MMAC1/PTEN TUMOR SUPPRESSOR AND BREAST CANCER

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DESCRIPTION: (adapted from the investigator's 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.