Effects of Thyroxine on Apoptosis and Proliferation of Mammary Tumors

Hypothyroidism is a protective factor against breast cancer but long-term exposure or overdoses of thyroid replacement therapy with thyroxine (T-4) may increase breast cancer risk. Objective: to study, in vivo and in vitro, the effects of T-4 on the proliferation and apoptosis of mammary tumors of hypo- and euthyroid rats, and the possible mechanisms involved in these effects. Material and Methods: 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 -PTU- in drinking water, n = 20), hypothyroidism treated with T-4 (HypoT + T-4; 0.01% PTU in drinking water and 0.25 mg/kg/day T-4 via sc; n = 20) and EUT (untreated control, n = 20). At sacrifice, tumor explants from HypoT and EUT rats were obtained and treated either with 10(-10) M T-4 in DMEM/F12 without phenol red with 1% Charcoalized Fetal Bovine Serum or DMEM/F12 only for 15 min to evaluate intracellular signaling pathways associated with T-4, and 24 h to evaluate changes in the expression of hormone receptors and proteins related to apoptosis and proliferation by immunohistochemistry and Western Blot. Results: In vivo, hypothyroidism retards mammary carcinogenesis but its treatment with T-4 reverted the protective effects. In vitro, the proliferative and anti-apoptosis mechanisms of T-4 were different regarding the thyroid status. In EUT tumors, the main signaling pathway involved was the cross-talk with other receptors, such as ER alpha, PgR, and HER2. In HypoT tumors, the non-genomic signaling pathway of Tzt was the chief mechanism involved since alpha v beta 3 integrin, HER2, beta-catenin and, downstream, PI3K/AKT and ERK signaling pathways were activated. Conclusion: T-4 can regulate mammary carcinogenesis by mainly activating its non-genomic signaling pathway and by interacting with other hormone or growth factor pathways endorsing that overdoses of thyroid replacement therapy with T-4 can increase the risk of breast cancer.