IN VITRO EFFECTS OF T4 ON APOPTOSIS AND PROLIFERATION OF MAMMARY TUMORS

ZYLA LE; SANTIANO FE; SASSO CV; PISTONE-CREDYT V; GOMEZ SE; BRUNA F; CARON RW; LOPEZ-FONTANA CM

BUENOS AIRES

Congreso; SAIC; 2017

SOCIEDAD ARGENTINA DE INVESTIGACIONES CLINICAS

Our aim was to study the genomic effects produced by thyroid hormones (TH) on mammary tumors from hypo-, eu- and hyperthyroid rats. Female Sprague‑Dawley rats were treated with a single dose of dimethylbenzathracene (15 mg/rat) at 55 days of age, and were divided into three groups: hypothyroidism (HypoT; 0.01% 6-N-propyl-2-thiouracil in drinking water, n=10), hyperthyroidism (Hyper, 0.25mg / kg / day Tyroxine -T4- via sc; n=10) and EUT (untreated control, n=10). At sacrifice, tumor explants were obtained and treated with 10-10 M T4 and/or 10-9 M 17β-estradiol (E2) in DMEM/F12 without phenol red with 1% Charcoalized Fetal Bovine Serum (SFBc) for 24 h to evaluate changes in the expression of hormone receptors and proteins related to apoptosis and proliferation by immunohistochemistry and Western Blot. Statistical analysis was performed using ANOVA I and Bonferroni?s test as post hoc. Administration of T4, E2 and T4+E2 induced a significant increase in KI67 expression in all tumors. Only T4 stimulation decreased total and cleaved caspase 3 and PARP expression in HypoT tumors while a slight increase of both apoptotic markers was observed in the Hyper tumors. No significant apoptotic changes were observed in the tumors of EUT. Regarding hormone receptors, administration of T4 increased cytoplasmic progesterone receptor (PgR), nuclear expression of thyroid hormone receptor β (TRβ) and favored the translocation to the nucleus of estrogen receptor (RE) β in HypoT tumors. T4 enhanced the nuclear and cytoplasmic expression of REα and REβ in Hyper tumors. T4 and T4+E2 augmented the expression of REα and PgR in EUT. E2 did not significantly modify the expression of hormone receptors. In conclusion, the administration of T4 induced a differential expression of hormone receptors according to the thyroid state of the tumor. It has a proliferative effect on all mammary tumors independent of the thyroid state but it only showed an antiapoptotic role in Hypot tumors