Estrogen signaling in the ovary is a fundamental component of normal ovarian function, and evidence also indicates that excessive estrogen is a risk factor for ovarian cancer. We have previously demonstrated that the gonadally enriched TFIID subunit TAF4B, a paralog of the general transcription factor TAF4A, is required for fertility in mice and for the proliferation of ovarian granulosa cells following hormonal stimulation. However, the relationship between TAF4B and estrogen signaling in the normal ovary or during ovarian tumor initiation and progression has yet to be defined. Herein, we show that Taf4b mRNA and TAF4B protein, but not Taf4a mRNA or TAF4A protein, are increased in whole ovaries and granulosa cells of the ovary after exposure to 17beta-estradiol or the synthetic estrogen diethylstilbestrol and that this response occurs within hours after stimulation. Furthermore, this increase occurs via nuclear estrogen receptors both in vivo and in a mouse granulosa cancer cell line, NT-1. We observe a significant increase in Taf4b mRNA in estrogen-supplemented mouse ovarian tumors, which correlates with diminished survival of these mice. These data highlight the novel response of the general transcription factor TAF4B to estrogen in the normal ovary and during ovarian tumor progression in the mouse, suggesting its potential role in regulating actions downstream of estrogen stimulation.
Female infertility affects approximately 10.9% of women ages 15-44 in the US, and the molecular mechanisms leading to this disorder are multifaceted and varied. We have previously demonstrated that the gonadal-enriched TFIID subunit TAF4B, a paralog of the general transcription factor TAF4A, is required for fertility in mice. Female mice deficient for TAF4B exhibit a phenotype resembling premature ovarian failure, including early oocyte loss, follicular atresia and severely reduced granulosa cell proliferation when treated with 17β-estradiol. The inability of estrogen to stimulate granulosa cell proliferation led us to hypothesize that TAF4B is involved in an estrogen signaling pathway within the ovary. A large percentage of Taf4b-knockout oocytes die by apoptosis immediately after birth, and this germ cell loss is attenuated by estrogen supplementation, further suggesting a connection between TAF4B and estrogen. Taf4b-knockout ovaries also display deregulated epigenetic marks, which can affect DNA repair during meiotic homologous recombination. Furthermore, estrogen is known to regulate epigenetic changes in the ovary, leading us to hypothesize that the estrogen rescue may occur via modulation of the epigenetic state and consequent repair of double-strand breaks during meiosis. Here, we show that Taf4b mRNA and TAF4B protein expression are upregulated by estrogens in whole ovaries and purified granulosa cells of the ovary and that this increase occurs via nuclear estrogen receptors. We observe significant increases of Taf4b mRNA in estrogen-exposed mouse ovarian tumors, and the mice exposed to estradiol had significantly diminished survival compared to those receiving a placebo pellet. Combined with the fact that epigenetic deregulation and DNA repair processes play a key role in tumorigenesis, these results suggest that in addition to fertility defects, TAF4B could also affect ovarian tumorigenesis later in life. Our preliminary data suggest that the loss of oocytes in Taf4b-knockout ovaries may occur due to deficiencies in epigenetic regulation and/or a deficiency in DNA repair during meiotic prophase, since DNA repair and meiosis related genes are significantly reduced in Taf4b-knockout ovaries. Future studies will determine if estrogen treatment of neonatal Taf4b-knockout ovaries ameliorates these epigenetic and DNA repair deficits, leading to the observed oocyte rescue, and will explore if ovarian tumorigenesis is altered in the absence of TAF4B. Citation Format: Jennifer R. Wardell, Kathryn J. Grive, Kendra M. Hodgkinson, April K. Binder, Kimberly A. Seymour, Lindsay A. Lovasco, Ken S. Korach, Barbara C. Vanderhyden and Richard N. Freiman. Estrogen-responsiveness of the TFIID subunit TAF4B and its potential function in ovarian cancer, epigenetic regulation and meiotic DNA repair. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A81.
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