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Submitted on February 15, 2005
Accepted on August 9, 2005
Ontogeny-Reproduction Research Unit, Centre Hospitalier Universitaire de Québec (CHUQ)-Centre Hospitalier de l'Université Laval (CHUL) Research Centre, Ste-Foy, Québec, Canada, G1V 4G2; Centre de Recherche en Biologie de la Reproduction (CRBR), Department of Obstetrics and Gynecology, Faculty of Medicine, Université Laval, Québec, Canada, G1K 7P4
* To whom correspondence should be addressed. E-mail: Robert.Viger{at}crchul.ulaval.ca.
Cancers, including that of the breast, are the result of multiple contributing factors including aberrant gene expression. Indeed, the CYP19 gene encoding P450 aromatase, the key enzyme for estrogen biosynthesis, is upregulated in breast tumors predominantly via the cAMP-responsive gonad-type PII promoter, ultimately leading to increased intratumoral estrogen production and tumor growth. Thus, identifying the molecular factors involved in aromatase PII promoter regulation is essential for our understanding and treatment of the disease. Since we have previously shown activity of the murine aromatase PII promoter to be markedly upregulated by GATA factors with respect to the gonads, we hypothesized that GATA factors are also key determinants of human PII promoter-driven aromatase transcription in breast tumors. We now show that GATA3 and GATA4 are indeed expressed in several breast cancer cells lines. Consistent with the cAMP dependence of the PII promoter, activation elicited by GATA3 or GATA4 alone and the striking synergism between GATA3 or GATA4 and the nuclear receptor LRH-1 was intimately linked to forskolin treatment or overexpression of protein kinase A (PKA) catalytic subunit. PKA-mediated phosphorylation increases the interaction between GATA3 and LRH-1 and the the requirement for PKA in aromatase PII promoter stimulation involves at least three specific amino acid residues: GATA3 Ser308, GATA4 Ser261, and LRH-1 Ser469. Finally, we show that the human LRH-1 promoter is itself a target for GATA factors. Thus, taken together, our results suggest that GATA factors likely contribute to aberrant aromatase expression in breast tumors through two distinct, yet complementary mechanisms.
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