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Cancers 2017, 9(5), 40; doi:10.3390/cancers9050040

HER2 in Breast Cancer Stemness: A Negative Feedback Loop towards Trastuzumab Resistance

Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, 8-35 Medical Sciences Building, 114 St., Edmonton, AB T6G 2H7, Canada
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Academic Editor: Samuel C. Mok
Received: 21 February 2017 / Revised: 10 April 2017 / Accepted: 21 April 2017 / Published: 26 April 2017
(This article belongs to the Special Issue EGFR Family Signaling in Cancer)
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Abstract

HER2 receptor tyrosine kinase that is overexpressed in approximately 20% of all breast cancers (BCs) is a poor prognosis factor and a precious target for BC therapy. Trastuzumab is approved by FDA to specifically target HER2 for treating HER2+ BC. However, about 60% of patients with HER2+ breast tumor develop de novo resistance to trastuzumab, partially due to the loss of expression of HER2 extracellular domain on their tumor cells. This is due to shedding/cleavage of HER2 by metalloproteinases (ADAMs and MMPs). HER2 shedding results in the accumulation of intracellular carboxyl-terminal HER2 (p95HER2), which is a common phenomenon in trastuzumab-resistant tumors and is suggested as a predictive marker for trastuzumab resistance. Up-regulation of the metalloproteinases is a poor prognosis factor and is commonly seen in mesenchymal-like cancer stem cells that are risen during epithelial to mesenchymal transition (EMT) of tumor cells. HER2 cleavage during EMT can explain why secondary metastatic tumors with high percentage of mesenchymal-like cancer stem cells are mostly resistant to trastuzumab but still sensitive to lapatinib. Importantly, many studies report HER2 interaction with oncogenic/stemness signaling pathways including TGF-β/Smad, Wnt/β-catenin, Notch, JAK/STAT and Hedgehog. HER2 overexpression promotes EMT and the emergence of cancer stem cell properties in BC. Increased expression and activation of metalloproteinases during EMT leads to proteolytic cleavage and shedding of HER2 receptor, which downregulates HER2 extracellular domain and eventually increases trastuzumab resistance. Here, we review the hypothesis that a negative feedback loop between HER2 and stemness signaling drives resistance of BC to trastuzumab. View Full-Text
Keywords: HER2/ERBB2; breast cancer; cancer stem cell; stemness; signaling; EMT; trastuzumab; metalloproteinase; p95HER2 HER2/ERBB2; breast cancer; cancer stem cell; stemness; signaling; EMT; trastuzumab; metalloproteinase; p95HER2
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Nami, B.; Wang, Z. HER2 in Breast Cancer Stemness: A Negative Feedback Loop towards Trastuzumab Resistance. Cancers 2017, 9, 40.

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