Herceptin Sensitizes ErbB2–Overexpressing Cells to Apoptosis by Reducing Antiapoptotic Mcl-1 Expression

Abstract

Purpose: Monoclonal antibodies, such as herceptin and trastuzumab, against the epidermal growth factor receptor ErbB2 (also known as HER2/neu) are an effective therapy for breast cancer patients with overexpression of ErbB2. Herceptin, in combination with standard chemotherapy, such as taxol or etoposide, gives a synergistically apoptotic response in breast tumors. Experimental Design: The mechanism underlying this synergy between chemotherapy and herceptin treatment is not well understood. Herein, we have determined that addition of herceptin, sensitized breast cancer cell lines MDA-MB-231 and MCF-7 to etoposide-or taxol-induced apoptosis.Results: This treatment resulted in reduced expression of ErbB2 and the antiapoptotic Bcl-2 family member Mcl-1 in MDA-MB-231 cells. Using antisense oligonucleotides against Mcl-1, MDA-MB-231cells were rendered sensitive to etoposide-induced apoptosis similar to herceptin, but combined treatment of antisense against Mcl-1 and herceptin failed to give a significant increase in apoptosis. In 29 human breast tumors immunostained for ErbB2 and Mcl-1, we found that when ErbB2 was overexpressed, there was a corresponding increase in Mcl-1expression. Discussion: Using murine fibroblasts that express human ErbB2, but no other ErbB family member (NE2), these cells showed resistance to both taxol-and etoposide-induced apoptosis compared with parental cells. In addition, NE2 cells preferentially express the antiapoptotic Bcl-2 family member Mcl-1compared with parental cells, and treatment with herceptin reduces Mcl-1 expression. Taken together, these results suggest that herceptin sensitizes ErbB2-overexpressing cells to apoptosis by reducing antiapoptotic Mcl-1protein levels.

Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity

“…On the contrary, as reported earlier (Cuello et al, 2001;Valabrega et al, 2005;Henson et al, 2006;Tseng et al, 2006;Scaltriti et al, 2007), trastuzumab alone resulted in overall downregulation of HER2. As for the combined treatment with lapatinib and trastuzumab, the net result was an accumulation of receptor at the cell surface of a similar magnitude to that of lapatinib alone at each time point for MCF-7HER2 cells and starting at 36 h of treatment for SKBR-3 cells.…”

Progressive loss of anti-HER2 CD4+ T-helper type 1 response in breast tumorigenesis and the potential for immune restoration

“…Several studies have demonstrated the ability of trastuzumab to reduce growth and induce apoptosis in HER2 pos tumors, 31 as well as to sensitize HER2 pos cells to the tumoricidal effects of cytotoxic chemotherapy. 4 Despite these benefits, the use of trastuzumab did not appreciably restore HER2-specific Th1 immunity in a majority of patients, including those with Stage I disease. In addition, an almost universal resistance to these HER2-targeted therapies is observed in advanced disease states.…”

“…2 HER2 overexpression, a molecular oncodriver in several tumor types including 20-25% of BCs, 3 is associated with an aggressive clinical course, resistance to chemotherapy, and a poor overall prognosis. 4,5 In incipient BC, HER2 overexpression is associated with enhanced invasiveness, 6 tumor cell migration, 7 and the expression of proangiogenic factors, 8 suggesting a critical role for HER2 in promoting a tumorigenic environment. Although HER2-targeted therapies (i.e., trastuzumab), in combination with chemotherapy, have significantly improved survival in HER2 pos BC, 9 a substantial proportion of patients become resistant to such therapies.…”

MKNK1 is a YB-1 target gene responsible for imparting trastuzumab resistance and can be blocked by RSK inhibition

“…Products of many of the anti-apoptotic YB-1 target genes have previously been implicated in drug resistance. For example, inhibition of inhibitor of apoptosis-family members cIAP1 (BIRC2) and cIAP2 (BIRC3) increases apoptosis in response to trastuzumab, lapatinib or gefitinib in HER2-overexpressing cells (Foster et al, 2009), whereas inhibition of MCL-1 sensitizes cells to both lapatinib and trastuzumab (Henson et al, 2006;Martin et al, 2008). Moreover, TNFSF18 and TCF7L1 are associated with tamoxifen and erlotinib resistance, respectively (Treeck et al, 2004;Halatsch et al, 2009).…”