The Role of Akt and its Substrates in Resistance of Breast Cancer to Trastuzumab

The broad scope aim of research conducted under this grant was to determine the role of Akt in ErbB2 tumorigenesis. The first two tasks aimed to determine substrates of Akt that are targets of trastuzumab and the results of these studies demonstrated that trastuzumab does not strongly induce apoptosis, and as such, targets downstream of Akt are not affected by trastuzumab. In the third task, we determined that overexpression of constitutively active Akt in the tumors of MMTV-c-ErbB2 mice accelerates mammary tumorigenesis. This acceleration is observed in the context of a reduced requirement for plasma membrane tyrosine kinase signaling and an increase in glucose metabolism. Finally, since Akt is known to effect glucose metabolism and the glucose transporter, GLUT1, we sought to determine the effects of reducing GLUT1 in breast cancer cells. Breast cancer cells with reduced GLUT1 have reduced glucose metabolism and reduced proliferation in vitro as well as reduced tumor growth in an athymic nude mouse breast cancer models.
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