HER2-Associated Radioresistance of Breast Cancer Stem Cells Isolated from HER2-Negative Breast Cancer Cells

Abstract

Purpose To understand the role of HER2-associated signaling network in breast cancer stem cells (BCSCs); using radiation-resistant breast cancer cells and clinical recurrent breast cancers to evaluate HER2-targeted therapy as a tumor eliminating strategy for recurrent HER2−/low breast cancers. Experimental Design HER2-expressing BCSCs (HER2+/CD44+/CD24−/low) were isolated from radiation-treated breast cancer MCF7 cells and in vivo irradiated MCF7 xenograft tumors. Tumor aggressiveness and radiation resistance were analyzed by gap filling, Matrigel invasion, tumor-sphere formation, and clonogenic survival assays. The HER2/CD44 feature was analyzed in 40 primary and recurrent breast cancer specimens. Protein expression profiling in HER2+/CD44+/CD24−/low versus HER2−/CD44+/CD24−/low BCSCs was conducted with 2-D DIGE and HPLC-MS/MS analysis and HER2-mediated signaling network was generated by MetaCore™ program. Results Compared to HER2-negative BCSCs, HER2+/CD44+/CD24−/low cells showed elevated aldehyde dehydrogenase (ALDH) activity and aggressiveness tested by matrigel invasion, tumor sphere formation and in vivo tumorigenesis. The enhanced aggressive phenotype and radioresistance of the HER2+/CD44+/CD24−/low cells were markedly reduced by inhibition of HER2 via siRNA or Herceptin treatments. Clinical breast cancer specimens revealed that cells co-expressing HER2 and CD44 were more frequently detected in recurrent (84.6%) than primary tumors (57.1%). In addition, 2-D DIGE and HPLC-MS/MS of HER2+/CD44+/CD24−/low versus HER2−/CD44+/CD24−/low BCSCs reported a unique HER2-associated protein profile including effectors involved in tumor metastasis, apoptosis, mitochondrial function and DNA repair. A specific feature of HER2-STAT3 network was identified. Conclusion This study provides the evidence that HER2-mediated pro-survival signaling network is responsible for the aggressive phenotype of breast cancer stem cells that could be targeted to control the therapy-resistant HER2−/low breast cancer.

ZEB1 is involved in regulating HER2-positive breast cancer radiosensitivity by controlling EMT

“…Radiotherapy for breast cancer is one of the main clinical applications currently available (3,4). However, the majority of cancers have exhibited radiotherapy resistance, which seriously impacts the effect of such treatment (5,6). Human epidermal growth factor receptor 2 (HER2) is widely expressed in various types of cancer, including gastric and prostate cancer (7,8).…”

Lapatinib inhibits stem/progenitor proliferation in preclinical in vitro models of ductal carcinoma in situ (DCIS)

“…[29][30][31][32][33] In the case of DCIS lapatinib may be used in combination with radiotherapy in patients at high risk of recurrence (high-grade, <40 y, ER-negative, HER2-positive), as laboratory evidence suggests that HER2 inhibitors may improve radio-sensitivity. 34 In conclusion, we demonstrate that lapatinib can reduce DCIS CSC activity via reduction of proliferation and suggest that further investigation into treatment of high-risk DCIS patients at the time of surgery and radiotherapy with anti-HER2 agents, to target DCIS CSCs, would be warranted.…”

Artemin, a Member of the Glial Cell Line-derived Neurotrophic Factor Family of Ligands, Is HER2-regulated and Mediates Acquired Trastuzumab Resistance by Promoting Cancer Stem Cell-like Behavior in Mammary Carcinoma Cells

“…Indeed, various reports have postulated that de novo or acquired resistance of mammary carcinoma to therapeutic interventions may be related to the capacity to enhance a CSC-like cell phenotype (2,17). HER2 expression has been similarly positively correlated with increased chemo-and radiotherapeutic acquired resistance in different carcinoma cell types and associated with an increased CSC-like cell phenotype (34,35). Both ARTN and HER2 have been previously demonstrated to increase the ALDH1 ϩ cell population (15,18).…”