Identifying Breast Cancer Oncogenes
Annual summary rept. 1 oct 2008-30 Sep 2011
DANA-FARBER CANCER INST BOSTON MA
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Identification of novel drivers of cancer is necessary to understand the mechanisms of transformation as well as reveal more efficient targets for cancer therapy. Various subtypes of human cancer show activation of the RAS-MAPK pathway however, activating mutations in the pathway are frequent only in a few subtypes. For instance, although human breast tumors show activated RAS-MAPK signaling, activating mutation of RAS or members of the MAPK pathway is rare, indicating that an alternate mechanism is in play to activate MAPK signaling in this subtype. We conducted a kinase ORF gain-of-function screen to identify kinases that can transform human mammary epithelial cells in a MAPK-dependent manner. We identified three kinases, PAK1, PTK6 and CAMK4, which promoted robust anchorage independent growth of HMLE cells. We further showed that PAK1 and PTK6 are amplified in human breast cancer and can activate the RAS-MAPK pathway for transformation. Moreover, PTK6 behaved in a cooperative manner to enhance transformation while PAK1 was shown to be a driver of transformation in mammary cells. Hence, we conclude that amplification of kinases such as PAK1 and PTK6 are alternative mechanisms by which the RAS-MAPK pathway can be activated in breast cancer.
- Anatomy and Physiology
- Medicine and Medical Research