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Abstract:

Using a model of medroxyprogesterone acetate (MPA)-induced mouse mammary tumors that transit through different stages of hormone dependence, we previously reported that the activation of the phosphatidylinositol 3-kinase (PI3K)/AKT (protein kinase B) pathway is critical for the growth of hormone-independent (HI) mammary carcinomas but not for the growth of hormone-dependent (HD) mammary carcinomas. The objective of this work was to explore whether the activation of the PI3K/AKT pathway is responsible for the changes in tumor phenotype and for the transition to autonomous growth. We found that the inhibition of the PI3K/AKT/mTOR (mammalian target of rapamycin) pathway suppresses HI tumor growth. In addition, we were able to induce mammary tumors in mice in the absence of MPA by inoculating HD tumor cells expressing a constitutively active form of AKT1, myristoylated AKT1 (myrAKT1). These tumors were highly differentiated and displayed a ductal phenotype with laminin-1 and cytokeratin 8 expression patterns typical of HI tumors. Furthermore, myrAKT1 increased the tumor growth of IBH-6 and IBH-7 human breast cancer cell lines. In the estrogen-dependent IBH-7 cell line, myrAKT1 induced estrogen-independent growth accompanied by the expression of the adhesion markers focal adhesion kinase and E-cadherin. Finally, we found that cells expressing myrAKT1 exhibited increased phosphorylation of the progesterone receptor at Ser190 and Ser294 and of the estrogen receptor α at Ser118 and Ser167, independently of exogenous MPA or estrogen supply. Our results indicate that the activation of the PI3K/AKT/mTOR pathway promotes tissue architecture remodeling and the activation of steroid receptors. © The Author 2011. Published by Oxford University Press. All rights reserved.

Registro:

Documento: Artículo
Título:PI3K/AKT pathway regulates phosphorylation of steroid receptors, hormone independence and tumor differentiation in breast cancer
Autor:Riggio, M.; Polo, M.L.; Blaustein, M.; Colman-lerner, A.; Lüthy, I.; Lanari, C.; Novaro, V.
Filiación:Laboratorio de Carcinogénesis Hormonal, Instituto de Biología y Medicina Experimental, Vuelta de Obligado 2490, C1428ADN Buenos Aires, Argentina
Instituto de Fisiología, Biología Molecular y Neurociencias, Consejo Nacional de Investigaciones Científicas y Técnicas (IBYME-CONICET), Vuelta de Obligado 2490, C1428ADN Buenos Aires, Argentina
Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, C1428EHA Buenos Aires, Argentina
Palabras clave:cytokeratin 8; estrogen; estrogen receptor alpha; focal adhesion kinase; laminin 1; mammalian target of rapamycin; phosphatidylinositol 3 kinase; progesterone receptor; protein kinase B; uvomorulin; animal experiment; animal model; animal tissue; article; breast cancer; cancer cell; cancer cell culture; cancer growth; controlled study; enzyme activation; female; human; human cell; mouse; myristylation; nonhuman; phenotype; priority journal; protein expression; protein phosphorylation; tumor differentiation; Animals; Cadherins; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Female; Focal Adhesion Protein-Tyrosine Kinases; Humans; Keratin-8; Laminin; Mammary Neoplasms, Experimental; Medroxyprogesterone Acetate; Mice; Mice, Inbred BALB C; Mice, Nude; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptors, Estrogen; Receptors, Progesterone; Signal Transduction; TOR Serine-Threonine Kinases
Año:2012
Volumen:33
Número:3
Página de inicio:509
Página de fin:518
DOI: http://dx.doi.org/10.1093/carcin/bgr303
Título revista:Carcinogenesis
Título revista abreviado:Carcinogenesis
ISSN:01433334
CODEN:CRNGD
CAS:phosphatidylinositol 3 kinase, 115926-52-8; protein kinase B, 148640-14-6; uvomorulin, 112956-45-3; Cadherins; Focal Adhesion Protein-Tyrosine Kinases, 2.7.10.2; Keratin-8; Laminin; Medroxyprogesterone Acetate, 71-58-9; Phosphatidylinositol 3-Kinases, 2.7.1.-; Proto-Oncogene Proteins c-akt, 2.7.11.1; Receptors, Estrogen; Receptors, Progesterone; TOR Serine-Threonine Kinases, 2.7.1.1; laminin 1; mTOR protein, mouse, 2.7.1.1
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_01433334_v33_n3_p509_Riggio

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Citas:

---------- APA ----------
Riggio, M., Polo, M.L., Blaustein, M., Colman-lerner, A., Lüthy, I., Lanari, C. & Novaro, V. (2012) . PI3K/AKT pathway regulates phosphorylation of steroid receptors, hormone independence and tumor differentiation in breast cancer. Carcinogenesis, 33(3), 509-518.
http://dx.doi.org/10.1093/carcin/bgr303
---------- CHICAGO ----------
Riggio, M., Polo, M.L., Blaustein, M., Colman-lerner, A., Lüthy, I., Lanari, C., et al. "PI3K/AKT pathway regulates phosphorylation of steroid receptors, hormone independence and tumor differentiation in breast cancer" . Carcinogenesis 33, no. 3 (2012) : 509-518.
http://dx.doi.org/10.1093/carcin/bgr303
---------- MLA ----------
Riggio, M., Polo, M.L., Blaustein, M., Colman-lerner, A., Lüthy, I., Lanari, C., et al. "PI3K/AKT pathway regulates phosphorylation of steroid receptors, hormone independence and tumor differentiation in breast cancer" . Carcinogenesis, vol. 33, no. 3, 2012, pp. 509-518.
http://dx.doi.org/10.1093/carcin/bgr303
---------- VANCOUVER ----------
Riggio, M., Polo, M.L., Blaustein, M., Colman-lerner, A., Lüthy, I., Lanari, C., et al. PI3K/AKT pathway regulates phosphorylation of steroid receptors, hormone independence and tumor differentiation in breast cancer. Carcinogenesis. 2012;33(3):509-518.
http://dx.doi.org/10.1093/carcin/bgr303