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.