Kim Sang Kyum, Jung Woo Hee, Koo Ja Seung
Department of Pathology, Severance Hospital, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.
PLoS One. 2014 Jun 30;9(6):e101004. doi: 10.1371/journal.pone.0101004. eCollection 2014.
Glycine and serine are well-known, classic metabolites of glycolysis. Here, we profiled the expression of enzymes associated with serine/glycine metabolism in different molecular subtypes of breast cancer and discuss their potential clinical implications.
We used western blotting and immunohistochemistry to examine five serine-/glycine-metabolism-associated proteins (PHGDH, PSAT, PSPH, SHMT, and GLDC) in six breast cancer cell lines and 709 breast cancer cases using tissue microarray (TMA).
PHGDH and PSPH, associated with serine metabolism, were highly expressed in the TNBC cells. GLDC, associated with glycine metabolism, was highly expressed in HER-2-positive MDA-MB-453 and TNBC-related MDA-MB-435S. TMA showed that the TNBC-type breast cancer tissues highly expressed PHGDH, PSPH, and SHMT1, but not the luminal-A-type tissues (p<0.001). PSPH and SHMT1 expression in the tumor stroma of HER-2-type cancers was the highest, but the luminal-A tissues showed the lowest expression (p<0.001). GLDC was most frequently expressed in cancer cells and stroma of the HER-2-positive cancers and least frequently in TNBC (p<0.001). By Cox multivariate analysis, tumor PSPH positivity (hazard ratio [HR]: 2.068, 95% confidence interval [CI]: 1.049-4.079, p = 0.036), stromal PSPH positivity (HR: 2.152, 95% CI: 1.107-4.184, p = 0.024), and stromal SHMT1 negativity (HR: 2.142, 95% CI: 1.219-3.764, p = 0.008) were associated with short overall survival.
Expression of serine-metabolism-associated proteins was increased in TNBC and decreased in the luminal-A cancers. Expression of glycine-metabolism-associated proteins was high in the tumor and stroma of HER-2-positive cancers.
甘氨酸和丝氨酸是糖酵解中众所周知的经典代谢产物。在此，我们分析了乳腺癌不同分子亚型中与丝氨酸/甘氨酸代谢相关的酶的表达情况，并探讨了它们潜在的临床意义。
我们使用蛋白质免疫印迹法和免疫组织化学方法，通过组织芯片（TMA）检测了六种乳腺癌细胞系和709例乳腺癌病例中五种与丝氨酸/甘氨酸代谢相关的蛋白质（磷酸甘油酸脱氢酶（PHGDH）、磷酸丝氨酸氨基转移酶（PSAT）、磷酸丝氨酸磷酸酶（PSPH）、丝氨酸羟甲基转移酶（SHMT）和甘氨酸脱羧酶（GLDC））。
与丝氨酸代谢相关的PHGDH和PSPH在三阴乳腺癌（TNBC）细胞中高表达。与甘氨酸代谢相关的GLDC在人表皮生长因子受体2（HER-2）阳性的MDA-MB-453细胞和与TNBC相关的MDA-MB-435S细胞中高表达。TMA显示，TNBC型乳腺癌组织中PHGDH、PSPH和丝氨酸羟甲基转移酶1（SHMT1）高表达，而管腔A型组织中则不高表达（p<0.001）。HER-2型癌症肿瘤基质中PSPH和SHMT1的表达最高，而管腔A型组织中表达最低（p<0.001）。GLDC在HER-2阳性癌症的癌细胞和基质中表达最频繁，在TNBC中表达最少（p<0.001）。通过Cox多因素分析，肿瘤PSPH阳性（风险比[HR]：2.068，95%置信区间[CI]：1.049-4.079，p = 0.036）、基质PSPH阳性（HR：2.152，95%CI：1.107-4.184，p = 0.024）和基质SHMT1阴性（HR：2.142，95%CI：1.219-3.764，p = 0.008）与总生存期缩短相关。
与丝氨酸代谢相关的蛋白质在TNBC中表达增加，在管腔A型癌症中表达降低。与甘氨酸代谢相关的蛋白质在HER-2阳性癌症的肿瘤和基质中高表达。
