Effects of thyroxine on apoptosis and proliferation of mammary tumors
| Autor: | Flavia Bruna, Constanza López Fontana, Leila E. Zyla, Silvina Gómez, Rubén W. Carón, Rocio Yasmin Cano, Flavia E. Santiano, Lara Rey, Alexa Escudero, Virginia Pistone Creydt |
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| Rok vydání: | 2021 |
| Předmět: |
endocrine system
medicine.medical_specialty Apoptosis Biochemistry Rats Sprague-Dawley Endocrinology Hypothyroidism Piperidines Cell Line Tumor Internal medicine medicine Animals Euthyroid Receptor Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway Cell Proliferation Anthracenes business.industry Thyroid Mammary Neoplasms Experimental Rats Gene Expression Regulation Neoplastic Thyroxine medicine.anatomical_structure Propylthiouracil Hormone receptor Hypot Female business Signal Transduction Hormone |
| Zdroj: | Molecular and Cellular Endocrinology. 538:111454 |
| ISSN: | 0303-7207 |
| DOI: | 10.1016/j.mce.2021.111454 |
| Popis: | Hypothyroidism is a protective factor against breast cancer but long-term exposure or overdoses of thyroid replacement therapy with thyroxine (T4) may increase breast cancer risk. Objective: to study, in vivo and in vitro, the effects of T4 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 T4 (HypoT + T4; 0.01% PTU in drinking water and 0.25 mg/kg/day T4 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 T4 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 T4, 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 T4 reverted the protective effects. In vitro, the proliferative and anti-apoptosis mechanisms of T4 were different regarding the thyroid status. In EUT tumors, the main signaling pathway involved was the cross-talk with other receptors, such as ERα, PgR, and HER2. In HypoT tumors, the non-genomic signaling pathway of T4 was the chief mechanism involved since αvβ3 integrin, HER2, β-catenin and, downstream, PI3K/AKT and ERK signaling pathways were activated. Conclusion: T4 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 T4 can increase the risk of breast cancer. |
| Databáze: | OpenAIRE |
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