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Hypothyroidism reduces mammary tumor progression via Β-catenin-activated intrinsic apoptotic pathway in rats

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Abstract

Experimental hypothyroidism retards mammary carcinogenesis promoting apoptosis of tumor cells. β-catenin plays a critical role in cell adhesion and intracellular signaling pathways conditioning the prognosis of breast cancer. However, the mechanistic connections associated with the expression of β-catenin in thyroid status and breast cancer are not known. Therefore, we studied the relationship between the expression and localization of β-catenin and apoptosis in mammary tumors induced by 7,12-dimethylbenz(a)anthracene (DMBA) in hypothyroid (Hypot) and euthyroid (EUT) rats. Female Sprague Dawley rats were treated with a dose of DMBA (15 mg/rat) at 55 days of age and were then divided into two groups: HypoT (0.01% 6-N-propyl-2-thiouracil in drinking water, n = 54) and EUT (untreated control, n = 43). Latency, incidence and progression of tumors were determined. At sacrifice, tumors were obtained for immunohistological studies and Western Blot. The latency was longer (p < 0.05), the incidence was lower (p < 0.0001) and tumor growth was slower (p < 0.01) in HypoT rats compared to EUT. The expression of Bax, cleaved caspase-9 and caspase-3 was significantly higher in tumors of HypoT than in EUT (p < 0.05) indicating the activation of the intrinsic pathway. In this group, β-catenin was expressed in the plasma membrane and with less intensity, while its expression was nuclear and with greater intensity in the EUT (p < 0.05). Moreover, the expression of survivin was reduced in tumors of HypoT rats (p < 0.05). In conclusion, decreased expression of β-catenin and its normal location in membrane of mammary tumors are associated with augmented apoptosis via activation of the intrinsic pathway in HypoT rats.

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Acknowledgements

The authors are deeply indebted to Mrs. Elina Guiñazú de Di Nasso, Mrs. Paula Ginevro and Mr. Juan Rosales for their excellent technical assistance.

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Authors and Affiliations

  1. Instituto de Medicina y Biología Experimental de Cuyo (IMBECU), CCT-Mendoza CONICET, Av. Adrián Ruiz-Leal s/n, CC855, Mendoza, Argentina

    C. M. López Fontana, L. E. Zyla, F. E. Santiano, C. V. Sasso, F. D. Cuello-Carrión, V. Pistone Creydt, M. A. Fanelli & R. W. Carón

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  1. C. M. López Fontana
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  2. L. E. Zyla
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  3. F. E. Santiano
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  4. C. V. Sasso
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  5. F. D. Cuello-Carrión
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  6. V. Pistone Creydt
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  7. M. A. Fanelli
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  8. R. W. Carón
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Correspondence to C. M. López Fontana.

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This study was funded by Instituto Nacional del Cáncer, Ministerio de Salud, Presidencia de la Nación, Argentina.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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López Fontana, C.M., Zyla, L.E., Santiano, F.E. et al. Hypothyroidism reduces mammary tumor progression via Β-catenin-activated intrinsic apoptotic pathway in rats. Histochem Cell Biol 147, 759–769 (2017). https://doi.org/10.1007/s00418-017-1544-x

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