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A novel interplay between AR and DAX‐1 controls aromatase expression in estrogen‐dependent cancers
Author(s) -
Lanzino Marilena,
Maris Pamela,
Sirianni Rosa,
Barone Ines,
Chimento Adele,
Giordano Cinzia,
Morelli Catia,
Trombino Giovanna Elvi,
Bonofiglio Daniela,
Catalano Stefania,
Andò Sebastiano
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.471.6
Subject(s) - aromatase , estrogen , androgen receptor , estrogen receptor , cancer research , endocrinology , medicine , androgen , biology , carcinogenesis , cancer , breast cancer , prostate cancer , hormone
In situ estrogen production by aromatase is a critical determinant for breast cancer growth and progression while androgens have a protective role in mammary carcinogenesis. Here we demonstrate in breast cancer cells, a novel androgen receptor (AR) mediated mechanism that negatively affects aromatase expression, reducing local estrogen production and cell proliferation. Ligand‐activated AR induces the expression of the orphan nuclear receptor DAX‐1 by binding to a newly identified ARE within the DAX‐1 promoter. In turn, increased DAX‐1 is recruited with the corepressor N‐CoR onto the SF‐1/LRH‐1 site of the aromatase promoter, thereby repressing aromatase expression and activity. Moreover DAX‐1 overexpression induces an apoptotic cell phenotype lying on an enhanced bad/bcl‐2 ratio. This molecular mechanism is reproduced in highly expressing aromatase R2C cells, a model for Leydig tumor, another estrogen‐dependent type of cancer. Interestingly, in vivo studies conducted in testes tissues from Fisher rats, spontaneously developing Leydig cell tumor, confirm the inverse relationship between AR/DAX‐1 and aromatase levels. In elucidating a novel mechanism by which androgens, through DAX‐1, inhibit aromatase expression in E2‐dependent tumors, these findings sustain the theory of androgen opposing estrogen action, opening new avenues for therapeutic intervention in endocrine‐related cancers.