Roles of class 1A PI3K isoforms in mammary epithelium function and breast cancer Abstract Section a. Summary Class IA phosphatidylinositol 3-kinases (PI3Ks) are activated by growth factor receptor tyrosine kinases (RTKs) and Ras to generate the primary intracellular lipid signal, phosphatidylinositol 3,4,5-trisphosphate (PIP3), essential for multiple cellular processes, including survival, proliferation and differentiation. The tumor suppressor PTEN, a lipid phosphatase, dephosphorylates PIP3 and therefore counteracts the action of PI3Ks. Constitutive activation of the class IA PI3K signaling pathway via direct or indirect mutagenic events is amongst the most frequent events in human breast cancer. Thus, class 1A PI3Ks are attractive targets for therapeutic intervention in breast cancer. In mammals, there are two class 1A PI3K catalytic isoforms, p110? and p110?, which are ubiquitously expressed in epithelial tissues/organs, among other sites. Despite their similarity in molecular structure and enzymatic activity, recent studies suggest that the two isoforms have distinct functions in cell signaling and oncogenic transformation. However, we have very limited understanding of the specific functions for each type of PI3K. All class IA PI3Ks display the same sensitivity to the classical PI3K inhibitors wortmannin and LY294002. Mice lacking p110? or p110? are early embryonic lethal, which precluded further delineation of their specific functions. We recently generated conditional knockout animals for the p110? and p110? genes via the Cre/loxP recombination system to facilitate the study of class 1A PI3Ks. In this application, we want to test our hypothesis that p110? and p110? have distinct biological roles in mammary epithelium function and tumorigenesis. This hypothesis leads to predictions that we propose to test in cell culture and animal models.
The Specific Aims are as follows. 1. To test the prediction that p110? and p110? have distinct roles in signal transduction and cell proliferation in mouse mammary epithelial cells (MMECs). 2. To test the prediction that p110? and p110? have distinct roles in mammary gland development. 3. To test the prediction that p110? and p110? have distinct functions in breast tumorigenesis driven by oncogenic Her2/Neu. These studies will advance our understanding of the functions of PI3K isoforms and provide information critical to developing effective, specific and less toxic PI3K inhibitors for cancer treatment. b. Relevance to Public Health The Class IA PI3K signaling pathway is hyper-activated in a high percentage of human cancers, including breast, brain and colon cancers, and is also highly suited for pharmacologic intervention. However, because PI3K activity is involved in multiple fundamental physiological functions, there is a considerable risk that its inhibition may have toxic side effects. The information derived from this study will not only provide us with comprehensive knowledge of PI3K isoforms in normal breast tissue function and tumor pathogenesis, but will also help us to evaluate critical drug targets to facilitate the development of more specific and less toxic drugs for breast cancer treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA134502-05
Application #
8301002
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Yassin, Rihab R,
Project Start
2008-09-26
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$324,985
Indirect Cost
$123,710
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Cheng, Hailing; Liu, Pixu; Zhang, Fan et al. (2014) A genetic mouse model of invasive endometrial cancer driven by concurrent loss of Pten and Lkb1 Is highly responsive to mTOR inhibition. Cancer Res 74:15-23
Hanker, Ariella B; Pfefferle, Adam D; Balko, Justin M et al. (2013) Mutant PIK3CA accelerates HER2-driven transgenic mammary tumors and induces resistance to combinations of anti-HER2 therapies. Proc Natl Acad Sci U S A 110:14372-7
Wang, Qi; Von, Thanh; Bronson, Roderick et al. (2013) Spatially distinct roles of class Ia PI3K isoforms in the development and maintenance of PTEN hamartoma tumor syndrome. Genes Dev 27:1568-80
Jia, Shidong; Gao, Xueliang; Lee, Sang Hyun et al. (2013) Opposing effects of androgen deprivation and targeted therapy on prostate cancer prevention. Cancer Discov 3:44-51
Sopasakis, Victoria Rotter; Liu, Pixu; Suzuki, Ryo et al. (2010) Specific roles of the p110alpha isoform of phosphatidylinsositol 3-kinase in hepatic insulin signaling and metabolic regulation. Cell Metab 11:220-30
Johannessen, Cory M; Boehm, Jesse S; Kim, So Young et al. (2010) COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468:968-72
Xu, Yong; Hill, Jennifer W; Fukuda, Makoto et al. (2010) PI3K signaling in the ventromedial hypothalamic nucleus is required for normal energy homeostasis. Cell Metab 12:88-95
Liu, Pixu; Cheng, Hailing; Roberts, Thomas M et al. (2009) Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 8:627-44
Jia, Shidong; Roberts, Thomas M; Zhao, Jean J (2009) Should individual PI3 kinase isoforms be targeted in cancer? Curr Opin Cell Biol 21:199-208
Hill, Jennifer W; Xu, Yong; Preitner, Frederic et al. (2009) Phosphatidyl inositol 3-kinase signaling in hypothalamic proopiomelanocortin neurons contributes to the regulation of glucose homeostasis. Endocrinology 150:4874-82

Showing the most recent 10 out of 12 publications