title: Androgens inhibit aromatase expression through DAX-1: insights into the molecular link between hormone balance and Leydig cancer development.
abstract: Leydig cell tumors (LCTs) of the testis are steroid-secreting tumors associated with various steroid biosynthetic abnormalities and endocrine dysfunctions. Despite their overall rarity, LCTs are still of substantial interest owing to the paucity of information regarding their exact nature and malignant potential. In the present study, we disclose the ability of androgens to inhibit Leydig tumor cell proliferation by opposing to self-sufficient in situ estrogen production. In rat Leydig tumor cells, R2C, androgen treatment significantly decreases the expression and the enzymatic activity of cytocrome P450 aromatase, responsible for the local conversion of androgens into estrogens. This inhibitory effect relies on androgen receptor (AR) activation and involves negative regulation of the CYP19 gene transcriptional activity through the nuclear orphan receptor DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1). Ligand-activated AR up-regulates the expression of DAX-1 and promotes its increased recruitment within the steroidogenic factor-1 site-containing region of the aromatase proximal promoter II in association with the nuclear receptor corepressor. The biological relevance in LCTs of the newly highlighted functional interplay between AR, DAX-1, and aromatase is underlined by our in vivo observations, revealing a marked down-regulation of AR and DAX-1 expression and a strong increase in aromatase levels in testes tissues from old Fischer rats with spontaneously developed Leydig cell neoplasia, compared with normal testes tissues from younger animals. In elucidating a mechanism by which androgens modulate the growth of Leydig tumor cells, our finding support the hypothesis that maintaining the adequate balance between androgen and estrogens may represent the key for blocking estrogen-secreting Leydigioma development, opening new prospects for therapeutic intervention.
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences (P.M., A.C., I.B., C.M., R.M., D.S., S.Aq., V.R., D.B., S.C., M.L., S.An.) and Centro Sanitario (C.G., D.S., S.Aq., D.B., S.C., M.L., S.An.), University of Calabria, 87036 Arcavacata di Rende (Cosenza), Italy.
authors.forename: Pamela
authors.initials: P
authors.lastname: Maris
authors.forename: Antonella
authors.initials: A
authors.lastname: Campana
authors.forename: Ines
authors.initials: I
authors.lastname: Barone
authors.forename: Cinzia
authors.initials: C
authors.lastname: Giordano
authors.forename: Catia
authors.initials: C
authors.lastname: Morelli
authors.forename: Rocco
authors.initials: R
authors.lastname: Malivindi
authors.forename: Diego
authors.initials: D
authors.lastname: Sisci
authors.forename: Saveria
authors.initials: S
authors.lastname: Aquila
authors.forename: Vittoria
authors.initials: V
authors.lastname: Rago
authors.forename: Daniela
authors.initials: D
authors.lastname: Bonofiglio
authors.forename: Stefania
authors.initials: S
authors.lastname: Catalano
authors.forename: Marilena
authors.initials: M
authors.lastname: Lanzino
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Andò
mesh_terms: D000728:Androgens / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001141:Aromatase / Q000378:metabolism*; D045744:Cell Line, Tumor; D057137:DAX-1 Orphan Nuclear Receptor / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007984:Leydig Cell Tumor / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013736:Testicular Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000728:Androgens; D057137:DAX-1 Orphan Nuclear Receptor; C539967:Nr0b1 protein, rat; D011944:Receptors, Androgen; D001141:Aromatase