Abstract
Breast cancer, the most prevalent female carcinoma, is characterized by the expression of steroid nuclear receptors in a subset of cases. The most important nuclear receptor with prognostic and therapeutic implications is the Estrogen Receptor (ER), which is expressed in about three out of four breast cancers. The Progesterone Receptor (PR) and the Androgen Receptor (AR) are also commonly expressed. Moreover, non-steroid nuclear receptors, including the vitamin D receptor (VDR) and the thyroid receptors (TRs), are also present in breast cancers and have pathophysiologic implications. Circulating thyroid hormones may influence breast cancer risk and breast cancer cell survival, through ligating their canonical receptors TRα and TRβ but also through additional membrane receptors that are expressed in breast cancer. The expression of TR subtypes and their respective isotypes have diverse effects in breast cancers through co-operation with ER and influence on other cancer-associated pathways. Other components of the TSH/thyroid hormone axis, such as TSH and selenoiodinase enzymes, have putative effects in breast cancer pathophysiology. This paper reviews the pathophysiologic and prognostic implications of the thyroid axis in breast cancer and provides a brief therapeutic perspective.
Highlights
Breast cancer is a major cause of morbidity and mortality in women across geographies and age groups
The expression of αvβ3 integrin marks vascular beds associated with tumor neovascularization [42]. αvβ3 integrin can differentiate tumor-associated endothelia better than CD31, which is expressed in normal endothelial cells. αvβ3 integrin is expressed in tumor vessel endothelial cells and tumor cells of breast cancer patients [43]. αvβ3 integrin expression is induced by Transforming Growth Factor beta (TGFβ) signaling in breast cancer cells [44]. αvβ3 integrin acts as a cellular receptor for the thyroid hormones, and its expression in breast cancer cells has an association with bone metastases in rats and in mice bearing human breast xenografts [45,46]
Other systemic effects of hypothyroidism observed in rats included a lower serum leptin level with preserved abdominal fat mass, while circulating progesterone and prolactin levels were not different compared with controls
Summary
Breast cancer is a major cause of morbidity and mortality in women across geographies and age groups. Αvβ integrin acts as a cellular receptor for the thyroid hormones, and its expression in breast cancer cells has an association with bone metastases in rats and in mice bearing human breast xenografts [45,46]. Other systemic effects of hypothyroidism observed in rats included a lower serum leptin level with preserved abdominal fat mass, while circulating progesterone and prolactin levels were not different compared with controls In another in vivo animal model of immunocompetent Balb/c mice, which were inoculated with triple-negative 4T1 breast cancer cells, tumors in hyperthyroid mice grew faster than tumors of hypothyroid animals and displayed decreased infiltration by cytotoxic lymphocytes [55]. The specific thyroid nuclear receptor expressed is critical in mediating thyroid hormone effects and, in addition, αvβ integrin is expressed in breast cancer cells and is important for the observed effects. In vitro evaluation with TRβ knockdown suggested that the tumor-suppressing effects of TRβ were mediated by the suppression of cAMP/Protein Kinase A (PKA) signalling [65]
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