Dissertation
Progesterone receptor membrane components 1 and 2 in female reproductive physiology and pathology
Doctor of Philosophy (PhD), Washington State University
01/2017
Handle:
https://hdl.handle.net/2376/111610
Abstract
The female sex steroid hormones estrogen (E2) and progesterone (P4) are critical for normal female fertility, and aberrant E2 and P4 signaling can lead to female reproductive diseases like infertility and cancer. While many of the actions of E2 and P4 are mediated via their classical genomic receptors, some actions are mediated via non-classical pathways. Two non-classical P4 receptors are progesterone receptor membrane component 1 (PGRMC1) and PGRMC2. PGRMC1/2 are implicated in both hormone-dependent and -independent actions in tissues throughout the body. Specifically in the female reproductive system, multiple studies have identified the expression patterns of PGRMC1/2 during cyclicity and pregnancy and shown that PGRMC1/2 are aberrantly expressed in many disease states. Other studies have examined the functions of PGRMC1/2 in vitro and implicated these hemoproteins in various cell processes. However, a major hole in the field was in vivo functional data for PGRMC1/2. This dissertation presents the use of novel Pgrmc1 and/or Pgrmc2 conditional knockout mice, in which the genes were ablated from various female reproductive tissues. These mice revealed that PGRMC1/2 are critical for female fertility, such that lack of PGRMC1/2 leads to miscarriages due to failures in decidualization, a cell differentiation process during early pregnancy; further, lack of PGRMC1/2 leads to premature reproductive senescence. Studies of the Pgrmc1/2 knockout mice also revealed that PGRMC1/2 are required for uterine epithelial cells to properly undergo mitosis in response to E2. This is important because E2 drives many female reproductive cancers, and PGRMC1/2 are overexpressed in many of these cancers. Of note, studies in this dissertation show that ablation of PGRMC2 in the uterus attenuates the severity of Pten loss-induced endometrial hyperplasia and cancer. Similarly, knockdown of PGRMC1 in breast cancer cells renders them more susceptible to chemotherapy and less able to generate xenograft tumors. Overall, the studies presented in this dissertation are novel because they are the first to analyze the function of PGRMC1/2 on an in vivo physiological level. Additionally, the Pgrmc1/2 knockout mice present a model system for studying recurrent miscarriage. Finally, PGRMC1/2 are identified as possible targets for pharmacological inhibition to treat breast and endometrial cancer.
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Details
- Title
- Progesterone receptor membrane components 1 and 2 in female reproductive physiology and pathology
- Creators
- Nicole Catherine Kelp
- Contributors
- James K Pru (Advisor)Jon M Oatley (Committee Member)Pat A Hunt (Committee Member)Wipawee Winuthayanon (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- School of Molecular Biosciences
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Number of pages
- 265
- Identifiers
- 99900581825301842
- Language
- English
- Resource Type
- Dissertation