THYROID-HORMONE ENHANCEMENT OF ESTRADIOL STIMULATION OF BREAST-CARCINOMA PROLIFERATION

Thyroid hormone (T-3) and estradiol (Est) modulate biological processe s by binding to nuclear receptor proteins that, through interactions w ith specific response elements in the regulatory regions of genes, mod ulate gene transcription. Est stimulation of estrogen receptor (ER)-po sitive breast carcinoma cell growth occurs through its ability to bind to the ER and activate gene transcription, We now report that physiol ogical concentrations of T-3 significantly enhance Est stimulation of growth of a number of human breast carcinoma cell lines, The effect of T-3 is specific for Est stimulation of growth and has no effect on in sulin-like growth factor I stimulation of growth, The effect of T-3 On enhancing Est-mediated growth was specifically blocked by the additio n of ligands inducing retinoid X receptor (RXR) homodimer receptor for mation, suggesting that RXR-thyroid nuclear receptor (TR) heterodimer formation is required for the T-3-mediated effect on estradiol-stimula ted growth, Four thyroid nuclear receptors have been described in tiss ues, TR alpha 1, alpha 2, beta 1, and beta 2, Breast carcinoma cells w ere found to express TR beta 1 and TR alpha 2 mRNA and very low levels of TR alpha 1 mRNA, T-3 did not increase ER mRNA or protein levels an d did not enhance Est-mediated increases in gene transcription of a nu mber of genes, i.e., transforming growth factor-a and pS2 which contai n estrogen-response elements (EREs) in their regulatory regions, Howev er, T-3 enhanced Est-stimulated ERE-TK-CAT activity, Thus significant cross-talk appears to occur between the TRs and ER and T-3 appears to enhance Est-mediated gene transcription. (C) 1995 Academic Press, Inc.