Abstract
Tamoxifen provided a successful treatment for ER-positive breast cancer for many years. However, most breast tumors develop tamoxifen resistance and are eventually refractory to tamoxifen therapy. The molecular mechanisms underlying development of tamoxifen resistance have not been well established. Recently, we reported that breast cancer cells with high levels of ER-α36, a variant of ER-α, were resistant to tamoxifen and knockdown of ER-α36 expression in tamoxifen resistant cells with the shRNA method restored tamoxifen sensitivity, indicating that gained ER-α36 expression is one of the underlying mechanisms of tamoxifen resistance. Here, we found that tamoxifen induced expression of ER-α36-EGFR/HER2 positive regulatory loops and tamoxifen resistant MCF7 cells (MCF7/TAM) expressed enhanced levels of the loops. Disruption of the ER-α36-EGFR/HER2 positive regulatory loops with the dual tyrosine kinase inhibitor Lapatinib or ER-α36 down-regulator Broussoflavonol B in tamoxifen resistant MCF7 cells restored tamoxifen sensitivity. In addition, we also found both Lapatinib and Broussoflavonol B increased the growth inhibitory activity of tamoxifen in tumorsphere cells derived from MCF7/TAM cells. Our results thus demonstrated that elevated expression of the ER-α36-EGFR/HER2 loops is one of the mechanisms by which ER-positive breast cancer cells escape tamoxifen therapy. Our results thus provided a rational to develop novel therapeutic approaches for tamoxifen resistant patients by targeting the ER-α36-EGFR/HER2 loops.
Highlights
Endocrine therapy using antiestrogen tamoxifen (TAM) is currently the most effective treatment for advanced ER-positive breast cancer
The steady state levels of ER-a36, EGFR and HER2 in ER-positive breast cancer MCF7 cells treated with 1 mM of TAM for different time periods were examined with Western blot analysis
We reported that breast cancer patients with tumors expressing high levels of endogenous ER-a36 less benefited from TAM therapy than those with low levels of ER-a36 expression [23], suggesting elevated expression of ER-a36 is a mechanism underlying acquired tamoxifen resistance
Summary
Endocrine therapy using antiestrogen tamoxifen (TAM) is currently the most effective treatment for advanced ER-positive breast cancer. Many researches were conducted to understand the molecular pathways involved in tamoxifen resistance and have revealed that multiple signaling molecules and pathways such as EGFR and HER2 [5,6]. All these pathways often bypass the requirement of estrogen signaling for growth of ER-positive breast cancer cells. Both experimental and clinical evidence have indicated that the HER2 (Human epidermal growth factor receptor 2) and EGFR (Epidermal growth factor receptor) signaling pathways interact with the estrogen-signaling pathway. Chu et al, reported that the dual kinase inhibitor Laptinib for HER2 and EGFR cooperates with tamoxifen to inhibit cell proliferation in antiestrogen resistant breast cancer [19]
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