The thyroid endocrine axis in breast cancer pathophysiology and prognosis

The Estrogen Receptor (ER) is a well-established regulator of the biologic behavior of breast cancer and a biomarker of response to endocrine treatments. Other steroid and non-steroid nuclear receptors, including Progesterone Receptor (PR), Androgen Receptor (AR), Vitamin D Receptor (VDR) and Thyroid Receptors (TRs), are often co-expressed with ER in breast cancers and modulate its biologic effects. In addition these receptors are also expressed in sub-sets of ER negative breast cancers and act as alternative transcription factors with cancer associated effects. The isotypes of TRs, TRα, TRβ, and other receptors of hormones of the thyroid axis such as the surface thyroid receptor, αvβ3 integrin and the receptor for TSH, TSH-R expressed in sub-sets of breast cancers, have both pro-carcinogenic and anti-carcinogenic functions that depend on the specific cancer cell environment. For TRs, co-expression of ER is important for their respective transcriptional output as these nuclear receptors interact at the chromatin level. The surface αvβ3 integrin receptor, on the other hand, activates signal transduction pathways that may affect ER function and its ability to execute its transcriptional program. Based on the role of the thyroid axis in breast cancer tissues, therapeutic opportunities from the manipulation of the axis in breast cancer arise, and initial studies have been performed with intriguing results. A biomarker based approach taking into consideration the breast cancer sub-types, including expression of other nuclear receptors and the expression of nuclear and surface thyroid receptors in breast cancer cells, could provide therapeutic opportunities, in a personalized manner.