PGR-KITLG signaling drives a tumor-mast cell regulatory feedback to modulate apoptosis of breast cancer cells

作者全名：Yang, Zeyu; Chen, Hongdan; Yin, Supeng; Mo, Hongbiao; Chai, Fan; Luo, Peng; Li, Yao; Ma, Le; Yi, Ziying; Sun, Yizeng; Chen, Yan; Wu, Jie; Wang, Weihua; Yin, Tingjie; Zhu, Junping; Shi, Chunmeng; Zhang, Fan

作者地址：[Yang, Zeyu; Chen, Hongdan; Yin, Supeng; Mo, Hongbiao; Chai, Fan; Li, Yao; Yi, Ziying; Sun, Yizeng; Wang, Weihua; Yin, Tingjie; Zhu, Junping; Zhang, Fan] Chongqing Gen Hosp, Dept Breast & Thyroid Surg, 118 Xingguang Ave, Chongqing, Peoples R China; [Luo, Peng; Ma, Le; Chen, Yan; Wu, Jie; Shi, Chunmeng] Army Med Univ, Mil Med Univ 3, Inst Rocket Force Med, State Key Lab Trauma & Chem Poisoning, Chongqing 400038, Peoples R China; [Yang, Zeyu; Zhang, Fan] Chongqing Med Univ, Grad Sch Med, Chongqing 400016, Peoples R China

通信作者：Zhang, F (通讯作者)，Chongqing Gen Hosp, Dept Breast & Thyroid Surg, 118 Xingguang Ave, Chongqing, Peoples R China.; Shi, CM (通讯作者)，Army Med Univ, Mil Med Univ 3, Inst Rocket Force Med, State Key Lab Trauma & Chem Poisoning, Chongqing 400038, Peoples R China.

来源：CANCER LETTERS

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001224844100001

JCR分区：Q1

影响因子：9.1

年份：2024

卷号：589

期号：　

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结束页：　

文献类型：Article

关键词：Mast cells; Breast cancer; PGR-KITLG signaling; GRN; Apoptosis

摘要：The immune microenvironment constructed by tumor-infiltrating immune cells and the molecular phenotype defined by hormone receptors (HRs) have been implicated as decisive factors in the regulation of breast cancer (BC) progression. Here, we found that the infiltration of mast cells (MCs) informed impaired prognoses in HR(+) BC but predicted improved prognoses in HR(-) BC. However, molecular features of MCs in different BC remain unclear. We next discovered that HR(-) BC cells were prone to apoptosis under the stimulation of MCs, whereas HR(+) BC cells exerted anti-apoptotic effects. Mechanistically, in HR(+) BC, the KIT ligand (KITLG), a major mast cell growth factor in recruiting and activating MCs, could be transcriptionally upregulated by the progesterone receptor (PGR), and elevate the production of MC-derived granulin (GRN). GRN attenuates TNF alpha induced apoptosis in BC cells by competitively binding to TNFR1. Furthermore, disruption of PGR-KITLG signaling by knocking down PGR or using the specific KITLG-cKIT inhibitor iSCK03 potently enhanced the sensitivity of HR(+) BC cells to MC-induced apoptosis and exerted anti-tumor activity. Collectively, these results demonstrate that PGR-KITLG signaling in BC cells preferentially induces GRN expression in MCs to exert antiapoptotic effects, with potential value in developing precision medicine approaches for diagnosis and treatment.

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