Expression of hypoxia inducible factor–dependent neuropeptide Y receptors Y1 and Y5 sensitizes hypoxic cells to NPY stimulation

Abstract

Neuropeptide Y (NPY) is an abundant neurohormone in the central and peripheral nervous system involved in feeding behavior, energy balance, nociception, and anxiety. Several NPY receptor (NPYR) subtypes display elevated expression in many cancers including in breast tumors where it is exploited for imaging and diagnosis. Here, we address how hypoxia, a common feature of the tumor microenvironment, influences the expression of the NPYRs. We show that NPY1R and NPY5R mRNA abundance is induced by hypoxia in a hypoxia inducible factor (HIF)-dependent manner in breast cancer cell lines MCF7 and MDA-MB-231. We demonstrate that HIFs bind to several genomic regions upstream of the NPY1R and NPY5R transcription start sites. In addition, the MAPK/ERK pathway is activated more rapidly upon NPY5R stimulation in hypoxic cells compared with normoxic cells. This pathway requires insulin-like growth factor 1 receptor (IGF1R) activity in normoxia, but not in hypoxic cells, which display resistance to the radiosensitizer and IGF1R inhibitor AG1024. Furthermore, hypoxic cells proliferate and migrate more when stimulated with NPY relative to normoxic cells and exhibit a more robust response to a Y5-specific agonist. Our data suggest that hypoxia-induced NPYRs render hypoxic cells more sensitive to NPY stimulation. Considering that breast tissue receives a constant supply of NPY, hypoxic breast tumors are the perfect storm for hyperactive NPYR. This study not only highlights a new relationship between the HIFs and NPYR expression and activity but may inform the use of chemotherapeutics targeting NPYRs and hypoxic cells. Neuropeptide Y (NPY) is an abundant neurohormone in the central and peripheral nervous system involved in feeding behavior, energy balance, nociception, and anxiety. Several NPY receptor (NPYR) subtypes display elevated expression in many cancers including in breast tumors where it is exploited for imaging and diagnosis. Here, we address how hypoxia, a common feature of the tumor microenvironment, influences the expression of the NPYRs. We show that NPY1R and NPY5R mRNA abundance is induced by hypoxia in a hypoxia inducible factor (HIF)-dependent manner in breast cancer cell lines MCF7 and MDA-MB-231. We demonstrate that HIFs bind to several genomic regions upstream of the NPY1R and NPY5R transcription start sites. In addition, the MAPK/ERK pathway is activated more rapidly upon NPY5R stimulation in hypoxic cells compared with normoxic cells. This pathway requires insulin-like growth factor 1 receptor (IGF1R) activity in normoxia, but not in hypoxic cells, which display resistance to the radiosensitizer and IGF1R inhibitor AG1024. Furthermore, hypoxic cells proliferate and migrate more when stimulated with NPY relative to normoxic cells and exhibit a more robust response to a Y5-specific agonist. Our data suggest that hypoxia-induced NPYRs render hypoxic cells more sensitive to NPY stimulation. Considering that breast tissue receives a constant supply of NPY, hypoxic breast tumors are the perfect storm for hyperactive NPYR. This study not only highlights a new relationship between the HIFs and NPYR expression and activity but may inform the use of chemotherapeutics targeting NPYRs and hypoxic cells. The 36-amino acid neuropeptide Y (NPY) neurohormone family is broadly distributed throughout the central and peripheral nervous systems and is the most abundant neuropeptide in the brain (1Brothers S.P. Wahlestedt C. Therapeutic potential of neuropeptide Y (NPY) receptor ligands.EMBO Mol. Med. 2010; 2: 429-439Google Scholar, 2Cabrele C. Beck-Sickinger A.G. Molecular characterization of the ligand-receptor interaction of the neuropeptide Y family.J. Pept. Sci. 2000; 6: 97-122Google Scholar). Within the central nervous system, NPY is involved in the regulation of feeding behavior, energy balance, nociception, and anxiety. In the peripheral nervous system, the pleiotropic actions of NPY include regulation of vascular tone, chemotaxis of endothelial and vascular smooth muscle cells, leukocyte migration, and angiogenesis (1Brothers S.P. Wahlestedt C. Therapeutic potential of neuropeptide Y (NPY) receptor ligands.EMBO Mol. Med. 2010; 2: 429-439Google Scholar, 3Dimitrijevic M. Stanojevic S. The intriguing mission of neuropeptide Y in the immune system.Amino Acids. 2013; 45: 41-53Google Scholar). Within the periphery, NPY is primarily stored and released from sympathetic nerves of the autonomic branch of the peripheral nervous system and is released following high-frequency neuronal stimulation (3Dimitrijevic M. Stanojevic S. The intriguing mission of neuropeptide Y in the immune system.Amino Acids. 2013; 45: 41-53Google Scholar). There are five well-defined NPY receptor (NPYR) subtypes in mammals: Y1, Y2, Y4, Y5, and Y6. However, NPY6R is encoded by a nonfunctional pseudogene in primates and NPY4R exhibits low affinity for NPY (4Michel M.C. Beck-Sickinger A. Cox H. Doods H.N. Herzog H. Larhammar D. Quirion R. Schwartz T. Westfall T. XVI. International Union of Pharmacology recommendations for the nomenclature of neuropeptide Y, peptide YY, and pancreatic polypeptide receptors.Pharmacol. Rev. 1998; 50: 143-150Google Scholar). Thus, NPY1R, NPY2R, and NPY5R are the most biologically significant subtypes in humans (3Dimitrijevic M. Stanojevic S. The intriguing mission of neuropeptide Y in the immune system.Amino Acids. 2013; 45: 41-53Google Scholar, 5Zhang L. Bijker M.S. Herzog H. The neuropeptide Y system: Pathophysiological and therapeutic implications in obesity and cancer.Pharmacol. Ther. 2011; 131: 91-113Google Scholar). NPYRs are class I rhodopsin-like family of G-protein–coupled receptors and mediate their effects through a trimeric inhibitory GTP-binding protein (Gi/o) (3Dimitrijevic M. Stanojevic S. The intriguing mission of neuropeptide Y in the immune system.Amino Acids. 2013; 45: 41-53Google Scholar). All NPYRs decrease adenylyl cyclase activity, but additional receptor-mediated signaling pathways are generally less understood based on subtype- and tissue-specific interactions (3Dimitrijevic M. Stanojevic S. The intriguing mission of neuropeptide Y in the immune system.Amino Acids. 2013; 45: 41-53Google Scholar, 6Nie M. Selbie L.A. Neuropeptide Y Y1 and Y2 receptor-mediated stimulation of mitogen-activated protein kinase activity.Regul. Pept. 1998; 75-76: 207-213Google Scholar). Sharing 60% of the same amino acids (7Weinberg D.H. Sirinathsinghji D.J. Tan C.P. Shiao L.L. Morin N. Rigby M.R. Heavens R.H. Rapoport D.R. Bayne M.L. Cascieri M.A. Strader C.D. Linemeyer D.L. MacNeil D.J. Cloning and expression of a novel neuropeptide Y receptor.J. Biol. Chem. 1996; 271: 16435-16438Google Scholar), NPY1R and NPY5R have been implicated in activating the MAPK pathway in cardiomyocytes (8Pellieux C. Sauthier T. Domenighetti A. Marsh D.J. Palmiter R.D. Brunner H.R. Pedrazzini T. Neuropeptide Y (NPY) potentiates phenylephrine-induced mitogen-activated protein kinase activation in primary cardiomyocytes via NPY Y5 receptors.Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 1595-1600Google Scholar) and breast cancer cells (9Medeiros P.J. Al-Khazraji B.K. Novielli N.M. Postovit L.M. Chambers A.F. Jackson D.N. Neuropeptide Y stimulates proliferation and migration in the 4T1 breast cancer cell line.Int. J. Cancer. 2012; 131: 276-286Google Scholar, 10Sheriff S. Ali M. Yahya A. Haider K.H. Balasubramaniam A. Amlal H. Neuropeptide Y Y5 receptor promotes cell growth through extracellular signal-regulated kinase signaling and cyclic AMP inhibition in a human breast cancer cell line.Mol. Cancer Res. 2010; Scholar), and in cells through with insulin-like growth receptor (IGF1R) S. L. Neuropeptide Y receptor activation of via of the Scholar). of NPYR expression with NPY1R and NPY5R expression been in several of and and tumors relative to tissue S. Ali M. Yahya A. Haider K.H. Balasubramaniam A. Amlal H. Neuropeptide Y Y5 receptor promotes cell growth through extracellular signal-regulated kinase signaling and cyclic AMP inhibition in a human breast cancer cell line.Mol. Cancer Res. 2010; Scholar, M. Neuropeptide Y receptors in primary human brain in Scholar, M. expression of neuropeptide Y receptors in tumors of the human and Cancer Res. Scholar, M. Neuropeptide Y receptor expression in human primary Scholar, M. of neuropeptide Y receptors in human cancer Scholar, M. of neuropeptide Y in Res. Scholar). of primary human breast exhibit elevated NPY1R expression S. Ali M. Yahya A. Haider K.H. Balasubramaniam A. Amlal H. Neuropeptide Y Y5 receptor promotes cell growth through extracellular signal-regulated kinase signaling and cyclic AMP inhibition in a human breast cancer cell line.Mol. Cancer Res. 2010; Scholar). Furthermore, many breast cancer cell lines MCF7 and NPY1R and NPY5R S. Ali M. Yahya A. Haider K.H. Balasubramaniam A. Amlal H. Neuropeptide Y Y5 receptor promotes cell growth through extracellular signal-regulated kinase signaling and cyclic AMP inhibition in a human breast cancer cell line.Mol. Cancer Res. 2010; Scholar). NPY5R expression in cells to of NPYR in the tissue is by the sympathetic nervous it is with a supply of NPY NPY in with NPYR to NPYR activity (9Medeiros P.J. Al-Khazraji B.K. Novielli N.M. Postovit L.M. Chambers A.F. Jackson D.N. Neuropeptide Y stimulates proliferation and migration in the 4T1 breast cancer cell line.Int. J. Cancer. 2012; 131: 276-286Google Scholar, 10Sheriff S. Ali M. Yahya A. Haider K.H. Balasubramaniam A. Amlal H. Neuropeptide Y Y5 receptor promotes cell growth through extracellular signal-regulated kinase signaling and cyclic AMP inhibition in a human breast cancer cell line.Mol. Cancer Res. 2010; Scholar). NPY1R and NPY5R stimulation promotes migration, and angiogenesis in breast cancer (9Medeiros P.J. Al-Khazraji B.K. Novielli N.M. Postovit L.M. Chambers A.F. Jackson D.N. Neuropeptide Y stimulates proliferation and migration in the 4T1 breast cancer cell line.Int. J. Cancer. 2012; 131: 276-286Google Scholar, M. NPY receptors in human of Scholar, P.J. Jackson D.N. Neuropeptide Y activation on breast cancer cells a system that stimulates expression and to 2013; Scholar). NPYRs not only of cancer but potential of therapeutic breast it is to how the tumor the of cancers and the regulation of the NPYRs. is a of tumors where supply to M.C. J. J. and Mol. Med. Scholar). hypoxia to resistance to and and promotes and Rev. Scholar). The hypoxia inducible are central of the response to transcription are to cancer and of an and a M.C. and the response to hypoxic 2010; Scholar, L. of cancer Cancer. 2: Scholar). The hypoxic of HIFs to of migration and of cancer cells, and and and most of their transcription but have of P.J. of factor 1 and in cell Biol. Scholar). Cancer cells to to a more tumor M.C. J. J. and Mol. Med. Scholar). In cells, hypoxia NPY activity from cell in to cell migration, and angiogenesis C. S. A. L.M. S. S. M. A. D. A. H. T. activity of neuropeptide Y in from to 2013; Scholar). Here, we the relationship between NPYR hypoxia, and the cell migration and proliferation of breast cancer cell lines MCF7 and MDA-MB-231. Our data show that NPY1R and NPY5R mRNA is induced in hypoxia in a Furthermore, the HIFs bind to several regions upstream of the NPY1R NPY5R transcription start We show that NPY stimulation the MAPK/ERK pathway through IGF1R but that pathway is to IGF1R inhibition in The of NPY1R and NPY5R hypoxic cells to NPY by activating MAPK/ERK more and more cell migration and relative to normoxic cells. Our data that hypoxic cancer cells in an with NPY, in the may to that IGF1R and are for NPYR MCF7 and cells in hypoxia for and and The of NPY1R and NPY5R mRNA via We the hypoxic expression is only with protein of hypoxic requires to L. T. R. S. H. A. J. A. L. S. of and to common is in promotes an Scholar). In the NPY1R a significant in mRNA abundance 1 of hypoxia and a significant to normoxic In NPY1R mRNA abundance a significant of hypoxia relative to The NPY5R mRNA abundance a significant in MCF7 cells and 1 in cells relative to the NPY1R and NPY5R mRNA abundance to by in MCF7 cells and it to in and The of on NPY1R and NPY5R mRNA in MCF7 and in a study S. Ali M. Yahya A. Haider K.H. Balasubramaniam A. Amlal H. Neuropeptide Y Y5 receptor promotes cell growth through extracellular signal-regulated kinase signaling and cyclic AMP inhibition in a human breast cancer cell line.Mol. Cancer Res. 2010; Scholar). We low of mRNA and that mRNA is not induced by hypoxia We NPY1R and NPY5R hypoxic protein expression with the the mRNA In cell NPY1R and NPY5R protein significant with that by several from the mRNA abundance data in The NPY1R protein by of hypoxic in MCF7 cells and and by in relative to and The NPY5R protein significant in the to in MCF7 cells with a of of hypoxic relative to and In NPY5R protein significant in the to with a of of hypoxic relative to and The NPY1R the protein of of NPY1R M. C. J. L. A. J. Neuropeptide Y receptor interactions Scholar). data suggest that NPY1R and NPY5R expression is induced in a manner in MCF7 and cells. an in for the hypoxic in NPY1R and NPY5R mRNA we cells with is a which hypoxia by the of the to their MCF7 and cells with 1 for 1 and by and and with to of and to effects of on that S. novel of on cell inhibition of Scholar). In a of for NPY1R mRNA 1 and for NPY5R mRNA relative to In NPY1R and NPY5R mRNA of with of and relative to and data that NPY1R and NPY5R mRNA abundance is not only by hypoxia in but via MCF7 and cells to NPY1R and NPY5R to that in by targeting via in hypoxia to NPYR expression from in and for NPY1R and 1 for NPY5R in In NPY1R mRNA abundance by in and by in hypoxia when relative to NPY1R mRNA abundance in MCF7 only in hypoxia by relative to NPY5R mRNA abundance in by when and in hypoxia by when relative to In normoxic cells, of significant in NPY1R for and for and NPY5R for and for mRNA abundance relative to and In hypoxia, cells a significant only in NPY5R mRNA abundance by when relative to data show that of the mRNA abundance of NPY1R and We to inhibition of We MCF7 and cells with of and for with and in hypoxia for an of to NPYR expression from the data to their normoxic inhibition of in hypoxic MCF7 cells NPY1R and NPY5R mRNA to and the of the and inhibition of hypoxic NPY1R and NPY5R mRNA to and the of the and hypoxic cells with NPY1R and NPY5R mRNA to and the of the and of cells with not the hypoxic mRNA of NPY1R NPY5R and data show that the HIFs are involved in the hypoxic of NPY1R and the HIFs are more implicated in the hypoxic of NPY1R and NPY5R we a HIFs hypoxia response in the of of to their hypoxic expression R.H. of signaling the Scholar). are activated when the an hypoxia to Cox T. S. vascular endothelial growth factor expression in endothelial cells. of a Res. Scholar). The NPY1R and NPY5R and upstream regions for and Several regions of and to genomic with by and with of the genomic regions and of the NPY1R in and of the regions in MCF7 and upstream of the NPY5R All for interaction in and of for in MCF7 not with of the regions upstream of the NPY1R in and of in MCF7 with the genomic regions upstream of the NPY5R in and of regions in MCF7 interaction with the and M. L. between growth factor receptor and pathways resistance to by Biol. Chem. Scholar) and M. S. of transcription in the Res. Scholar), I and data show that and upstream of the NPY1R in with the NPY1R and NPY5R and upstream We to the hypoxic of NPY1R and NPY5R by the activity of signaling NPY1R and NPY5R have been implicated in activating the MAPK pathway with in (9Medeiros P.J. Al-Khazraji B.K. Novielli N.M. Postovit L.M. Chambers A.F. Jackson D.N. Neuropeptide Y stimulates proliferation and migration in the 4T1 breast cancer cell line.Int. J. Cancer. 2012; 131: 276-286Google Scholar, 10Sheriff S. Ali M. Yahya A. Haider K.H. Balasubramaniam A. Amlal H. Neuropeptide Y Y5 receptor promotes cell growth through extracellular signal-regulated kinase signaling and cyclic AMP inhibition in a human breast cancer cell line.Mol. Cancer Res. 2010; Scholar). We stimulated normoxic and hypoxic MCF7 and cells with NPY stimulation of MCF7 cells more rapidly to NPY and Y5 with a significant and relative to of stimulation and stimulation of MCF7 cells with Y1 a significant in relative to hypoxia but throughout the of the cells more rapidly to NPY and Y5 relative to with and of and stimulation of cells activation of and in and hypoxia data suggest that hypoxic cells are to to NPY more rapidly normoxic cells through NPY5R NPYR mediate the activation of via with IGF1R in cells S. L. Neuropeptide Y receptor activation of via of the Scholar), we IGF1R activity for in breast cancer cells. We MCF7 and cells with the IGF1R inhibitor for 1 stimulated with NPY to In normoxic MCF7 cells, of NPY stimulation relative to normoxic with an decrease that relative to In hypoxic MCF7 cells, not of and relative to for NPY with In normoxic cells, a that of NPY stimulation relative to In the of normoxic with relative to In the of hypoxic cells to with a of of NPY stimulation relative to to the with NPY data suggest that stimulation of the MAPK/ERK pathway requires IGF1R activity in but not in The of stimulates cell proliferation and migration the hypoxic tumor C. D. J. C. D. promotes cancer cell proliferation and tumor growth by 2010; Scholar, A. J. H. S. stimulates migration of breast cancer cells via the of the protein Cancer Res. 2013; Scholar). we of hypoxic MCF7 and cells more sensitive to NPY and Y5 stimulation more cell proliferation and migration in NPY stimulation in MCF7 cells cell migration in a in and hypoxia relative to their but the in hypoxia relative to Furthermore, only hypoxic MCF7 cells an in cell migration when stimulated with Y5 with a relative to In the only that a significant in migration relative to the Y5 in hypoxia with a to the In NPY stimulation a in migration in hypoxia in relative to their The Y5 only an in migration in hypoxic MCF7 cells with a significant relative to of the an in cell migration in the the of hypoxia In cell lines and cell migration the Y1 not an in migration but the by hypoxia and proliferation in cell but the only in NPY and Y5 stimulation proliferation by and relative to hypoxic In cells, Y1 and Y5 proliferation of and relative to hypoxic data show that stimulation with NPY, through a on cell migration in stimulation with NPY more proliferation in hypoxic cells through NPY1R and is to cells to NPY NPY1R and NPY5R mRNA induced in the hypoxic breast cell The NPYRs have in the of their in a of human cancer in of of NPYR and compared with tumors M. of neuropeptide Y in Res. Scholar). This been exploited to of NPY that are in breast cancer imaging and R. S. Beck-Sickinger A.G. of neuropeptide for Scholar, S. S. T. Beck-Sickinger A.G. and in and in of an neuropeptide Y for imaging of breast cancer by Scholar, D. M. H. Beck-Sickinger A.G. by neuropeptide Y to Chem. 2010; Scholar). We show that NPY1R and NPY5R mRNA induced by hypoxia in breast cells, and by a compared with relative to cancer cells and This is a response that is by cancer cells through the hypoxia and activity in tumors M. M.R. M. hypoxia for Scholar). breast tissue is by the sympathetic nervous system, the NPY to NPYR activity and the perfect storm for tumor (9Medeiros P.J. Al-Khazraji B.K. Novielli N.M. Postovit L.M. Chambers A.F. Jackson D.N. Neuropeptide Y stimulates proliferation and migration in the 4T1 breast cancer cell line.Int. J. Cancer. 2012; 131: 276-286Google Scholar, 10Sheriff S. Ali M. Yahya A. Haider K.H. Balasubramaniam A. Amlal H. Neuropeptide Y Y5 receptor promotes cell growth through extracellular signal-regulated kinase signaling and cyclic AMP inhibition in a human breast cancer cell line.Mol. Cancer Res. 2010; Scholar). cancer are the NPYRs. We NPYR expression in breast cancer cells sensitive to in is a feature of the tumor that is exploited by imaging to and through imaging and in breast Cancer. Scholar). Furthermore, hypoxia NPY activity from cell to cell migration, and angiogenesis in cells C. S. A. L.M. S. S. M. A. D. A. H. T. activity of neuropeptide Y in from to 2013; Scholar). We have implicated the HIFs in the hypoxic of NPY1R and The breast cancer cell lines in study of breast cancer MCF7 is an of the and is a breast cancer J. J. T. L. N. T. S. A. of breast cancer cell lines for the study of cancer Scholar). We a of to cell lines hypoxic NPY1R and and and The hypoxic of NPY1R and NPY5R a in cell lines with 1 by a to The NPY1R in cells that to display a significant in mRNA abundance The and and NPY1R and NPY5R hypoxic in cells, which to and Furthermore, on NPY1R and NPY5R hypoxic in cells but have an in where are low and are less the HIFs many of their in hypoxia M. N. R. H. P.J. D.R. of the and transcription in Scholar). Considering we that normoxic expression of HIFs have a in However, when HIFs NPY1R NPY5R we of to in and hypoxia relative to their The breast cancer which an elevated hypoxic relative to subtypes N. of human breast 2012; Scholar). a pathway activation and in to a signaling that S. H. S. J. of by in breast Scholar, J. M. L. J. T. A.F. Molecular of breast cancer cell lines tumor and a for cancer Scholar). we a hypoxic of in compared with MCF7 cells, to in normoxic cells Our data that the HIFs are involved in the hypoxic of NPY1R and NPY5R and that is the in subtypes of We via with the NPY1R that M. C. J. L. A. J. Neuropeptide Y receptor interactions Scholar). to in cell lines by hypoxia and an of of NPY1R and NPY5R not that the HIFs are a a of to NPY1R and NPY5R The HIFs bind to but of the to to of R.H. of signaling the Scholar). been through in and to the but interactions A. D. N. J. L. of factor and by a data and in Res. 2010; Scholar). The of regions to of Cox T. S. vascular endothelial growth factor expression in endothelial cells. of a Res. Scholar). of the through and that HIFs bind to from the 60% of and of more from the with J. S. J. P.J. D.R. of by 2011; Scholar). The of through in study between and from the NPY1R and NPY5R more in regions and a for which is with a more pathway N. of human breast 2012; Scholar, S. H. S. J. of by in breast Scholar, J. M. L. J. T. A.F. Molecular of breast cancer cell lines tumor and a for cancer Scholar) and a for and There is in the that the HIFs genomic but we that NPY1R and NPY5R expression is induced by to NPY1R and NPY5R genomic However, of the of by and S. M. of expression by of the hypoxic the Scholar). cells to NPY stimulation where in normoxic cells. This is in an cell with S. R. H. S. L. S. J. A. kinase activity that in breast Scholar), where normoxic NPY stimulation in compared with significant in hypoxia Furthermore, of the only the Y5 hypoxic and that NPY5R a in the we show that IGF1R activity is involved in activation of MAPK/ERK in normoxic cells but not in hypoxic cells and cells more to NPY and Y5 normoxic cells with to cell migration and the an of MAPK/ERK The Y1 the hypoxic in cell migration in cell lines and and not cell proliferation in MCF7 compared with hypoxic NPY1R stimulation including cell growth in MCF7 J. L. A. T. J. A. Neuropeptide Y Y1 receptors mediate of with to breast cancer cells with and potential for breast cancer Scholar). Our data suggest that hypoxic cells are more sensitive normoxic cells to NPY through This to the of NPY1R and NPY5R in IGF1R is a hypoxia-induced protein J. A. M.R. J. M. A. S. in the protein 2012; Scholar), which the with inhibitor the of on hypoxic cells. hypoxia and C. of hypoxia on activity and Scholar), a In breast NPY stimulation of NPY5R have a in of that to the and of breast NPY to proliferation (9Medeiros P.J. Al-Khazraji B.K. Novielli N.M. Postovit L.M. Chambers A.F. Jackson D.N. Neuropeptide Y stimulates proliferation and migration in the 4T1 breast cancer cell line.Int. J. Cancer. 2012; 131: 276-286Google Scholar, 10Sheriff S. Ali M. Yahya A. Haider K.H. Balasubramaniam A. Amlal H. Neuropeptide Y Y5 receptor promotes cell growth through extracellular signal-regulated kinase signaling and cyclic AMP inhibition in a human breast cancer cell line.Mol. Cancer Res. 2010; Scholar) migration (9Medeiros P.J. Al-Khazraji B.K. Novielli N.M. Postovit L.M. Chambers A.F. Jackson D.N. Neuropeptide Y stimulates proliferation and migration in the 4T1 breast cancer cell line.Int. J. Cancer. 2012; 131: 276-286Google Scholar, 10Sheriff S. Ali M. Yahya A. Haider K.H. Balasubramaniam A. Amlal H. Neuropeptide Y Y5 receptor promotes cell growth through extracellular signal-regulated kinase signaling and cyclic AMP inhibition in a human breast cancer cell line.Mol. Cancer Res. 2010; Scholar), and angiogenesis P.J. Jackson D.N. Neuropeptide Y activation on breast cancer cells a system that stimulates expression and to 2013; NPYR activity in hypoxia to in a breast cancer Our that NPYRs are sensitive to in the that NPY in a low may to tumor and tumor neuronal of NPY of NPY is by hypoxia in C. S. A. L.M. S. S. M. A. D. A. H. T. activity of neuropeptide Y in from to 2013; Scholar). in may the effects of hypoxia on activity, and the of the NPY system the tumor Our data NPY1R and NPY5R hypoxia inducible and hypoxic cells more sensitive to NPY stimulation. This study inform the and use of NPYR in breast cancer targeting the NPY5R a in hypoxic cells, which are more and Rev. Scholar). and cells from the from the and for and by and cells in a and cells in a and The hypoxia 1 for and in The inhibitor and the inhibitor to cells for hypoxic is a that activity D. A.G. M. A. R.H. a inhibitor of Res. Scholar). the to with and The inhibitor of IGF1R to cells 1 to with NPYR NPY NPY1R NPY5R the a transcription to NPY1R, and NPY2R, and and and with in expression the and to and NPY1R NPY5R MAPK MAPK and and expression the following expression in a a from and a from that in and their with with in of and to cells for by with for an additional cells in hypoxia protein and MCF7 and cells with by of to with for with and in to cells and 1 1 inhibitor 1 on for to to the and the and on The in 1 inhibitor and via The with 1 inhibitor and with in and the to the in immune immune immune 1 and a and 1 The of and with for with 1 of for by 1 and for 1 the and on an via a to NPY1R and NPY5R and and and cells in a and to with and with in a by a with with NPY, NPY1R NPY5R to that in and for MCF7 for the and with migration with to cell of cells in the in NPY1R NPY5R to the of in and hypoxia, cells from the with a and cells in and with The on and on a cells by a B.K. P.J. Novielli N.M. Jackson D.N. for cells in migration 2011; Scholar). in a by of The with NPY, in hypoxia for and with for an additional The is from the and the The a and data are between by by All data are the This The that have of with the of We for We and for their This by the of and and the Cancer J. S. A. S. M. and A. J. S. A. and S. M. J. S. A. S. M. and J. U. J. U. J. U. This by the and of to J. U.

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