Tissue-Specific Pathways for Estrogen Regulation of Ovarian Cancer Growth and Metastasis

Abstract

Menopausal estrogen (E2) replacement therapy increases the risk of estrogen receptor (ER)-positive epithelial ovarian cancers (EOC). Whether E2 is tumorigenic or promotes expansion of undiagnosed pre-existing disease is unknown. To determine E2 effects on tumor promotion, we developed an intraperitoneal mouse xenograft model using ZsGreen fluorescent ER− 2008 and ER+ PEO4 human EOC cells. Tumor growth was quantified by in vivo fluorescent imaging. In ER+ tumors, E2 significantly increased size, induced progesterone receptors, and promoted lymph node metastasis, confirming that ER are functional and foster aggressiveness. Laser captured human EOC cells from ER− and ER+ xenografted tumors were profiled for expression of E2-regulated genes. Three classes of E-regulated EOC genes were defined, but less than 10% were shared with E-regulated breast cancer genes. Since breast cancer selective ER modulators (SERMs) are therapeutically ineffective in EOC, we suggest that our EOC-specific E-regulated genes can assist pharmacologic discovery of ovarian targeted SERM.

Discovery of an orally active small-molecule irreversible inhibitor of protein disulfide isomerase for ovarian cancer treatment

“…Compared with normal tissues, PDI is overexpressed in ovarian tumors (8). In addition, estrogen has been reported to increase PDI expression (29), bind PDI (30), and promote ovarian cancer progression (31). Based on these evidences, PDI is a promising drug target for ovarian cancer therapy.…”

Potential Therapeutic Targets for the Primary Gallbladder Carcinoma: Estrogen Receptors

“…It is well known that all of the various biological effects of estrogen are mediated by binding to the specific estrogen receptors (ERs), which belong to the nuclear receptor superfamily, a family of ligand-regulated transcription factors (Evans,1988). In fact, ERs have been detectable in a range of human tumor tissues, such as breast (Yamaguchi and Hayashi, 2009;Welsh et al, 2012), the alimentary tract (Sica et al, 1984), melanoma (Fisher et al, 1976), endometrial (Wallace et al, 2010), ovarian (Spillman et al, 2010), pancreas (Greenway et al, 1981), biliary tract (Yamamoto et al, 1990;DeMorrow, 2009;Mancino et al, 2009;Park et al, 2009;Isse et al, 2010;Gupta et al, 2012;Hunsawong et al, 2012). Thereby, ERs may be the possible carcinogenic factors.…”

Cytokeratin 5 positive cells represent a therapy resistant subpopulation in epithelial ovarian cancer

“…Although ~60% of ovarian cancers express ER, a role for estrogens and ERs in ovarian cancer remains an enigma. Although estrogens increase ovarian cancer cell growth in pre-clinical models (23,24), targeted hormonal therapy has minimal efficacy in treating ovarian cancers (38). ERs, however, may have prognostic significance.…”

“…Around 60% of ovarian cancers are ER+ (22), a similar proportion to breast cancer (21). There is some evidence that estrogens are tumor promotional in pre-clinical models of ovarian cancer (23,24). However, targeted endocrine therapies are mostly ineffective in patients (25)(26)(27).…”