LRH-1 containing region of the aromatase promoter, thereby repressing aromatase expression and activity. In elucidating a novel mechanism by which androgens, through DAX-1, inhibit aromatase expression in breast cancer cell lines, these findings reinforce the theory of androgen- opposing estrogen-action, opening new avenues for therapeutic intervention in estrogen-dependent breast tumors.
AuthorsM Lanzino, P Maris, R Sirianni, I Barone, I Casaburi, A Chimento, C Giordano, C Morelli, D Sisci, P Rizza, D Bonofiglio, S Catalano, S Andò
JournalCell death & disease (Cell Death Dis) Vol. 4 Pg. e724 (Jul 11 2013) ISSN: 2041-4889 [Electronic] England
PMID23846226 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Androgens
  • DAX-1 Orphan Nuclear Receptor
  • Estrogens
  • NR0B1 protein, human
  • Receptors, Androgen
  • Nandrolone
  • mibolerone
  • Aromatase
  • CYP19A1 protein, human
Topics
  • Androgens (pharmacology)
  • Apoptosis
  • Aromatase (genetics, metabolism)
  • Base Sequence
  • Breast Neoplasms
  • Cell Proliferation
  • DAX-1 Orphan Nuclear Receptor (genetics, metabolism)
  • Enzyme Repression
  • Estrogens (physiology)
  • Female
  • Gene Expression
  • Gene Expression Regulation, Neoplastic
  • Humans
  • MCF-7 Cells
  • Nandrolone (analogs & derivatives, pharmacology)
  • Neoplasms, Hormone-Dependent
  • Promoter Regions, Genetic
  • Receptors, Androgen (metabolism)
  • Response Elements

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