Tamoxifen overcomes the trastuzumab-resistance of SK-BR-3 tumorspheres by targeting crosstalk between cytoplasmic estrogen receptor α and the EGFR/HER2 signaling pathway

Abstract

Since trastuzumab-resistance remains a major obstacle to the successful treatment of HER2-positive breast cancer, a detailed understanding of the mechanisms responsible is required to direct future pharmacotherapeutic strategies. Recently, several studies have indicated that the quiescent natures of cancer stem cells contribute to treatment resistance and tumor recurrence. Thus, in this study, we investigated the mechanism underlying trastuzumab resistance in a quiescent cell population using tumorsphere cultures and explored better therapeutic strategies to overcome trastuzumab resistance in HER2-positive breast cancer patients. We observed that most cells in SK-BR-3 tumorspheres were quiescent, showing the accumulation of cells at the G0/G1 phase as compared to cells in monolayer culture. Furthermore, SK-BR-3 tumorspheres exhibited enhanced EGFR/HER2 signaling, which was incompletely inhibited by trastuzumab, and subsequently led to trastuzumab-resistance. Interestingly, cytoplasmic estrogen receptor α (ERα) expression was markedly elevated in tumorspheres and was associated with enhanced EGFR/HER2 signaling. Accordingly, inhibition of ERα with tamoxifen selectively targeted tumorspheres rather than cells in monolayer culture and overcame trastuzumab resistance in tumorspheres. Taken together, our findings indicate that crosstalk between cytoplasmic ERα and the HER2/EGFR signaling pathway can be considered a novel therapeutic target for quiescent cell populations within HER2-positive breast cancer and that simultaneous inhibition of ER and the EGFR/HER2 pathway may prevent trastuzumab resistance. We hope that these results provide a basis for the use of combinations of tamoxifen and trastuzumab in HER2-positive breast cancer patients.