Loss of the PTEN tumor suppressor potently activates PI3K signaling, which enhances DNA replication, cell size, cell survival, genomic instability and migration in some circumstances and DNA double-strand breaks and senescence in others. We have recently determined that a PI3K pathway/PTEN-loss gene expression signature can be detected in breast cancer and other malignancies and is predictive of distant organ metastasis. In multiple independent data sets, over half of all BBC have a measurable reduction in the expression of PTEN protein and mRNA. Over 75% of basal-like breast cancers (BBC) display expression of the PI3K pathway/PTENloss gene expression signature. A further link between PTEN and BBC has been found in mouse model systems, where germline mutations of PTEN lead to the development of basal-like mammary tumors. In a significant portion of BBC from BRCA1 cases, loss of PTEN expression has been traced to a specific form of mutation that occurs through somatic rearrangements of PTEN genomic DNA. For the majority of all BBC cases, however, the basis for PI3K/PTEN pathway alterations is not understood and may be due to changes that affect the PTEN gene or the expression of factors that modify PTEN protein or PI3K signaling. Furthermore, despite the importance of the PTEN pathway to BBC, it is unclear which of the cellular processes regulated by PTEN are contributing to BBC pathogenesis. To better understand the role of PTEN and the PI3K/PTEN pathway in BBC development, we propose the following three specific aims: 1) To define the basis for partial and complete inactivation of the PTEN gene and determine the pattern of intragenic rearrangements in human BBC. 2) To determine the mechanism through which PTEN and the PIS kinase pathway contribute to DNA replication, DNA repair, senescence, cell survival and sensitivity to chemotherapy. In addition, pathway alterations will be measured in tumors and correlated with disease progression and response to treatment 3) To determine the mechanism through which a basal-like signature gene regulates PI3K signaling, cell survival and proliferation in BBC.
Basal-like breast cancer is highly proliferative, has high metastatic potential and is not suitable for therapy targeting HER2 or estrogen receptor. Identifying the driving force for this type of breast cancer will lead to better treatment options. Our data suggests that the PI3K pathway is a major driving force for basal-like breast cancer that can be activated by different mechanisms.
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