DAX-1, as an androgen-target gene, inhibits aromatase expression: A novel mechanism blocking estrogendependent breast cancer cell proliferation

M. Lanzino, P. Maris, R. Sirianni, I. Barone, I. Casaburi, A. Chimento, C. Giordano, C. Morelli, D. Sisci, P. Rizza, D. Bonofiglio, S. Catalano, S. Ando

Research output: Contribution to journalArticle

41 Scopus citations

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.

Original languageEnglish (US)
Article numbere724
JournalCell Death and Disease
Volume4
Issue number7
DOIs
StatePublished - Jul 1 2013

Keywords

  • Androgen receptor
  • Aromatase
  • Breast cancer
  • DAX-1

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

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    Lanzino, M., Maris, P., Sirianni, R., Barone, I., Casaburi, I., Chimento, A., Giordano, C., Morelli, C., Sisci, D., Rizza, P., Bonofiglio, D., Catalano, S., & Ando, S. (2013). DAX-1, as an androgen-target gene, inhibits aromatase expression: A novel mechanism blocking estrogendependent breast cancer cell proliferation. Cell Death and Disease, 4(7), [e724]. https://doi.org/10.1038/cddis.2013.235