Hormonal Crosstalk Between Thyroid and Breast Cancer

Abstract

Differentiated thyroid cancer and breast cancer account for a significant portion of endocrine-related malignancies and predominately affect women. As hormonally responsive tissues, the breast and thyroid share endocrine signaling. Breast cells are responsive to thyroid hormone signaling and are affected by altered thyroid hormone levels. Thyroid cells are responsive to sex hormones, particularly estrogen, and undergo protumorigenic processes upon estrogen stimulation. Thyroid and sex hormones also display significant transcriptional crosstalk that influences oncogenesis and treatment sensitivity. Obesity-related adipocyte alterations-adipocyte estrogen production, inflammation, feeding hormone dysregulation, and metabolic syndromes-promote hormonal alterations in breast and thyroid tissues. Environmental toxicants disrupt endocrine systems, including breast and thyroid homeostasis, and influence pathologic processes in both organs through hormone mimetic action. In this brief review, we discuss the hormonal connections between the breast and thyroid and perspectives on hormonal therapies for breast and thyroid cancer. Future research efforts should acknowledge and further explore the hormonal crosstalk of these tissues in an effort to further understand the prevalence of thyroid and breast cancer in women and to identify potential therapeutic options.

Keywords: breast cancer; estrogen; obesity; thyroid cancer; thyroid hormones.

Figure 1.

Breast and thyroid within the hypothalamic-pituitary hormone system. The hypothalamus is a part of the brain that secretes gonadotropin (GnRH)- and thyrotropin (TRH)- releasing hormones, which stimulate the anterior pituitary gland. In response to these hormones, the pituitary gland activates the thyroid via thyroid-stimulating hormone (TSH) and the gonadal axes via luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Endocrine targets downstream of the anterior pituitary gland, such as the thyroid and ovaries, release thyroid hormones (T3 and T4) or androgens, estrogen, and progesterone to regulate various physiological targets, including the thyroid and breast. Figure created with BioRender.com.

Figure 2.

Hormone signaling crosstalk between thyroid and breast. Thyroid and sex hormone signaling is driven either by interactions with membrane receptors (eg, MCT8/10, integrin avb3, TSHR, EGRF, IGFR, or ER among others) or direct access to the cytoplasm or the nucleus. The mechanisms of action of these hormones are often overlapping between thyroid and breast cells, ultimately resulting in transcriptional changes at the nucleus. While genomic actions involve the interaction of the thyroid (T3 or T4) or sex hormones (eg, estrogen) to nuclear receptor (TR or ER), they can also regulate target tissues by transcription-independent mechanisms. Nongenomic actions are initiated in the cytoplasm and include the activation of signal transduction kinases in the MAPK or PI3K/AKT pathway prior the stimulation of TR and ER. Thyroid hormones and estrogen also display cytoplasmic and nuclear crosstalk through MAPK-induced estrogen receptor modification, shared nuclear coregulators (eg, NCOA1, SMART, and NCOR1), and hormone response element ambiguity. Figure created with BioRender.com.