title: Dysregulated estrogen receptor signaling in the hypothalamic-pituitary-ovarian axis leads to ovarian epithelial tumorigenesis in mice.
abstract: The etiology of ovarian epithelial cancer is poorly understood, mainly due to the lack of an appropriate experimental model for studying the onset and progression of this disease. We have created a mutant mouse model in which aberrant estrogen receptor alpha (ERα) signaling in the hypothalamic-pituitary-ovarian axis leads to ovarian epithelial tumorigenesis. In these mice, termed ERαd/d, the ERα gene was conditionally deleted in the anterior pituitary, but remained intact in the hypothalamus and the ovary. The loss of negative-feedback regulation by estrogen (E) at the level of the pituitary led to increased production of luteinizing hormone (LH) by this tissue. Hyperstimulation of the ovarian cells by LH resulted in elevated steroidogenesis, producing high circulating levels of steroid hormones, including E. The ERαd/d mice exhibited formation of palpable ovarian epithelial tumors starting at 5 months of age with 100% penetrance. By 15 months of age, 80% of ERαd/d mice die. Besides proliferating epithelial cells, these tumors also contained an expanded population of luteinized stromal cells, which acquire the ability to express P450 aromatase and synthesize E locally. In response to the elevated levels of E, the ERα signaling was accentuated in the ovarian epithelial cells of ERαd/d mice, triggering increased ERα-dependent gene expression, abnormal cell proliferation, and tumorigenesis. Consistent with these findings, treatment of ERαd/d mice with letrozole, an aromatase inhibitor, markedly reduced circulating E and ovarian tumor volume. We have, therefore, developed a unique animal model, which serves as a useful tool for exploring the involvement of E-dependent signaling pathways in ovarian epithelial tumorigenesis.
authors.affiliation: Department of Comparative Biosciences, University of Illinois Urbana/Champaign, Urbana, Illinois, United States of America.
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Laws
authors.affiliation: Department of Comparative Biosciences, University of Illinois Urbana/Champaign, Urbana, Illinois, United States of America.
authors.forename: Athilakshmi
authors.initials: A
authors.lastname: Kannan
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois Urbana/Champaign, Urbana, Illinois, United States of America.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Pawar
authors.affiliation: Department of Pathobiology, University of Illinois Urbana/Champaign, Urbana, Illinois, United States of America.
authors.forename: Wanda M
authors.initials: WM
authors.lastname: Haschek
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois Urbana/Champaign, Urbana, Illinois, United States of America.
authors.forename: Milan K
authors.initials: MK
authors.lastname: Bagchi
authors.affiliation: Department of Comparative Biosciences, University of Illinois Urbana/Champaign, Urbana, Illinois, United States of America.
authors.forename: Indrani C
authors.initials: IC
authors.lastname: Bagchi
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D000077216:Carcinoma, Ovarian Epithelial; D047628:Estrogen Receptor alpha / Q000096:biosynthesis* / Q000235:genetics; D004967:Estrogens / Q000008:administration & dosage / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism; D000077289:Letrozole; D051379:Mice; D009375:Neoplasms, Glandular and Epithelial / Q000209:etiology / Q000235:genetics* / Q000473:pathology*; D009570:Nitriles / Q000008:administration & dosage; D010051:Ovarian Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology*; D010053:Ovary / Q000378:metabolism / Q000473:pathology; D010902:Pituitary Gland / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014230:Triazoles / Q000008:administration & dosage
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; D009570:Nitriles; D014230:Triazoles; D007987:Gonadotropin-Releasing Hormone; D000077289:Letrozole