Authors' Affiliations: Department of Medical Oncology and Pathology, Hospital Clínic, Institut d'Investigacions Biomediques August Pi i Sunyer, Department of Medicine, University of Barcelona; Department of Cell Biology, Immunology, and Neurosciences, Medical School, University of Barcelona, Barcelona, Spain; Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea; Department of Genetics, Oslo University Hospital Radiumhospitalet, Norway; and Department of Medicine and Experimental Oncology, Torino University, Turin, Italy.
Cancer Res. 2013 Nov 1;73(21):6424-34. doi: 10.1158/0008-5472.CAN-12-4573. Epub 2013 Sep 12.
ERBB receptor transmodulation by heterologous G-protein-coupled receptors (GPCR) generates functional diversity in signal transduction. Tachykinins are neuropeptides and proinflammatory cytokines that promote cell survival and cancer progression by activating several GPCRs. In this work, we found that the pain-associated tachykinin Substance P (SP) contributes to persistent transmodulation of the ERBB receptors, EGFR and HER2, in breast cancer, acting to enhance malignancy and therapeutic resistance. SP and its high-affinity receptor NK-1R were highly expressed in HER2(+) primary breast tumors (relative to the luminal and triple-negative subtypes) and were overall correlated with poor prognosis factors. In breast cancer cell lines and primary cultures derived from breast cancer samples, we found that SP could activate HER2. Conversely, RNA interference-mediated attenuation of NK-1R, or its chemical inhibition, or suppression of overall GPCR-mediated signaling, all strongly decreased steady-state expression of EGFR and HER2, establishing that their basal activity relied upon transdirectional activation by GPCR. Thus, SP exposure affected cellular responses to anti-ERBB therapies. Our work reveals an important oncogenic cooperation between NK-1R and HER2, thereby adding a novel link between inflammation and cancer progression that may be targetable by SP antagonists that have been clinically explored.
异源 G 蛋白偶联受体 (GPCR) 对 ERBB 受体的转调节产生了信号转导功能的多样性。激肽原是神经肽和前炎性细胞因子，通过激活几种 GPCR 促进细胞存活和癌症进展。在这项工作中，我们发现与疼痛相关的激肽原 P 物质 (SP) 通过持续转调节乳腺癌中的 ERBB 受体 EGFR 和 HER2 发挥作用，增强恶性肿瘤和治疗耐药性。SP 及其高亲和力受体 NK-1R 在 HER2(+)原发性乳腺癌肿瘤中高表达（相对于腔型和三阴性亚型），并且总体上与预后不良因素相关。在乳腺癌细胞系和源自乳腺癌样本的原代培养物中，我们发现 SP 可以激活 HER2。相反，通过 RNA 干扰介导的 NK-1R 衰减，或其化学抑制，或抑制整体 GPCR 介导的信号转导，都强烈降低了 EGFR 和 HER2 的稳定表达，证实它们的基础活性依赖于 GPCR 的反式激活。因此，SP 暴露影响了细胞对抗 ERBB 治疗的反应。我们的工作揭示了 NK-1R 和 HER2 之间的一种重要致癌协同作用，从而在炎症和癌症进展之间增加了一个新的联系，这可能是临床上已经探索过的 SP 拮抗剂的靶向目标。
