Overexpression of antiapoptotic gene products and resistance to trastuzumab treatment of breast cancer

Breast cancer is a prevalent cancer worldwide and the leading cause of cancer deaths in women. It is a heterogeneous group of subtypes with different phenotypes, molecular profiles, and cell surface biomarkers. Accordingly, the current treatment strategies are designed based on the phenotype of each cancer subtype. One of the most aggressive forms is overexpressing the human epidermal growth factor 2 (HER2), which represents >20% of breast cancers and is treated with antibodies directed against HER2. The first FDA-approved anti-HER2 monoclonal antibody, trastuzumab, has been very effective in treating a large subset of HER2-overexpressing breast cancer patients with prolongation of survival. However, a subset of patients is not responsive and many treated patients with trastuzumab have experienced relapses and resistance to further treatment. The underlying mechanisms of trastuzumab-mediated activities include the inhibition of HER2-mediated survival signaling pathways, ADCC, activation of the antitumor immune response, and the induction of apoptosis. The induction of apoptosis results from trastuzumab-mediated downregulation of several antiapoptotic gene products (e.g., Bcl-2, Bclxl, Mcl-1, and survivin). Breast cancer cells overexpressing these antiapoptotic gene products were resistant to trastuzumab. Therefore, here in, the mechanisms underlying trastuzumab-mediated downregulation of antiapoptotic gene products in sensitive cells and the resistance of cells overexpressing these gene products are discussed. In addition, strategies to target these antiapoptotic gene products to reverse trastuzumab resistance of HER2 expressing breast cancer have been suggested as well as novel approaches of using conjugates of trastuzumab coupled with small molecule inhibitors of antiapoptotic gene products.