Stromal-epithelial interactions and tamoxifen resistance

Abstract

Tamoxifen, a selective estrogen receptor modulator, is the standard endocrine treatment for hormone receptor positive breast cancer, both in the initial adjuvant therapy and as treatment of patients with metastatic disease. However, about one third of patients with estrogen receptor (ER)-á positive tumors are refractory to tamoxifen therapy and a high percentage of patients who initially respond to tamoxifen develop resistance. Most breast cancers that acquire endocrine resistance retain ER-á expression, suggesting that loss of ER is not a common mechanism of resistance to endocrine therapy. Diverse signal transduction pathways influence the functional activity of ER, in addition to steroid ligand, and are critical in the responsiveness of tumors to anti-hormonal drugs. In particular, it is now well established that activation of several growth factor signaling cascades can promote resistance. However, although these pathways can be modulated by the tumor microenvironment, no studies to our knowledge have investigated this subject in an ER-á positive cell context. In this article we discuss the development of a new mouse model of estrogen responsive/tamoxifen sensitive breast cancer and propose that microenvironmental factors may be critical in the response to endocrine therapy, and could in the future be a rational target for the treatment of tamoxifen resistant breast cancer.á positive tumors are refractory to tamoxifen therapy and a high percentage of patients who initially respond to tamoxifen develop resistance. Most breast cancers that acquire endocrine resistance retain ER-á expression, suggesting that loss of ER is not a common mechanism of resistance to endocrine therapy. Diverse signal transduction pathways influence the functional activity of ER, in addition to steroid ligand, and are critical in the responsiveness of tumors to anti-hormonal drugs. In particular, it is now well established that activation of several growth factor signaling cascades can promote resistance. However, although these pathways can be modulated by the tumor microenvironment, no studies to our knowledge have investigated this subject in an ER-á positive cell context. In this article we discuss the development of a new mouse model of estrogen responsive/tamoxifen sensitive breast cancer and propose that microenvironmental factors may be critical in the response to endocrine therapy, and could in the future be a rational target for the treatment of tamoxifen resistant breast cancer.á expression, suggesting that loss of ER is not a common mechanism of resistance to endocrine therapy. Diverse signal transduction pathways influence the functional activity of ER, in addition to steroid ligand, and are critical in the responsiveness of tumors to anti-hormonal drugs. In particular, it is now well established that activation of several growth factor signaling cascades can promote resistance. However, although these pathways can be modulated by the tumor microenvironment, no studies to our knowledge have investigated this subject in an ER-á positive cell context. In this article we discuss the development of a new mouse model of estrogen responsive/tamoxifen sensitive breast cancer and propose that microenvironmental factors may be critical in the response to endocrine therapy, and could in the future be a rational target for the treatment of tamoxifen resistant breast cancer.á positive cell context. In this article we discuss the development of a new mouse model of estrogen responsive/tamoxifen sensitive breast cancer and propose that microenvironmental factors may be critical in the response to endocrine therapy, and could in the future be a rational target for the treatment of tamoxifen resistant breast cancer.