title: 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.
authors.affiliation: Department of Pharmacy and Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende (CS), Italy.
authors.forename: M
authors.initials: M
authors.lastname: Lanzino
authors.forename: P
authors.initials: P
authors.lastname: Maris
authors.forename: R
authors.initials: R
authors.lastname: Sirianni
authors.forename: I
authors.initials: I
authors.lastname: Barone
authors.forename: I
authors.initials: I
authors.lastname: Casaburi
authors.forename: A
authors.initials: A
authors.lastname: Chimento
authors.forename: C
authors.initials: C
authors.lastname: Giordano
authors.forename: C
authors.initials: C
authors.lastname: Morelli
authors.forename: D
authors.initials: D
authors.lastname: Sisci
authors.forename: P
authors.initials: P
authors.lastname: Rizza
authors.forename: D
authors.initials: D
authors.lastname: Bonofiglio
authors.forename: S
authors.initials: S
authors.lastname: Catalano
authors.forename: S
authors.initials: S
authors.lastname: Andò
mesh_terms: D000728:Androgens / Q000494:pharmacology; D017209:Apoptosis; D001141:Aromatase / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D001943:Breast Neoplasms; D049109:Cell Proliferation; D057137:DAX-1 Orphan Nuclear Receptor / Q000235:genetics* / Q000378:metabolism; D004794:Enzyme Repression; D004967:Estrogens / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D009277:Nandrolone / Q000031:analogs & derivatives / Q000494:pharmacology; D009376:Neoplasms, Hormone-Dependent; D011401:Promoter Regions, Genetic; D011944:Receptors, Androgen / Q000378:metabolism; D020218:Response Elements
chemical_list: D000728:Androgens; D057137:DAX-1 Orphan Nuclear Receptor; D004967:Estrogens; C539965:NR0B1 protein, human; D011944:Receptors, Androgen; D009277:Nandrolone; C100075:mibolerone; D001141:Aromatase; C561410:CYP19A1 protein, human