(497d) Unveiling the Cell Cycle Mediated Apoptosis Mechanism and Therapeutic Efficacy in Breast Cancer Cells

HER2-positive breast cancer accounts for almost 15-20% of the all the breast cancer patients. This subgroup of patient’s tumor is characterized by HER2/ERBB2 gene copy number amplification resulting in HER2 overexpression. HER2 activates RAS-RAF-MAPK and PI3K-AKT mitogenic signaling pathways. This also leads to the deregulation of cell cycle regulatory genes including CCND1, CDK4/6, CCNE1, loss of tumor suppressor gene PTEN and loss of p53 (Figure 1). The molecular and genetic aberrations are heterogeneous and often acquire resistance to the intervened therapy in early stage. It is hypothesized that the mechanism of resistance is regulated by the cell cycle. HER2-positive breast cancer cells were arrested in different phases of the cell cycle G_o, G1, S and G2-M using serum deprivation, Trastuzumab or Rapamycin, 5-fluorouracil and Paclitaxel or Doxorubicin, respectively. We also used Trastuzumab functionalized Paclitaxel drug nanorods (PTXNR-TTZ) that arrest cells in G2-M phase and induce apoptosis synergistically on HER2-positive breast cancer cells. Untreated cells were mostly arrested in G_o/G1 phase. We investigated the genetic and molecular alterations in cells using Next Generation Sequencing (NGS) technique. Our study includes the discovery of key driver genes and genetic network responsible for cell cycle dependent therapeutic resistance and therapeutic outcomes.