title: Hypothyroidism reduces mammary tumor progression via Β-catenin-activated intrinsic apoptotic pathway in rats.
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.
authors.affiliation: Instituto de Medicina y Biología Experimental de Cuyo (IMBECU), CCT-Mendoza CONICET, Av. Adrián Ruiz-Leal s/n, CC855, Mendoza, Argentina. clopezfontana@mendoza-conicet.gob.ar.
authors.forename: C M
authors.initials: CM
authors.lastname: López Fontana
authors.affiliation: Instituto de Medicina y Biología Experimental de Cuyo (IMBECU), CCT-Mendoza CONICET, Av. Adrián Ruiz-Leal s/n, CC855, Mendoza, Argentina.
authors.forename: L E
authors.initials: LE
authors.lastname: Zyla
authors.affiliation: Instituto de Medicina y Biología Experimental de Cuyo (IMBECU), CCT-Mendoza CONICET, Av. Adrián Ruiz-Leal s/n, CC855, Mendoza, Argentina.
authors.forename: F E
authors.initials: FE
authors.lastname: Santiano
authors.affiliation: Instituto de Medicina y Biología Experimental de Cuyo (IMBECU), CCT-Mendoza CONICET, Av. Adrián Ruiz-Leal s/n, CC855, Mendoza, Argentina.
authors.forename: C V
authors.initials: CV
authors.lastname: Sasso
authors.affiliation: Instituto de Medicina y Biología Experimental de Cuyo (IMBECU), CCT-Mendoza CONICET, Av. Adrián Ruiz-Leal s/n, CC855, Mendoza, Argentina.
authors.forename: F D
authors.initials: FD
authors.lastname: Cuello-Carrión
authors.affiliation: Instituto de Medicina y Biología Experimental de Cuyo (IMBECU), CCT-Mendoza CONICET, Av. Adrián Ruiz-Leal s/n, CC855, Mendoza, Argentina.
authors.forename: V
authors.initials: V
authors.lastname: Pistone Creydt
authors.affiliation: Instituto de Medicina y Biología Experimental de Cuyo (IMBECU), CCT-Mendoza CONICET, Av. Adrián Ruiz-Leal s/n, CC855, Mendoza, Argentina.
authors.forename: M A
authors.initials: MA
authors.lastname: Fanelli
authors.affiliation: Instituto de Medicina y Biología Experimental de Cuyo (IMBECU), CCT-Mendoza CONICET, Av. Adrián Ruiz-Leal s/n, CC855, Mendoza, Argentina.
authors.forename: R W
authors.initials: RW
authors.lastname: Carón
mesh_terms: D000818:Animals; D017209:Apoptosis; D018450:Disease Progression; D005260:Female; D007037:Hypothyroidism / Q000139:chemically induced / Q000378:metabolism*; D015674:Mammary Neoplasms, Animal / Q000378:metabolism*; D011441:Propylthiouracil; D051381:Rats; D017207:Rats, Sprague-Dawley; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051176:beta Catenin; D011441:Propylthiouracil
keywords: Bax; Caspase-3; Caspase-9; Dimethylbenz(a)anthracene; Survivin