Jiao Xuanmao, Tian Lifeng, Zhang Zhao, Balcerek Joanna, Kossenkov Andrew V, Casimiro Mathew C, Wang Chenguang, Liu Yichuan, Ertel Adam, Soccio Raymond E, Chen Eric R, Liu Qin, Ashton Anthony W, Tong Wei, Pestell Richard G
Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Wynnewood, PA 19096, USA.
Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Cancers (Basel). 2021 Apr 30;13(9):2171. doi: 10.3390/cancers13092171.
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 restrained mammary tumor progression, lipogenesis, and induced local mammary tumor macrophage infiltration, without affecting other tissue hematopoietic stem cell pools. Endogenous induced expression of both an EphA2-Amphiregulin and an inflammatory INFγ and Cxcl5 signaling module, that was recapitulated in human breast cancer. bound directly to growth promoting and proinflammatory target genes in the context of chromatin. We conclude promotes ErbB2-induced tumor growth and inflammation and represents a relevant target for therapeutic coextinction. Herein, endogenous 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 may provide the rationale for complementary coextinction programs in ErbB2 tumors.
HER2与临床侵袭性疾病相关，在15% - 20%的乳腺癌（BC）中过表达。宿主免疫系统参与HER2阳性乳腺癌的治疗反应。识别参与ErbB2诱导肿瘤的基因程序可能为协同消除治疗方法提供理论基础。过氧化物酶体增殖物激活受体γ（PPARγ）在多种恶性肿瘤中表达，通过转录程序调控生物学功能。在此，内源性PPARγ的基因缺失抑制乳腺肿瘤进展、脂肪生成，并诱导局部乳腺肿瘤巨噬细胞浸润，而不影响其他组织造血干细胞池。内源性PPARγ诱导EphA2-双调蛋白以及炎症性INFγ和Cxcl5信号模块的表达，这在人类乳腺癌中得到重现。PPARγ在染色质背景下直接与促进生长和促炎的靶基因结合。我们得出结论，PPARγ促进ErbB2诱导的肿瘤生长和炎症，是治疗协同消除的相关靶点。在此，内源性PPARγ促进ErbB2介导的乳腺肿瘤发生和进展。PPARγ1增加了EGF-EphA2受体酪氨酸激酶模块和细胞因子/趋化因子1转录模块的表达。PPARγ诱导的促肿瘤炎症状态可能为ErbB2肿瘤的互补协同消除方案提供理论依据。
