TY - JOUR
T1 - DAX-1, as an androgen-target gene, inhibits aromatase expression
T2 - A novel mechanism blocking estrogendependent breast cancer cell proliferation
AU - Lanzino, M.
AU - Maris, P.
AU - Sirianni, R.
AU - Barone, I.
AU - Casaburi, I.
AU - Chimento, A.
AU - Giordano, C.
AU - Morelli, C.
AU - Sisci, D.
AU - Rizza, P.
AU - Bonofiglio, D.
AU - Catalano, S.
AU - Ando, S.
N1 - Funding Information:
Acknowledgements. The authors thank Dr. E.R. Simpson, Dr. C.D. Clyne and Dr. M.J. McPhaul for generously providing P450 aromatase promoter plasmids. This work was supported by Progetti di Ricerca di Interesse Nazionale (PRIN)-Ministero Istruzione Università e Ricerca (MIUR) [grant number 20085Y7XT5]; and Associazione Italiana Ricerca sul Cancro (AIRC) [grant number 11595]. Reintegration AIRC/Marie Curie International Fellowship in Cancer Research to I. Barone.
PY - 2013/7
Y1 - 2013/7
N2 - 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.
AB - 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.
KW - Androgen receptor
KW - Aromatase
KW - Breast cancer
KW - DAX-1
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U2 - 10.1038/cddis.2013.235
DO - 10.1038/cddis.2013.235
M3 - Article
C2 - 23846226
AN - SCOPUS:84881055860
SN - 2041-4889
VL - 4
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 7
M1 - e724
ER -