Hypothyroidism impacts mammary tumor-associated adipose tissue and breast cancer epithelial cell dialogue

Abstract

Thyroid hormones play a key role in adipose tissue development and function. Hypothyroidism (HypoT) can delay mammary tumor development in rats, possibly by altering mammary adipose tissue (MAT) and its interaction with epithelial cells. To explore this hypothesis, we evaluated the effects of conditioned media derived from mammary adipose tissue (MAT-CMs) of hypothyroid (HypoT) and euthyroid (EUT) rats, with and without mammary tumors, on the behavior of mammary epithelial cells. Specifically, we assessed cell viability, proliferation, apoptosis, adhesion, and migration in tumorigenic (MCF-7, MDA-MB-231) and non-tumorigenic (MCF-10A) human mammary epithelial cell lines exposed to the MAT-CMs. Mammary tumors were induced in female Sprague–Dawley rats using 7,12-dimethylbenz[a]anthracene (15 mg/rat), and animals were randomly assigned to HypoT (0.01% 6-N-propyl-2-thiouracil in drinking water; n = 30) or EUT (tap water; n = 30) groups. MAT fragments were incubated in M199 medium for 24 hours, and the resulting CMs were collected and applied to cell cultures. In vivo, HypoT rats exhibited larger mammary fat pads, reduced tumor incidence, volume, and growth rate, and extended tumor-free survival. In vitro, non-tumor MAT-CMs from HypoT rats promoted apoptosis in MCF-10A cells, reduced viability and adhesion of MCF-7 cells, and increased proliferation while decreasing adhesion in MDA-MB-231 cells. Tumor MAT-CMs from HypoT rats stimulated proliferation in tumorigenic cells and inhibited apoptosis in MCF-10A cells. In conclusion, these findings indicate that HypoT modifies the secretory profile of MAT, with tumor MAT-CMs from HypoT potentially enhancing tumorigenic behaviors in mammary tumor cells.