Abstract

Background: The MMAC1 (a.k.a. PTEN/TEP tumor suppressor gene on 10q23 is mutated in sporadic breast cancer as well as in the Cowden's breast cancer predisposition syndrome. MMAC1 has been shown to be a multifunctional phosphatase capable of dephophorylating proteins as well as the 3' hydroxyl of the inositol ring of membrane phosphatidylinositols (Ptdlns). This suggests that MMAC1 targets the signaling cascade initiated by phosphatidyl inositol 3'kinase (P13K). Expression of MMAC1 in MMAC1 mutant glioma cells decreases growth rates and decreases migration and formation of focal adhesion complexes. The effects of MMAC1 on breast cancer cells has not been explored. Preliminary data: Our preliminary data indicates that the MMAC1 tumor suppressor gene inhibits signaling through the P13K pathway without affecting the RAS/MAPK pathway. Expression of MMAC1 or inhibition of P13K with LY294002 in breast cancer cells with mutant MMAC1 leads to a marked decrease in proliferation, which is associated with increased rates of apoptosis and anoikis. Rationale: The proposed studies will characterize the mechanisms by which MMAC1 regulates the P13K signaling cascade in breast cancer cells and the functional consequence of this cascade in breast cancer initiation, progression and metastases. An understanding of the mechanism(s) by which inactivation of the MMAC1 tumor suppressor contributes to breast tumorigenesis could provide important new information related to the development, prognosis and treatment of sporadic breast cancers as well as to genetic predisposition to breast cancer. Further, characterization of the mechanisms by which MMAC1 regulates the P13K cascade could identify new targets for therapy of breast cancer. Hypothesis: That MMAC1 acts as a tumor suppressor by inhibiting the P13K signaling cascade at multiple levels.
Specific Aim #1 : To determine the role of MMAC1 in signal transduction in breast cancer cells.
Specific Aim #2 : To determine the functional role of MMAC1 in breast cancer pathogenesis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA082716-05
Application #
6607185
Study Section
Special Emphasis Panel (ZRG1-PTHB (01))
Program Officer
Perry, Mary Ellen
Project Start
1999-09-01
Project End
2005-06-30
Budget Start
2003-07-01
Budget End
2005-06-30
Support Year
5
Fiscal Year
2003
Total Cost
$269,658
Indirect Cost

  Institution

Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030

  Publications

Liu, Shuying; Umezu-Goto, Makiko; Murph, Mandi et al. (2009) Expression of autotaxin and lysophosphatidic acid receptors increases mammary tumorigenesis, invasion, and metastases. Cancer Cell 15:539-50
Liu, Shuying; Murph, Mandi; Panupinthu, Nattapon et al. (2009) ATX-LPA receptor axis in inflammation and cancer. Cell Cycle 8:3695-701
Liu, Shuying; Fang, Xianjun; Hall, Hassan et al. (2008) Homozygous deletion of glycogen synthase kinase 3beta bypasses senescence allowing Ras transformation of primary murine fibroblasts. Proc Natl Acad Sci U S A 105:5248-53
Yu, Shuangxing; Murph, Mandi M; Lu, Yiling et al. (2008) Lysophosphatidic acid receptors determine tumorigenicity and aggressiveness of ovarian cancer cells. J Natl Cancer Inst 100:1630-42
Liu, Shuying; Yu, Shuangxing; Hasegawa, Yutaka et al. (2004) Glycogen synthase kinase 3beta is a negative regulator of growth factor-induced activation of the c-Jun N-terminal kinase. J Biol Chem 279:51075-81
Fang, Xianjun; Yu, Shuangxing; Bast, Robert C et al. (2004) Mechanisms for lysophosphatidic acid-induced cytokine production in ovarian cancer cells. J Biol Chem 279:9653-61
Kohn, Elise C; Lu, Yiling; Wang, Hongwei et al. (2004) Molecular therapeutics: promise and challenges. Semin Oncol 31:39-53
Mills, Gordon B; Kohn, Elise; Lu, Yiling et al. (2003) Linking molecular diagnostics to molecular therapeutics: targeting the PI3K pathway in breast cancer. Semin Oncol 30:93-104
Lu, Yiling; Yu, Qinghua; Liu, Jue Hui et al. (2003) Src family protein-tyrosine kinases alter the function of PTEN to regulate phosphatidylinositol 3-kinase/AKT cascades. J Biol Chem 278:40057-66
Knuefermann, Christiane; Lu, Yang; Liu, Bolin et al. (2003) HER2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells. Oncogene 22:3205-12

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