The Role of Notch-1-Mediated Repression of PTEN on Growth and Cancer Stem Cell Survival in Trastuzumab Resistant, Her2+ Breast Cancer

Trastuzumab targets the ErbB2 (HER2) receptor on breast cancer cells to attenuate HER2 driven tumor formation. Trastuzumab reduces both downstream PI3K/Akt and MAPK pathway signaling as well as the breast cancer stem cell (BCSC) population. BCSCs are hypothesized to be responsible for tumor recurrence, metastasis, as well as drug resistance. Today, resistance to trastuzumab remains a major clinical problem for women diagnosed with HER2+ breast cancer. Attenuation of PI3K/Akt and MAPK pathways may occur through the tumor suppressor, PTEN. Women with HER2+ breast tumors expressing less PTEN and increased PI3K/Akt or MAPK activity have worse overall outcome. Previously we have shown that trastuzumab resistant cells have increased expression of Notch-1 which drives cell proliferation in vitro as well as tumor recurrence in vivo. Here, we show, to our knowledge for the first time, that Notch-1 directly represses PTEN transcript RNA expression to promote trastuzumab resistant HER2+ breast cancer cell proliferation at least in part through activation of ERK1/2. Furthermore, we demonstrate that Notch-1 mediated inhibition of PTEN promotes BCSC survival and self-renewal both in vitro and in vivo