Endometrial cancer is the most common malignancy of the female genital tract. It is now accepted that the long-term use of synthetic estrogen receptor modulators (SERM) such as tamoxifen are associated with an increased risk of developing endometrial cancer. In addition to endometrial cancer, tamoxifen use has also been associated with endometrial thickening, dysfunctional uterine bleeding, endometrial polyps, endometrial hyperplasia, and uterine sarcoma. Despite the remarkable growth of information about the clinical utility of SERM, the progress in understanding the mechanism by which cellular target(s) of SERMs modulate endometrial carcinogenesis remains elusive. As described below, our recent work suggests that stimulation of p21-activated kinase (Pak1), a serine/threonine signaling kinase, plays a significant role in cell motility, invasiveness and survival, all of which are required for tumor progression (7). Our preliminary studies have discovered that SERM stimulates the expression and activity of Pak1, that dynein light chain 1 (DLC1) is a physiological target of Pak1, and that the Pak1-DLC1 pathway may be involved in the molecular pathogenesis of endometrial cancer. Here we propose to investigate the molecular mechanism by which Pak1 and DLC1 participate in the regulation of estrogen receptor (ER) functions and tumorigenic phenotypes in endometrial cancer cells upon SERM exposure. Since hyperexpression of Pak1 and DLC1 may contribute to the development of aggressive phenotypes, dysfunction in the Pak1 pathway in the endometrium may constitute an important early step(s) in endometrial cancer development. Thus, our working hypotheses are """"""""SERM-mediated deregulation of Pakl activity stimulates DL C phosphorylation and ER functions, and consequently, contributes to an enhanced cell survival, anchorage-independence, and progression of endometrial cancer cells; these phenotypic effects of Pakl might be controlled by ER phosphorylation by Pak1 and further potentiated by Pak1 modulation of DLC1-ER interaction"""""""". In addition, we will also delineate ER-independent tumorigenic functions of Pak1 and DLC1 in endometrial cancer cells. To address these hypotheses, our specific aims are to determine: (1) The biochemical basis and functional significance of SERM regulation of Pak1 in endometrial cancer cells; (2) The influence of DLC overexpression and Pak1 regulation of DLC1 functions on the phenotypic changes associated with the progression of endometrial cancer; (3) The influence of SERM on the functions of Pakl and DLC1, and on the biology endometrial tumorigenesis using the Pten heterozygous mice progression model; and (4) he expression characteristics and significance of Pak1 and DLC1 during multi-step endometrial cancer pathogenesis in humans. An innovative aspect of our proposal is the use of novel in vitro, in vivo transgenic models, and human endometrial tumors with follow-up data to gain new insight about the roles of Pak1 and DLC1 in the biology and tumorigenesis of endometrial cancer. These studies will uniquely define the mechanisms through which DLC1 and its upstream Pak1 kinase regulate survival, mitogenesis and tumorigenesis of endometrial cancer cells. Our proposed research is significant in that the knowledge gained from this research will enhance our understanding of the roles of newly identified cellular targets of SERM in the biology of endometrium. A better understanding of critical regulatory pathways with roles in cancer progression is likely to form the basis for new advances in identifying novel molecular targets, detecting, and treating endometrial cancer, by identifying Pak1-DLC as key regulatory signaling nodule in the action of SERM.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA109379-02
Application #
6929343
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2004-08-01
Project End
2009-05-31
Budget Start
2005-08-01
Budget End
2006-05-31
Support Year
2
Fiscal Year
2005
Total Cost
$309,550
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Microbiology/Immun/Virology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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Manavathi, Bramanandam; Kumar, Rakesh (2006) Steering estrogen signals from the plasma membrane to the nucleus: two sides of the coin. J Cell Physiol 207:594-604

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