17?-Estradiol (E2) controls uterine growth and receptivity at the time of implantation, and also plays major roles in development and progression of human diseases such as breast and endometrial cancer and endometriosis. Major E2 effects are primarily mediated through estrogen receptor 1 (ESR1). Most ESR1 is nuclear, but 5-10% is located in cell membranes. Understanding how E2 induces its actions and relative roles of nuclear and membrane ESR1 (nESR1 and mESR1, respectively) in both normal physiology and pathology is an important goal in steroid endocrinology. Dr. Levin from our group has developed two unique and powerful mouse models, the nuclear-only ESR1 (NOER) mouse, which lacks mESR1 but retains nESR1, and the membrane-only ESR1 (MOER) mouse, which expresses mESR1, but lacks nESR1. Critically, female NOER mice are infertile, with extensive reproductive abnormalities, and E2 stimulation of uterine epithelial proliferation is impaired in these animals. This led to the unexpected conclusion that mESR1 and nESR1 must work in concert to allow normal E2 regulation of uterine epithelial proliferation and other parameters, and suggests that the classical model of estrogen action focusing on nESR1 is not totally correct. Our long-term goal is to use NOER and MOER mice to define how mESR1 and nESR1 work together to mediate E2-induced uterine epithelial mitogenesis and other E2 effects. The objective of this research is to compare E2-induced uterine epithelial proliferation in ovariectomized WT and NOER mice to determine the specific aspects of nESR1 signaling that may be impaired by lack of mESR1. Identifying differences in E2 responses of WT and NOER uteri will allow us to determine the critical role(s) of mESR1 in facilitating nESR1 signaling to allow E2-induced epithelial proliferation. Extensive evidence suggests that mESR1 effects are mediated through the phosphatidylinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways, and downstream events induced by this signaling may be critical for mESR1 effects. This work will also determine the relative roles of the MAPK and PI3K pathways in mESR1 action. Finally, we have developed a compound transgenic mouse to determine if the truncated mESR1 used to develop the MOER mouse can rescue the fertility and other deficits in E2 signaling in the NOER mouse. Our overall hypothesis is that mESR1, acting through protein kinases, is critical for one or more steps in the nESR1 signaling cascade initiated by E2, and that the truncated mESR1 used to develop MOER mice will be capable of restoring fertility and E2 responsiveness in NOER mice. Proposed experiments will test this hypothesis and provide new and important information regarding nESR1 and mESR1's roles in mitogenic and other effects of E2. These experiments will provide a mechanistic basis for understanding the role of mESR1 in one of the most critical uterine effects of E2, and delineate how mESR1 facilitates normal E2/nESR1 signaling. These results have the potential to be iconoclastic and literally change our model of steroid hormone action developed over the past half century, and also have clinical significance for female reproductive pathologies.
Estrogens act through estrogen receptors (ERs) located either in the cell membrane or nucleus; both fractions of receptors are critical for normal female reproductive tract development and function, but the role of membrane ERs has only recently begun to be elucidated. The goal of this research is to better understand the function of membrane ERs and how membrane and nuclear ER in the uterus work together to regulate normal estrogen responses. This work will have major human clinical significance, because membrane ERs may be involved in many important female reproductive pathologies in addition to their role in normal estrogen responses.
| Rosenfeld, Cheryl S; Cooke, Paul S (2018) Endocrine disruption through membrane estrogen receptors and novel pathways leading to rapid toxicological and epigenetic effects. J Steroid Biochem Mol Biol : |
| Hess, Rex A; Cooke, Paul S (2018) Estrogen in the male: a historical perspective. Biol Reprod 99:27-44 |
| Cunha, Gerald R; Kurita, Takeshi; Cao, Mei et al. (2018) Tissue interactions and estrogenic response during human female fetal reproductive tract development. Differentiation 101:39-45 |
| Nanjappa, Manjunatha K; Hess, Rex A; Medrano, Theresa I et al. (2016) Membrane-Localized Estrogen Receptor 1 Is Required for Normal Male Reproductive Development and Function in Mice. Endocrinology 157:2909-19 |
