Abstract
BackgroundOverexpression of heregulin, a HER3 ligand, is one mechanism that confers resistance to the anti-HER2 agents trastuzumab and lapatinib. We investigated the impact of heregulin expression on the efficacy of HER2-targeted therapeutic agents, including trastuzumab, trastuzumab emtansine (T-DM1) and lapatinib, in vitro and in vivo and evaluated the heregulin messenger RNA (mRNA) levels in specimens from patients with HER2-positive breast or gastric cancer.ResultsCell proliferation and apoptosis assays demonstrated that heregulin conferred robust resistance to lapatinib and trastuzumab via HER3-Akt pathway activation followed by survivin overexpression; however, heregulin conferred minimal or no resistance to T-DM1 and paclitaxel. The heregulin mRNA level of one of 10 patients was up-regulated after the acquisition of resistance to trastuzumab-based therapy.Materials and MethodsSK-BR-3, NCI-N87, BT-474, MDA-MB-453, HCC1954, SNU-216 and 4-1ST cells were pharmacologically treated with recombinant heregulin or transfected with the heregulin gene. We also assessed the expression of heregulin mRNA in HER2-positive breast or gastric cancer samples before and after trastuzumab-based therapy using a RT-PCR-based method.ConclusionsmRNA up-regulation of heregulin was observed in clinical breast cancer specimens during trastuzumab-based treatment, but heregulin overexpression had a limited effect on the sensitivity to T-DM1 in vitro and in vivo.
Highlights
The human epidermal growth factor receptor (HER) family consists of receptor-type tyrosine kinases that regulate various cell functions, including cell proliferation, apoptosis, migration and differentiation
Cell proliferation and apoptosis assays demonstrated that heregulin conferred robust resistance to lapatinib and trastuzumab via HER3-Akt pathway activation followed by survivin overexpression; heregulin conferred minimal or no resistance to T-DM1 and paclitaxel
Conclusions: messenger RNA (mRNA) up-regulation of heregulin was observed in clinical breast cancer specimens during trastuzumab-based treatment, but heregulin overexpression had a limited effect on the sensitivity to T-DM1 in vitro and in vivo
Summary
The human epidermal growth factor receptor (HER) family consists of receptor-type tyrosine kinases that regulate various cell functions, including cell proliferation, apoptosis, migration and differentiation. In breast and gastric cancer, the HER2 gene is amplified in approximately 20% of patients, and its amplification is closely correlated with the efficacy of anti-HER2 agents [4, 5]. The anti-HER2 agents currently prescribed in clinical settings include lapatinib, trastuzumab and trastuzumab emtansine (T-DM1). These drugs inhibit cancer cell proliferation via a specific and unique mechanism. Overexpression of heregulin, a HER3 ligand, is one mechanism that confers resistance to the anti-HER2 agents trastuzumab and lapatinib. We investigated the impact of heregulin expression on the efficacy of HER2-targeted therapeutic agents, including trastuzumab, trastuzumab emtansine (T-DM1) and lapatinib, in vitro and in vivo and evaluated the heregulin messenger RNA (mRNA) levels in specimens from patients with HER2-positive breast or gastric cancer
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