Thyroid Hormone Enhancement of Estradiol Stimulation of Breast Carcinoma Proliferation

Thyroid hormone (T₃) and estradiol (Est) modulate biological processes by binding to nuclear receptor proteins that, through interactions with specific response elements in the regulatory regions of genes, modulate gene transcription. Est stimulation of estrogen receptor (ER)-positive breast carcinoma cell growth occurs through its ability to bind to the ER and activate gene transcription. We now report that physiological concentrations of T₃ significantly enhance Est stimulation of growth of a number of human breast carcinoma cell lines. The effect of T₃ is specific for Est stimulation of growth and has no effect on insulin-like growth factor-I stimulation of growth. The effect of T₃ on enhancing Est-mediated growth was specifically blocked by the addition of ligands inducing retinoid X receptor (RXR) homodimer receptor formation, suggesting that RXR-thyroid nuclear receptor (TR) heterodimer formation is required for the T₃-mediated effect on estradiol-stimulated growth. Four thyroid nuclear receptors have been described in tissues, TRα1, α2, β1, and β2. Breast carcinoma cells were found to express TRβ1 and TRα2 mRNA and very low levels of TRαl mRNA. T₃ did not increase ER mRNA or protein levels and did not enhance Est-mediated increases in gene transcription of a number of genes, i.e., transforming growth factor-α and pS2 which contain estrogen-response elements (EREs) in their regulatory regions. However, T₃ enhanced Est-stimulated ERE-TK-CAT activity. Thus significant cross-talk appears to occur between the TRs and ER and T₃ appears to enhance Est-mediated gene transcription.