Breast Cancer

Biography

Biography: Bolin Liu

Abstract

Gene amplification/overexpression of erbB2 (HER2/neu) is observed in approximately 25-30% of invasive breast cancers and significantly associated with a worse prognosis. ErbB2-targeted therapies, including trastuzumab (or Herceptin) and lapatinib (or Tykerb) have been successfully used in breast cancer patients with erbB2-positive tumors. However, both de novo and acquired resistance to these agents frequently occurs, representing a significant clinical problem. Our recent studies revealed a co-expression of three receptor tyrosine kinases (RTKs), erbB2, erbB3, and the insulin-like growth factor-I receptor (IGF-IR), in both trastuzumab-resistant and -sensitive breast cancer cells, and an enhanced activation of the downstream signaling in the resistant cells. The three RTKs actually interacted with each other to form a heterotrimeric complex only in the trastuzumab-resistant breast cancer cells. Specific knockdown of either erbB3 or IGF-IR expression was able to re-sensitize the resistant cells to trastuzumab-mediated inactivation of downstream signaling and growth inhibition. Interestingly, the trastuzumab-resistant sublines also exhibited refractoriness to lapatinib. While knockdown of erbB3 dramatically re-sensitized the cells to lapatinib-induced apoptosis, specific knockdown of IGF-1R did not alter the cells’ responsiveness to lapatinib. Moreover, a specific inhibitor of Akt, but not Src, significantly enhanced lapatinib-mediated anti-proliferative/anti-survival effects on the trastuzumab-resistant cells. These data indicate that erbB3 signaling is critical for both trastuzumab and lapatinib resistances mainly through activation of the PI-3K/Akt pathway, whereas IGF-1R-initiated Src activation results in trastuzumab resistance without affecting lapatinib sensitivity. Our findings may facilitate the development of precision therapeutic regimens for erbB2-positive breast cancer patients who become resistant to erbB2-targeted therapy.