Authors' Affiliations: Departments of Biochemistry and Molecular Biology, Biostatistics and Epidemiology, and Pathology; Cancer Center; Vision Science Discovery Institute, Georgia Regents University; Augusta, Georgia.
Cancer Res. 2014 Feb 15;74(4):1166-78. doi: 10.1158/0008-5472.CAN-13-1451. Epub 2013 Dec 26.
GPR109A, a G-protein-coupled receptor, is activated by niacin and butyrate. Upon activation in colonocytes, GPR109A potentiates anti-inflammatory pathways, induces apoptosis, and protects against inflammation-induced colon cancer. In contrast, GPR109A activation in keratinocytes induces flushing by activation of Cox-2-dependent inflammatory signaling, and the receptor expression is upregulated in human epidermoid carcinoma. Thus, depending on the cellular context and tissue, GPR109A functions either as a tumor suppressor or a tumor promoter. However, the expression status and the functional implications of this receptor in the mammary epithelium are not known. Here, we show that GPR109A is expressed in normal mammary tissue and, irrespective of the hormone receptor status, its expression is silenced in human primary breast tumor tissues, breast cancer cell lines, and in tumor tissues of three different murine mammary tumor models. Functional expression of this receptor in human breast cancer cell lines decreases cyclic AMP production, induces apoptosis, and blocks colony formation and mammary tumor growth. Transcriptome analysis revealed that GPR109A activation inhibits genes, which are involved in cell survival and antiapoptotic signaling, in human breast cancer cells. In addition, deletion of Gpr109a in mice increased tumor incidence and triggered early onset of mammary tumorigenesis with increased lung metastasis in MMTV-Neu mouse model of spontaneous breast cancer. These findings suggest that GPR109A is a tumor suppressor in mammary gland and that pharmacologic induction of this gene in tumor tissues followed by its activation with agonists could be an effective therapeutic strategy to treat breast cancer.
GPR109A 是一种 G 蛋白偶联受体，可被烟酸和丁酸盐激活。在结肠细胞中被激活后，GPR109A 增强抗炎途径，诱导细胞凋亡，并预防炎症诱导的结肠癌。相比之下，GPR109A 在角质细胞中的激活通过激活 Cox-2 依赖性炎症信号诱导潮红，并且该受体在人表皮样癌细胞中上调。因此，根据细胞环境和组织的不同，GPR109A 既可以作为肿瘤抑制因子，也可以作为肿瘤促进因子发挥作用。然而，该受体在乳腺上皮中的表达状态和功能意义尚不清楚。在这里，我们表明 GPR109A 在正常乳腺组织中表达，并且无论激素受体状态如何，其在人原发性乳腺癌组织、乳腺癌细胞系以及三种不同的小鼠乳腺肿瘤模型的肿瘤组织中均被沉默。该受体在人乳腺癌细胞系中的功能性表达会降低 cAMP 的产生，诱导细胞凋亡，并阻断集落形成和乳腺肿瘤生长。转录组分析表明，GPR109A 的激活会抑制涉及细胞存活和抗凋亡信号的基因在人乳腺癌细胞中的表达。此外，在小鼠中删除 Gpr109a 会增加肿瘤发生率，并在自发性乳腺癌的 MMTV-Neu 小鼠模型中引发乳腺肿瘤发生的早期发作和肺转移增加。这些发现表明 GPR109A 是乳腺中的肿瘤抑制因子，并且在肿瘤组织中诱导该基因的表达，然后用激动剂激活它，可能是治疗乳腺癌的有效治疗策略。
