The role of the unfolded protein response in human breast cancer and trastuzumab resistance

The HER2 growth receptor is upregulated in approximately 30% of human breast cancer, which remains the leading cause of cancer deaths in women. The HER2 subtype is more aggressive than others, and less responsive to traditional treatments, including chemotherapy and hormone therapy. Due to this decreased responsiveness, trastuzumab, a humanized antibody that blocks HER2 activity, is used. Although trastuzumab treatment is initially very successful, it has been shown clinically that the effectiveness of trastuzumab becomes severely diminished in a majority of patients after approximately one year of treatment. This occurrence is known as trastuzumab/HER2 resistance, a phenomenon that severely impacts survival rates and treatment options. The tumorigenic role of HER2 in breast cancer has been linked to its activation of the phosphoinositol-3-kinase (PI3K)/AKT signaling pathway, a critical regulator of cell proliferation, and to lipocalin 2 (LCN2), an onco-protein correlated with tumorgenesis and changes in tumor stage. Previous research in this lab has shown that activation of the unfolded protein response (UPR), a microenvironmental stress adaptation mechanism, results in the increased expression of LCN2. Using HER2⁺ SKBr3 human breast cancer cells, we found that induction of the UPR abrogated trastuzumab-mediated LCN2 downregulation. Furthermore, through use of PI3K/AKT inhibitors, we discovered that the upregulation of LCN2 by the UPR was AKT-dependent. Taken together, this suggests that the UPR may serve to reactivate tumorigenic signaling pathways downstream of HER2, thus initiating trastuzumab resistance, making it a possible novel target in therapy in HER2 positive breast cance