Very little is known about the molecular mechanisms that underlie the pathophysiology of leiomyoma uteri. In contrast to carcinomas which are generally singular and for which the stages of tumorigenesis and associated molecular alterations are well described, leiomyoma uteri are usually multiple and events that determine their long-term sequelae have not been elucidated. Furthermore, the natural history of individual leiomyomas within a single woman may be quite different. This indicates that even though tumors within a given woman are exposed to the same hormonal mileu, inter-tumor heterogeneity in hormone responsiveness must exist. Such inter-tumor heterogeneity may be the result of differences in molecular etiology, which could also determine responsiveness to hormonal therapy and the impact of environmental estrogen exposure. Loss of the tuberous sclerosis complex 2 (TSC-2) tumor suppressor gene results in the development of leiomyoma uteri in the Eker rat model for this disease. However, defects in TSC-2 or the pathways in which this tumor suppressor gene participate have not been investigated in human leiomyomas. Recently, the TSC- 2 gene product tuberin has been shown to play an important role in PI3K signaling, which can impact both estrogen receptor signaling and cell cycle control via p27. Our preliminary data from the Eker rat model and translational studies utilizing primary human tumors suggest that TSC-2 and p27 play important, and possibly inter-related, roles in the molecular etiology of leiomyoma uteri. Recognition of the involvement of TSC-2, PI3K signaling and p27 in the etiology of leiomyoma uteri now provides a unique avenue for understanding the molecular basis of aberrant cell cycle regulation and hormonal responsiveness in this disease. The goal of this proposal is to identify the mechanisms responsible for differential cell cycle regulation in leiomyoma uteri that may underlie inter-tumor heterogeneity and responsiveness. To accomplish this goal, the Specific Aims of this proposal are: 1) Determine the mechanism responsible for diminished p27 function in leiomyoma uteri and the role of PI3K signaling and tuberin in this process; 2) Test the hypothesis that alteration of p27 expression levels is a critical regulator of normal and neoplastic myometrial cell growth that can determine natural history of this disease; and 3) Determine if diminished p27 levels and/or aberrant P13K/AKT signaling enhances estrogen-receptor signaling in leiomyomas and potentiates the activity of SERMs and environmental estrogens in these tumors. Data generated from these experiments will help elucidate how defective cell cycle regulation and estrogen receptor signaling to contribute to the pathophysiology of leiomyoma uteri.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD046282-02
Application #
6804104
Study Section
Special Emphasis Panel (ZRG1-ENR (50))
Program Officer
Parrott, Estella C
Project Start
2003-09-24
Project End
2008-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
2
Fiscal Year
2004
Total Cost
$302,000
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Greathouse, K Leigh; Bredfeldt, Tiffany; Everitt, Jeffrey I et al. (2012) Environmental estrogens differentially engage the histone methyltransferase EZH2 to increase risk of uterine tumorigenesis. Mol Cancer Res 10:546-57
Itamochi, Hiroaki; Yoshida, Tomokazu; Walker, Cheryl Lyn et al. (2011) Novel mechanism of reduced proliferation in ovarian clear cell carcinoma cells: cytoplasmic sequestration of CDK2 by p27. Gynecol Oncol 122:641-7
Short, John D; Dere, Ruhee; Houston, Kevin D et al. (2010) AMPK-mediated phosphorylation of murine p27 at T197 promotes binding of 14-3-3 proteins and increases p27 stability. Mol Carcinog 49:429-39
McCampbell, Adrienne S; Broaddus, Russell R; Walker, Cheryl L (2010) Loss of inhibitory insulin receptor substrate-1 phosphorylation: An early event in endometrial hyperplasia and progression to carcinoma. Cell Cycle 9:2698-9
McCampbell, Adrienne S; Harris, Heather A; Crabtree, Judy S et al. (2010) Loss of inhibitory insulin receptor substrate-1 phosphorylation is an early event in mammalian target of rapamycin-dependent endometrial hyperplasia and carcinoma. Cancer Prev Res (Phila) 3:290-300
Kim, Jinhee; Jonasch, Eric; Alexander, Angela et al. (2009) Cytoplasmic sequestration of p27 via AKT phosphorylation in renal cell carcinoma. Clin Cancer Res 15:81-90
Short, John D; Houston, Kevin D; Dere, Ruhee et al. (2008) AMP-activated protein kinase signaling results in cytoplasmic sequestration of p27. Cancer Res 68:6496-506
McCampbell, Adrienne S; Walker, Cheryl L; Broaddus, Russell R et al. (2008) Developmental reprogramming of IGF signaling and susceptibility to endometrial hyperplasia in the rat. Lab Invest 88:615-26
Greathouse, K L; Cook, J D; Lin, K et al. (2008) Identification of uterine leiomyoma genes developmentally reprogrammed by neonatal exposure to diethylstilbestrol. Reprod Sci 15:765-78
Woodruff, Teresa K; Walker, Cheryl Lyn (2008) Fetal and early postnatal environmental exposures and reproductive health effects in the female. Fertil Steril 89:e47-51

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