Roles of full-length and truncated neurokinin-1 receptors on tumor progression and distant metastasis in human breast cancer

Substance P (SP) regulates various physiologic and pathophysiologic responses predominantly by acting through its primary receptor, the neurokinin-1 receptor (NK1R). There are two naturally occurring forms of NK1R: full-length NK1R-FL and truncated NK1R-Tr. SP-coupled NK1R can directly or indirectly regulate the proliferation and metastatic progression of many types of human cancer cells. However, the exact roles played by the two isoforms of NK1R in breast carcinogenesis still remain largely unclear. In the present study, we first examined the expression profile of total NK1Rs, NK1R-FL and NK1R-Tr in multiple breast cancer cell lines as well as in breast tumor samples. We found that total NK1Rs are present in normal, benign and breast tumor tissues; while, NK1R-FL expression are significantly decreased in tumor specimens, particularly in metastatic carcinomas. More interestingly, NK1R-FL is highly expressed in nontumorigenic HBL-100 breast cells, whereas MDA-MB-231, MCF-7 and T47D breast cancer cells express only NK1R-Tr. To further investigate potential implications of NK1R-FL and NK1R-Tr in the malignant phenotypes of breast cancer, we studied the impacts of ectopically overexpressed NK1R-FL and NK1R-Tr in MDA-MB-231 and HBL-100 cells, respectively. Our in vitro and in vivo data showed that NK1R-FL expression was inversely associated with proliferation, invasiveness and metastasis of MDA-MB-231 cells, but overexpression of NK1R-Tr was able to promote malignant transformation of HBL-100 cells and NK1R-Tr may contribute to tumor progression and promote distant metastasis in human breast cancer. A long-term treatment of NK1R antagonist ASN-1377642 exerted antitumor action in breast cancer cells with NK1R-Tr high expression.