TY - JOUR
T1 - Pparγ1 facilitates ErbB2-mammary adenocarcinoma in mice
AU - Jiao, Xuanmao
AU - Tian, Lifeng
AU - Zhang, Zhao
AU - Balcerek, Joanna
AU - Kossenkov, Andrew V.
AU - Casimiro, Mathew C.
AU - Wang, Chenguang
AU - Liu, Yichuan
AU - Ertel, Adam
AU - Soccio, Raymond E.
AU - Chen, Eric R.
AU - Liu, Qin
AU - Ashton, Anthony W.
AU - Tong, Wei
AU - Pestell, Richard G.
N1 - Funding Information:
Author Contributions: Conceptualization, R.G.P. and W.T.; Data curation, X.J., L.T., Z.Z., M.C.C. and R.G.P.; Formal analysis, X.J., L.T., Z.Z., J.B., A.V.K., M.C.C., C.W., Y.L., A.E., R.E.S., Q.L., A.W.A. and W.T.; Funding acquisition, R.G.P. and W.T.; Investigation, X.J., L.T., Z.Z., J.B., E.R.C. and A.W.A.; Methodology, X.J., L.T., A.V.K., M.C.C., C.W., Y.L., R.E.S. and W.T.; Project administration, R.G.P.; Supervision, X.J., C.W., W.T. and R.G.P.; Writing–original draft, R.P. and X.J.; Writing–review & editing, R.G.P., X.J. and W.T. All authors have read and agreed to the published version of the manuscript Funding: R.G.P is supported in part by funding from the National Institutes of Health National Cancer Institute (R01CA132115, R21CA235139-01 and the Breast Cancer Research Program (W81XWH1810605, Breakthrough Award) from the Department of Defense. W.T. is supported by NIH grants R01HL095675 and R01HL133828, awards from Fanconi Anemia Research Fund, Department of Defense, Leukemia Lymphoma Society and the Basser Center for BRCA. J.B. was supported by a NRSA F31CA180604 and the Patel Family Award.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/5/1
Y1 - 2021/5/1
N2 - HER2, which is associated with clinically aggressive disease, is overexpressed in 15–20% of breast cancers (BC). The host immune system participates in the therapeutic response of HER2+ breast cancer. Identifying genetic programs that participate in ErbB2-induced tumors may provide the rational basis for co-extinction therapeutic approaches. Peroxisome proliferator-activated receptor γ (PPARγ), which is expressed in a variety of malignancies, governs biological functions through transcriptional programs. Herein, genetic deletion of endogenous Pparγ1 restrained mammary tumor progression, lipogenesis, and induced local mammary tumor macrophage infiltration, without affecting other tissue hematopoietic stem cell pools. Endogenous Pparγ1 induced expression of both an EphA2-Amphiregulin and an inflammatory INFγ and Cxcl5 signaling module, that was recapitulated in human breast cancer. Pparγ1 bound directly to growth promoting and proinflammatory target genes in the context of chromatin. We conclude Pparγ1 promotes ErbB2-induced tumor growth and inflammation and represents a relevant target for therapeutic coextinction. Herein, endogenous Pparγ1 promoted ErbB2-mediated mammary tumor onset and progression. PPARγ1 increased expression of an EGF-EphA2 receptor tyrosine kinase module and a cytokine/chemokine 1 transcriptional module. The induction of a pro-tumorigenic inflammatory state by Pparγ1 may provide the rationale for complementary coextinction programs in ErbB2 tumors.
AB - HER2, which is associated with clinically aggressive disease, is overexpressed in 15–20% of breast cancers (BC). The host immune system participates in the therapeutic response of HER2+ breast cancer. Identifying genetic programs that participate in ErbB2-induced tumors may provide the rational basis for co-extinction therapeutic approaches. Peroxisome proliferator-activated receptor γ (PPARγ), which is expressed in a variety of malignancies, governs biological functions through transcriptional programs. Herein, genetic deletion of endogenous Pparγ1 restrained mammary tumor progression, lipogenesis, and induced local mammary tumor macrophage infiltration, without affecting other tissue hematopoietic stem cell pools. Endogenous Pparγ1 induced expression of both an EphA2-Amphiregulin and an inflammatory INFγ and Cxcl5 signaling module, that was recapitulated in human breast cancer. Pparγ1 bound directly to growth promoting and proinflammatory target genes in the context of chromatin. We conclude Pparγ1 promotes ErbB2-induced tumor growth and inflammation and represents a relevant target for therapeutic coextinction. Herein, endogenous Pparγ1 promoted ErbB2-mediated mammary tumor onset and progression. PPARγ1 increased expression of an EGF-EphA2 receptor tyrosine kinase module and a cytokine/chemokine 1 transcriptional module. The induction of a pro-tumorigenic inflammatory state by Pparγ1 may provide the rationale for complementary coextinction programs in ErbB2 tumors.
KW - Breast cancer
KW - Lipogenesis
KW - Peroxisome proliferator-activated receptor gamma (PPARγ), nuclear receptor
UR - https://www.scopus.com/pages/publications/85116559708
U2 - 10.3390/cancers13092171
DO - 10.3390/cancers13092171
M3 - Article
AN - SCOPUS:85116559708
SN - 2072-6694
VL - 13
JO - Cancers
JF - Cancers
IS - 9
M1 - 2171
ER -
