Macrophage PPAR-Gamma Inhibits Gpr132 to Mediate the Anti-Tumor Effects of Rosiglitazone

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dc.contributor.advisorBrekken, Rolf A.en
dc.contributor.committeeMemberWan, Yihongen
dc.contributor.committeeMemberMinna, John D.en
dc.contributor.committeeMemberPearson, Gray W.en
dc.creatorCheng, Wing Yinen
dc.date.accessioned2018-06-04T18:50:24Z
dc.date.available2018-06-04T18:50:24Z
dc.date.created2016-05
dc.date.issued2016-04-04
dc.date.submittedMay 2016
dc.date.updated2018-06-04T18:42:06Z
dc.description.abstractTumor-associated macrophage (TAM) significantly contributes to tumorigenesis. Human cancer is enhanced by PPARgamma loss-of-function mutations, and inhibited by the thiazolidinedione (TZD) class of synthetic PPARgamma agonists and type 2 diabetes drugs such as rosiglitazone. However, it remains enigmatic whether and how macrophage contributes to PPARgamma tumor-suppressive functions. Here we uncover that macrophage PPARgamma deletion in mice exacerbates mammary tumor development by increasing the number and pro-inflammatory property of TAMs, which in turn stimulate cancer cell proliferation. Macrophage PPARgamma loss also impairs the anti-tumor effects of rosiglitazone. Mechanistically, we identify Gpr132 as a novel direct PPARgamma target in macrophage whose expression is enhanced by PPARgamma loss but repressed by PPARgamma activation. Functionally, macrophage Gpr132 is pro-inflammatory and protumor. Genetic Gpr132 deletion not only retards inflammation and cancer growth but also abrogates the anti-tumor effects of PPARgamma and rosiglitazone. Pharmacological Gpr132 inhibition significantly impedes mammary tumor malignancy. These findings identify macrophage PPARgamma and Gpr132 as critical TAM modulators, new cancer therapeutic targets, and essential mediators of TZD anti-cancer effects.en
dc.format.mimetypeapplication/pdfen
dc.identifier.oclc1038532833
dc.identifier.urihttps://hdl.handle.net/2152.5/5295
dc.language.isoenen
dc.subjectAntineoplastic Agentsen
dc.subjectCell Cycle Proteinsen
dc.subjectMacrophagesen
dc.subjectMammary Neoplasms, Experimentalen
dc.subjectPPAR gammaen
dc.subjectReceptors, G-Protein-Coupleden
dc.subjectThiazolidinedionesen
dc.titleMacrophage PPAR-Gamma Inhibits Gpr132 to Mediate the Anti-Tumor Effects of Rosiglitazoneen
dc.typeThesisen
dc.type.materialtexten
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineCancer Biologyen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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