The niacin/butyrate receptor GPR109A suppresses mammary tumorigenesis by inhibiting cell survival.
The niacin/butyrate receptor GPR109A suppresses mammary tumorigenesis by inhibiting cell survival.
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DOI：
10.1158/0008-5472.can-13-1451
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发表时间：
2014-02-15
期刊：
影响因子：
11.2
通讯作者：
Thangaraju M
中科院分区：
文献类型：
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作者：
Elangovan S;Pathania R;Ramachandran S;Ananth S;Padia RN;Lan L;Singh N;Martin PM;Hawthorn L;Prasad PD;Ganapathy V;Thangaraju M
GPR 109 A是一种G蛋白偶联受体，可被烟酸和丁酸盐激活。在结肠细胞中激活后，GPR 109 A增强抗炎途径，诱导细胞凋亡，并防止炎症诱导的结肠癌。相反，角质形成细胞中的GPR 109 A激活通过激活考克斯-2依赖性炎症信号传导诱导潮红，并且受体表达在人表皮样癌中上调。因此，根据细胞环境和组织，GPR 109 A作为肿瘤抑制剂或肿瘤促进剂发挥作用。然而，这种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，GPR 109 A在正常乳腺组织中表达，无论激素受体的状态，其表达是沉默的人原发性乳腺肿瘤组织，乳腺癌细胞系，并在三个不同的小鼠乳腺肿瘤模型的肿瘤组织。该受体在人乳腺癌细胞系中的功能性表达降低cAMP产生，诱导细胞凋亡，并阻断集落形成和乳腺肿瘤生长。转录组分析显示，GPR 109 A激活抑制了人类乳腺癌细胞中参与细胞存活和抗凋亡信号传导的基因。此外，在自发性乳腺癌的MMTV-Neu小鼠模型中，小鼠中Gpr 109 a的缺失增加了肿瘤发生率，并引发了乳腺肿瘤发生的早期发作和肺转移的增加。这些发现表明，GPR 109 A是乳腺中的肿瘤抑制因子，并且在肿瘤组织中药理学诱导该基因，然后用激动剂激活该基因可能是治疗乳腺癌的有效治疗策略。
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 cAMP 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 anti-apoptotic 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 pharmacological induction of this gene in tumor tissues followed by its activation with agonists could be an effective therapeutic strategy to treat breast cancer.