In vivo acquired resistance to tamoxifen is associated with irreversible loss of IGF1R, upregulation of insulin receptor and enhanced sensitivity to insulin

Abstract

Selective estrogen receptor modulators (SERMs) like tamoxifen are used to treat hormone receptor positive (HR+) breast cancers. Several models of in vitro acquired resistance to tamoxifen using HR+ breast cancer cell lines have been developed. There are few models of resistance to tamoxifen that are generated in vivo. Here, we generated a model of in vivo resistance to tamoxifen. We show that in vivo tamoxifen resistance is associated with loss of IGF1R. This loss is irreversible as it persists even when tamoxifen is removed. In vivo tamoxifen resistance is also associated with upregulation of insulin receptor, specifically the A isoform of IR (IR-A). These resistant cells show enhanced insulin sensitivity compared to the parental endocrine sensitive or in vitro acquired tamoxifen resistant cells. Finally, we demonstrate that in vivo resistance to tamoxifen results in enhanced proliferation in response to insulin. These studies establish that some mechanisms of in vivo resistance to tamoxifen differ from those observed for in vitro acquired resistance and increased dependence on insulin signaling drives endocrine resistance in HR+ breast cancer. Taken together, these studies present that targeting IR-A in combination with newer targets of tamoxifen resistance could be tested in endocrine resistant breast cancer.