Expansion of CD11b+Ly6G+Ly6Cint cells driven by medroxyprogesterone acetate in mice bearing breast tumors restrains NK cell effector functions

The progesterone analog medroxyprogesterone acetate (MPA) is widely used as a hormone replacement therapy in postmenopausal women and as contraceptive. However, prolonged administration of MPA is associated with increased incidence of breast cancer through ill-defined mechanisms. Here, we explored w...

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Autores principales:	Ziblat, Andrea, Domaica, Carolina Inés, Rossi, Lucas Ezequiel, Fuertes, Mercedes Beatriz, Salatino, Mariana
Publicado:	2013
Materias:	Breast cancer Medroxyprogesterone acetate Myeloid-derived suppressor cells NK cells CD11b antigen dexamethasone glucocorticoid receptor medrosterona medroxyprogesterone acetate mifepristone progesterone receptor unclassified drug animal cell animal experiment animal model apoptosis article bone marrow bone marrow cell breast tumor cell differentiation cell expansion cell function cell line cell motility controlled study cytotoxicity degranulation drug efficacy drug exposure effector cell female human human cell immunosurveillance in vitro study in vivo study mouse myeloid derived suppressor cell natural killer cell nonhuman priority journal protein expression spleen tumor cell tumor growth tumor volume tumor xenograft Animals Antigens, CD11b Antigens, Ly Antineoplastic Agents, Hormonal Blotting, Western Breast Neoplasms Cell Differentiation Cell Proliferation Cytotoxicity, Immunologic Female Flow Cytometry Fluorescent Antibody Technique Humans Killer Cells, Natural Medroxyprogesterone Acetate Mice Mice, Inbred BALB C Mice, Inbred C57BL Myeloid Cells Receptors, Glucocorticoid STAT3 Transcription Factor Tumor Cells, Cultured
Acceso en línea:	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_03407004_v62_n12_p1781_Spallanzani http://hdl.handle.net/20.500.12110/paper_03407004_v62_n12_p1781_Spallanzani
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

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spelling	paper:paper_03407004_v62_n12_p1781_Spallanzani2023-06-08T15:34:09Z Expansion of CD11b+Ly6G+Ly6Cint cells driven by medroxyprogesterone acetate in mice bearing breast tumors restrains NK cell effector functions Ziblat, Andrea Domaica, Carolina Inés Rossi, Lucas Ezequiel Fuertes, Mercedes Beatriz Salatino, Mariana Breast cancer Medroxyprogesterone acetate Myeloid-derived suppressor cells NK cells CD11b antigen dexamethasone glucocorticoid receptor medrosterona medroxyprogesterone acetate mifepristone progesterone receptor unclassified drug animal cell animal experiment animal model apoptosis article bone marrow bone marrow cell breast tumor cell differentiation cell expansion cell function cell line cell motility controlled study cytotoxicity degranulation drug efficacy drug exposure effector cell female human human cell immunosurveillance in vitro study in vivo study mouse myeloid derived suppressor cell natural killer cell nonhuman priority journal protein expression spleen tumor cell tumor growth tumor volume tumor xenograft Animals Antigens, CD11b Antigens, Ly Antineoplastic Agents, Hormonal Blotting, Western Breast Neoplasms Cell Differentiation Cell Proliferation Cytotoxicity, Immunologic Female Flow Cytometry Fluorescent Antibody Technique Humans Killer Cells, Natural Medroxyprogesterone Acetate Mice Mice, Inbred BALB C Mice, Inbred C57BL Myeloid Cells Receptors, Glucocorticoid STAT3 Transcription Factor Tumor Cells, Cultured The progesterone analog medroxyprogesterone acetate (MPA) is widely used as a hormone replacement therapy in postmenopausal women and as contraceptive. However, prolonged administration of MPA is associated with increased incidence of breast cancer through ill-defined mechanisms. Here, we explored whether exposure to MPA during mammary tumor growth affects myeloid-derived suppressor cells (MDSCs; CD11b+Gr-1+, mostly CD11b +Ly6G+Ly6Cint and CD11b+Ly6G -Ly6Chigh cells) and natural killer (NK) cells, potentially restraining tumor immunosurveillance. We used the highly metastatic 4T1 breast tumor (which does not express the classical progesterone receptor and expands MDSCs) to challenge BALB/c mice in the absence or in the presence of MPA. We observed that MPA promoted the accumulation of NK cells in spleens of tumor-bearing mice, but with reduced degranulation ability and in vivo cytotoxic activity. Simultaneously, MPA induced a preferential expansion of CD11b +Ly6G+Ly6Cint cells in spleen and bone marrow of 4T1 tumor-bearing mice. In vitro, MPA promoted nuclear mobilization of the glucocorticoid receptor (GR) in 4T1 cells and endowed these cells with the ability to promote a preferential differentiation of bone marrow cells into CD11b+Ly6G+Ly6Cint cells that displayed suppressive activity on NK cell degranulation. Sorted CD11b+Gr-1 + cells from MPA-treated tumor-bearing mice exhibited higher suppressive activity on NK cell degranulation than CD11b+Gr-1 + cells from vehicle-treated tumor-bearing mice. Thus, MPA, acting through the GR, endows tumor cells with an enhanced capacity to expand CD11b+Ly6G+Ly6Cint cells that subsequently display a stronger suppression of NK cell-mediated anti-tumor immunity. Our results describe an alternative mechanism by which MPA may affect immunosurveillance and have potential implication in breast cancer incidence. © 2013 Springer-Verlag Berlin Heidelberg. Fil:Ziblat, A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Domaica, C.I. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Rossi, L.E. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Fuertes, M.B. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Salatino, M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2013 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_03407004_v62_n12_p1781_Spallanzani http://hdl.handle.net/20.500.12110/paper_03407004_v62_n12_p1781_Spallanzani
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	Breast cancer Medroxyprogesterone acetate Myeloid-derived suppressor cells NK cells CD11b antigen dexamethasone glucocorticoid receptor medrosterona medroxyprogesterone acetate mifepristone progesterone receptor unclassified drug animal cell animal experiment animal model apoptosis article bone marrow bone marrow cell breast tumor cell differentiation cell expansion cell function cell line cell motility controlled study cytotoxicity degranulation drug efficacy drug exposure effector cell female human human cell immunosurveillance in vitro study in vivo study mouse myeloid derived suppressor cell natural killer cell nonhuman priority journal protein expression spleen tumor cell tumor growth tumor volume tumor xenograft Animals Antigens, CD11b Antigens, Ly Antineoplastic Agents, Hormonal Blotting, Western Breast Neoplasms Cell Differentiation Cell Proliferation Cytotoxicity, Immunologic Female Flow Cytometry Fluorescent Antibody Technique Humans Killer Cells, Natural Medroxyprogesterone Acetate Mice Mice, Inbred BALB C Mice, Inbred C57BL Myeloid Cells Receptors, Glucocorticoid STAT3 Transcription Factor Tumor Cells, Cultured
spellingShingle	Breast cancer Medroxyprogesterone acetate Myeloid-derived suppressor cells NK cells CD11b antigen dexamethasone glucocorticoid receptor medrosterona medroxyprogesterone acetate mifepristone progesterone receptor unclassified drug animal cell animal experiment animal model apoptosis article bone marrow bone marrow cell breast tumor cell differentiation cell expansion cell function cell line cell motility controlled study cytotoxicity degranulation drug efficacy drug exposure effector cell female human human cell immunosurveillance in vitro study in vivo study mouse myeloid derived suppressor cell natural killer cell nonhuman priority journal protein expression spleen tumor cell tumor growth tumor volume tumor xenograft Animals Antigens, CD11b Antigens, Ly Antineoplastic Agents, Hormonal Blotting, Western Breast Neoplasms Cell Differentiation Cell Proliferation Cytotoxicity, Immunologic Female Flow Cytometry Fluorescent Antibody Technique Humans Killer Cells, Natural Medroxyprogesterone Acetate Mice Mice, Inbred BALB C Mice, Inbred C57BL Myeloid Cells Receptors, Glucocorticoid STAT3 Transcription Factor Tumor Cells, Cultured Ziblat, Andrea Domaica, Carolina Inés Rossi, Lucas Ezequiel Fuertes, Mercedes Beatriz Salatino, Mariana Expansion of CD11b+Ly6G+Ly6Cint cells driven by medroxyprogesterone acetate in mice bearing breast tumors restrains NK cell effector functions
topic_facet	Breast cancer Medroxyprogesterone acetate Myeloid-derived suppressor cells NK cells CD11b antigen dexamethasone glucocorticoid receptor medrosterona medroxyprogesterone acetate mifepristone progesterone receptor unclassified drug animal cell animal experiment animal model apoptosis article bone marrow bone marrow cell breast tumor cell differentiation cell expansion cell function cell line cell motility controlled study cytotoxicity degranulation drug efficacy drug exposure effector cell female human human cell immunosurveillance in vitro study in vivo study mouse myeloid derived suppressor cell natural killer cell nonhuman priority journal protein expression spleen tumor cell tumor growth tumor volume tumor xenograft Animals Antigens, CD11b Antigens, Ly Antineoplastic Agents, Hormonal Blotting, Western Breast Neoplasms Cell Differentiation Cell Proliferation Cytotoxicity, Immunologic Female Flow Cytometry Fluorescent Antibody Technique Humans Killer Cells, Natural Medroxyprogesterone Acetate Mice Mice, Inbred BALB C Mice, Inbred C57BL Myeloid Cells Receptors, Glucocorticoid STAT3 Transcription Factor Tumor Cells, Cultured
description	The progesterone analog medroxyprogesterone acetate (MPA) is widely used as a hormone replacement therapy in postmenopausal women and as contraceptive. However, prolonged administration of MPA is associated with increased incidence of breast cancer through ill-defined mechanisms. Here, we explored whether exposure to MPA during mammary tumor growth affects myeloid-derived suppressor cells (MDSCs; CD11b+Gr-1+, mostly CD11b +Ly6G+Ly6Cint and CD11b+Ly6G -Ly6Chigh cells) and natural killer (NK) cells, potentially restraining tumor immunosurveillance. We used the highly metastatic 4T1 breast tumor (which does not express the classical progesterone receptor and expands MDSCs) to challenge BALB/c mice in the absence or in the presence of MPA. We observed that MPA promoted the accumulation of NK cells in spleens of tumor-bearing mice, but with reduced degranulation ability and in vivo cytotoxic activity. Simultaneously, MPA induced a preferential expansion of CD11b +Ly6G+Ly6Cint cells in spleen and bone marrow of 4T1 tumor-bearing mice. In vitro, MPA promoted nuclear mobilization of the glucocorticoid receptor (GR) in 4T1 cells and endowed these cells with the ability to promote a preferential differentiation of bone marrow cells into CD11b+Ly6G+Ly6Cint cells that displayed suppressive activity on NK cell degranulation. Sorted CD11b+Gr-1 + cells from MPA-treated tumor-bearing mice exhibited higher suppressive activity on NK cell degranulation than CD11b+Gr-1 + cells from vehicle-treated tumor-bearing mice. Thus, MPA, acting through the GR, endows tumor cells with an enhanced capacity to expand CD11b+Ly6G+Ly6Cint cells that subsequently display a stronger suppression of NK cell-mediated anti-tumor immunity. Our results describe an alternative mechanism by which MPA may affect immunosurveillance and have potential implication in breast cancer incidence. © 2013 Springer-Verlag Berlin Heidelberg.
author	Ziblat, Andrea Domaica, Carolina Inés Rossi, Lucas Ezequiel Fuertes, Mercedes Beatriz Salatino, Mariana
author_facet	Ziblat, Andrea Domaica, Carolina Inés Rossi, Lucas Ezequiel Fuertes, Mercedes Beatriz Salatino, Mariana
author_sort	Ziblat, Andrea
title	Expansion of CD11b+Ly6G+Ly6Cint cells driven by medroxyprogesterone acetate in mice bearing breast tumors restrains NK cell effector functions
title_short	Expansion of CD11b+Ly6G+Ly6Cint cells driven by medroxyprogesterone acetate in mice bearing breast tumors restrains NK cell effector functions
title_full	Expansion of CD11b+Ly6G+Ly6Cint cells driven by medroxyprogesterone acetate in mice bearing breast tumors restrains NK cell effector functions
title_fullStr	Expansion of CD11b+Ly6G+Ly6Cint cells driven by medroxyprogesterone acetate in mice bearing breast tumors restrains NK cell effector functions
title_full_unstemmed	Expansion of CD11b+Ly6G+Ly6Cint cells driven by medroxyprogesterone acetate in mice bearing breast tumors restrains NK cell effector functions
title_sort	expansion of cd11b+ly6g+ly6cint cells driven by medroxyprogesterone acetate in mice bearing breast tumors restrains nk cell effector functions
publishDate	2013
url	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_03407004_v62_n12_p1781_Spallanzani http://hdl.handle.net/20.500.12110/paper_03407004_v62_n12_p1781_Spallanzani
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Expansion of CD11b+Ly6G+Ly6Cint cells driven by medroxyprogesterone acetate in mice bearing breast tumors restrains NK cell effector functions

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