Endometrial cancer (EC) is the fourth most frequent cancer in women, ranking first in incidence and second in mortality among female genital tract tumors. Although several genetic lesions associated with EEC have been identified, numerous grey areas still exist, especially regarding the mechanism of action of these mutations and their relative contribution to the progression from hyperplasia to metastatic cancer. A relationship between excess estrogen and type I EC (EEC) has been recognized for decades; however little is known about the molecular basis of this association. The broad, long- term objective of this project is to determine the role of the PI3K/PTEN/AKT pathway in endometrial hyperplastic and neoplastic transformation, and to elucidate the mechanisms relevant to these functions. As with most other neoplastic diseases, the elucidation of the pathogenetic basis of EC initiation and progression at the molecular level are greatly facilitated by laboratory models. Emerging reagents and strategies allow us to use the mouse in more and more sophisticated ways to define the molecular, cellular and physiological events that lead to cancer initiation and progression. We have developed a mouse strain that closely recapitulates several features of the progression from endometrial hyperplasia to neoplasia. We propose to utilize a combination of direct in vivo genetic approaches and ex vivo and in vitro experiments to carry out the following specific aims:
Aim 1, To test the hypothesis that AKT activation in EEC causes a physiologically relevant alteration of ER1-mediated signaling.
Aim 2, To identify and characterize, in mutant mice and cells, novel specific pathogenetic mechanisms activated by Pten loss during EEC initiation. The proper diagnosis and management of endometrial cancer are still major challenges in clinical oncology, as we still do not understand clearly the mechanisms that are altered during the progression from hyperplasia to cancer. This proposal is designed to dissect several specific biochemical and genetic pathways controlled by PTEN in its tumor suppressive function in the endometrial epithelium, and to define novel mechanisms involved in neoplastic transformation using engineered model systems that closely mimic the molecular events taking place in human lesions. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA097097-05A1
Application #
7461350
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Mietz, Judy
Project Start
2002-07-01
Project End
2009-04-30
Budget Start
2008-06-01
Budget End
2009-04-30
Support Year
5
Fiscal Year
2008
Total Cost
$344,347
Indirect Cost
Name
Fox Chase Cancer Center
Department
Type
DUNS #
073724262
City
Philadelphia
State
PA
Country
United States
Zip Code
19111
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Dima, Mariavittoria; Miller, Kelly A; Antico-Arciuch, Valeria Gabriela et al. (2011) Establishment and characterization of cell lines from a novel mouse model of poorly differentiated thyroid carcinoma: powerful tools for basic and preclinical research. Thyroid 21:1001-7
Herrero-Gonzalez, Sandra; Di Cristofano, Antonio (2011) New routes to old places: PIK3R1 and PIK3R2 join PIK3CA and PTEN as endometrial cancer genes. Cancer Discov 1:106-7
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Yeager, Nicole; Brewer, Charlene; Cai, Kathy Qi et al. (2008) Mammalian target of rapamycin is the key effector of phosphatidylinositol-3-OH-initiated proliferative signals in the thyroid follicular epithelium. Cancer Res 68:444-9
Di Cristofano, Antonio; Ellenson, Lora Hedrick (2007) Endometrial carcinoma. Annu Rev Pathol 2:57-85
Lian, Zenglin; De Luca, Pasquale; Di Cristofano, Antonio (2006) Gene expression analysis reveals a signature of estrogen receptor activation upon loss of Pten in a mouse model of endometrial cancer. J Cell Physiol 208:255-66
Vilgelm, Anna; Lian, Zenglin; Wang, Hong et al. (2006) Akt-mediated phosphorylation and activation of estrogen receptor alpha is required for endometrial neoplastic transformation in Pten+/- mice. Cancer Res 66:3375-80

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