A Model System to Investigate the Effect of BRCA1 and/or p53 Inactivation in the Ovarian Stroma on Growth and Transformation Potential of the Ovarian Epithelium

Abstract

Abstract : The tumor microenvironment plays an important role in cancer progression. The tumor stroma promotes angiogenesis and is a source of growth factors, chemokincs, and extracellular matrix (ECM) molecules that promotes carcinoma progression. We are investigating the effects of loss of function of BRCAl and Trp53 in the stroma on the growth and neoplastic transformation of epithelial cells using 2-D and 3-D in vitro culture models. Wamcn carrying gerrnline mutations in BRCAl are at high risk for developing ovarian cancer and mutations in pS3 arc frequently detected in ovarim tumors. Further, inactivation of BRCAl in mouse granulosa cells results in the development of benign epithelial neoplasm in the ovary and uterine horn, but the lesions themselves express wild-type BRCAl. Inactivation of BRACl also causes arrest at the G21M transition and significantly increases population doubling times; an effect that is reversed by inactivation of Trp53. 'Therefore, to directly test the hypothesis that stromal cells excrt a ccll-nonautonomous effect on ovarian epithelial cell growth and neoplastic transformation, we will examine the effects of culturing mouse ovarian surface epithelial (MOSE) cells with ECM and conditioned media from stromal calls in which BRACl and Trp53 have been inactivated (alone or in combination).