Introduction: In polycystic ovary syndrome (PCOS), there is increased formation of androgens by thecal cells. Moreover, PCOS ovaries have been shown to have decreased levels of cFos transcription factor. We hypothesize that cFos expression inhibits CYP17 activity in the human ovary and its decreased expression seen in PCOS may lead to elevated CYP17 transcription, resulting in increased androgen production.

Objective: To define the role of the activator protein-1 (AP-1) transcription factors, namely cFos, in the regulation of CYP17 expression in theca cells.

Methods: Human ovarian thecal-like tumor (HOTT) cells were used for all experiments. The following techniques were used: steroid quantification, mRNA extraction, microarray analysis, transfection, siRNA and immunohistochemistry.

Results: Stimulation of HOTT cells with the PKA pathway activator forskolin resulted in stimulation of C19 androgen production. In contrast, treatment with the PKC pathway activator tetradecanoylphorbol acetate (TPA) resulted in decreased androgen production with a shift towards C21 progesterone production. TPA also led to complete inhibition of CYP17. Microarray data showed a 37 fold increase in cFos after treatment with TPA. Transfection with SF1 resulted in an increase in CYP17 promoter activity, which was significantly inhibited in the presence of cFos. cFos gene silencing led to an increase in CYP17 mRNA levels. Immunohistochemical staining for cFos in ovaries demonstrated strong staining in granulosa cells but not theca.

Conclusions: The AP-1 transcription factor cFos plays a role in the inhibition of CYP17 expression. The decreased levels of cFos expression in polycystic ovaries may be responsible for increased CYP17 levels in PCOS.