Uterine leiomyomata are the most common human gynecologic tumors, and recent retrospective studies report an incidence approaching 70%. Although not all of these women are symptomatic, these tumors represent a significant cause of morbidity in the United states and are responsible for over 200,000 surgeries annually. Leiomyomas are often associated with infertility and an additional 18,000 myomectomies are performed each year to reduce tumor burden while sparing the uterus. At present, non-surgical treatments include Danazol and GnRH agonists that induce a hypoestrogenic milieu, but cause important side effects including androgenization and bone loss. Following short term treatment, the tumors often return, sometimes within a few months. There is presently a controversy, that has significant therapeutic implications, concerning the relative importance of estrogen versus progesterone in the development of normal myometrium and uterine leiomyomata. One of the primary responses to estrogen in many tissues is the upregulation of PR, but the role of PR in estrogen-induced pathways of proliferation and tumorigenesis is not clear. It has been difficult to dissect out the contribution of these two hormones because of the interrelationship of the two receptor pathways including the increase in PR expression induced by estrogen. The goal of the proposed studies is to evaluate the relative contributions of progesterone and estrogen in normal and neoplastic myometrium using a recently developed PR knock-out (PR-/-) mouse.
The specific aims of this project are: 1} To evaluate the role of PR in estrogen stimulated myometrial cell proliferation; 2) To determine at the molecular level which genes activated by estrogen stimulation require and functional PR, and 3} To test the hypothesis that PR plays a critical role in myometrial tumorigenesis. These studies will yield valuable mechanistic information about steroid hormone action and the relationship between hormonally induced proliferation and tumorigenesis. Results from these experiments will also provide critical insight into factors affecting leiomyomata development and could significantly impact drug development by directing efforts to specific members of relevant hormone receptor pathways.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29CA077863-05
Application #
6475816
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Sathyamoorthy, Neeraja
Project Start
1998-01-07
Project End
2002-11-30
Budget Start
2001-12-01
Budget End
2002-11-30
Support Year
5
Fiscal Year
2002
Total Cost
$65,070
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Organized Research Units
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Walker, C L; Burroughs, K D; Davis, B et al. (2000) Preclinical evidence for therapeutic efficacy of selective estrogen receptor modulators for uterine leiomyoma. J Soc Gynecol Investig 7:249-56
Gamage, S D; Bischoff, E D; Burroughs, K D et al. (2000) Efficacy of LGD1069 (Targretin), a retinoid X receptor-selective ligand, for treatment of uterine leiomyoma. J Pharmacol Exp Ther 295:677-81