Long term hipothyroidism impact on mammary cell survival and cell cycle control

ZYLA, LE; SANTIANO, FE; LÓPEZ FONTANA, CM; CAMPO VERDE ARBOCCO, F; BERNAL, GN; BRUNA, FA; SASSO, CV; HAPON, MB; CARÓN, RW; PERSIA, FA; GÓMEZ, SE; PISTONE CREYDT, V; JAHN, GA

Mendoza

Congreso; XXXVI Reunión Científica Anual de la Sociedad de Biología de Cuyo; 2018

Sociedad de Biología de Cuyo

After a reproductive event, at weaning, the mammary tissue involution is characterized by programmed death of epithelial cells and return to a pre-gestational like tissue histoarchitecture. Hypothyroidism (HypoT) alters intracellular events that regulate mammary cell differentiation and involution, and cause both, mammary development in virgin rats and premature involution of tissue in lactating rats. Beyond lactation, the long term impact of hypoT on the mammary gland is unknown. Therefore, we investigated the mammary glands of hypothyroid Sprague Dawley (HypoT) and euthyroid (Ctrl) rats that have undergone a complete cycle of gestation, lactation and involution. On day 28 after weaning we dissected inguinal mammary glands for western blot and for histological analysis. We evaluated the hormonal receptors level, cell cycle regulatory proteins and apoptosis related proteins. HypoT increased the p53 and p21 protein level and decreased the Retinoblastome phosphorylation level. Despite these results indicating cell cycle arrest, we also found an increase in the Ki67, Survivin and Bcl-2 protein level, which suggest an atypical cell survival. The thyroid hormone receptor expression increased with HypoT and although it did not change the protein level of the estrogen beta receptor, progesterone receptor decreased by HypoT. The tissue histological analysis revealed an architecture similar to the pre-gestational stage in the Ctrl group. Surprisingly the HypoT group showed mammary tissue architecture altered with atypical alveoli, with epithelium areas stratified and disordered, with hyperplasic characteristics similar to fibroadenomas. Added to this, one of the animals showed alveolar secretory development and cell masses similar to in situ carcinoma. These results proved that the impact of hypothyroidism in mammary physiology is not only limited to gestation and lactation but also after the reproductive event, the mammary epithelium remains subject to intracellular and extracellular modifications which promote cell survival and an atypical epithelium, possibly more sensitive to the pathologic development