PI3K/AKT pathway regulates phosphorylation of steroid receptors, hormone independence and tumor differentiation in breast cancer
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-ind...
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todo:paper_01433334_v33_n3_p509_Riggio2023-10-03T14:59:18Z PI3K/AKT pathway regulates phosphorylation of steroid receptors, hormone independence and tumor differentiation in breast cancer Riggio, M. Polo, M.L. Blaustein, M. Colman-lerner, A. Lüthy, I. Lanari, C. Novaro, V. 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 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. Fil:Riggio, M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Blaustein, M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Colman-lerner, A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Lüthy, I. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Lanari, C. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Novaro, V. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_01433334_v33_n3_p509_Riggio |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
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Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
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 |
| spellingShingle |
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 Riggio, M. Polo, M.L. Blaustein, M. Colman-lerner, A. Lüthy, I. Lanari, C. Novaro, V. PI3K/AKT pathway regulates phosphorylation of steroid receptors, hormone independence and tumor differentiation in breast cancer |
| topic_facet |
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 |
| description |
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. |
| format |
JOUR |
| author |
Riggio, M. Polo, M.L. Blaustein, M. Colman-lerner, A. Lüthy, I. Lanari, C. Novaro, V. |
| author_facet |
Riggio, M. Polo, M.L. Blaustein, M. Colman-lerner, A. Lüthy, I. Lanari, C. Novaro, V. |
| author_sort |
Riggio, M. |
| title |
PI3K/AKT pathway regulates phosphorylation of steroid receptors, hormone independence and tumor differentiation in breast cancer |
| title_short |
PI3K/AKT pathway regulates phosphorylation of steroid receptors, hormone independence and tumor differentiation in breast cancer |
| title_full |
PI3K/AKT pathway regulates phosphorylation of steroid receptors, hormone independence and tumor differentiation in breast cancer |
| title_fullStr |
PI3K/AKT pathway regulates phosphorylation of steroid receptors, hormone independence and tumor differentiation in breast cancer |
| title_full_unstemmed |
PI3K/AKT pathway regulates phosphorylation of steroid receptors, hormone independence and tumor differentiation in breast cancer |
| title_sort |
pi3k/akt pathway regulates phosphorylation of steroid receptors, hormone independence and tumor differentiation in breast cancer |
| url |
http://hdl.handle.net/20.500.12110/paper_01433334_v33_n3_p509_Riggio |
| work_keys_str_mv |
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| _version_ |
1807317338730528768 |