MCT1 in Invasive Ductal Carcinoma: Monocarboxylate Metabolism and Aggressive Breast Cancer.
MCT1 in Invasive Ductal Carcinoma: Monocarboxylate Metabolism and Aggressive Breast Cancer.
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DOI：
10.3389/fcell.2017.00027
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发表时间：
2017
影响因子：
5.5
通讯作者：
Martinez-Outschoorn UE
中科院分区：
文献类型：
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作者：
Johnson JM;Cotzia P;Fratamico R;Mikkilineni L;Chen J;Colombo D;Mollaee M;Whitaker-Menezes D;Domingo-Vidal M;Lin Z;Zhan T;Tuluc M;Palazzo J;Birbe RC;Martinez-Outschoorn UE
前言：单羧酸转运体1(MCT1)是乳酸、丙酮酸等单羧酸盐的进口体，也是线粒体代谢的标志物。MCT1在肿瘤细胞亚群中高度表达，以允许从肿瘤微环境中摄取分解代谢物质，以支持线粒体代谢。我们研究了广泛的乳腺浸润性导管癌标本中MCT1的蛋白表达，以确定其与乳腺癌亚型和预后的关系。方法：应用组织芯片免疫组织化学方法检测MCT1的表达。其中雌激素受体和/或孕激素受体阳性(ER+和/或PR+)257例，人表皮生长因子受体2阳性(HER2+)62例，三阴性乳腺癌56例。用Aperio软件进行数字病理学定量分析MCT1的表达。使用协同定位算法在连续范围内(0-黑色到255-亮白色)测量染色强度。使用线性混合模型进行统计分析。结果：与ER+和/或PR+、HER-2+相比，TNBC中MCT1的高表达更为常见(p<；0.001)。具有原位成分的肿瘤不太可能对MCT1进行强烈染色(p<；0.05)。核级别越高，MCT1染色越高(p<；0.01)。T分期越高的肿瘤MCT1的表达越高(p<；0.05)。癌细胞中MCT1的高表达与较短的无进展生存期、较高的复发风险和较大的体积与TNBC状态无关(p<；0.05)。结论：MCT1的表达是乳腺浸润性导管癌高代谢代谢和线粒体代谢的标志，与乳腺癌复发有关。通过数字图像分析量化MCT1的表达，可能有助于作为预后生物标记物和设计使用MCT1抑制剂的临床试验。
Introduction: Monocarboxylate transporter 1 (MCT1) is an importer of monocarboxylates such as lactate and pyruvate and a marker of mitochondrial metabolism. MCT1 is highly expressed in a subgroup of cancer cells to allow for catabolite uptake from the tumor microenvironment to support mitochondrial metabolism. We studied the protein expression of MCT1 in a broad group of breast invasive ductal carcinoma specimens to determine its association with breast cancer subtypes and outcomes. Methods: MCT1 expression was evaluated by immunohistochemistry on tissue micro-arrays (TMA) obtained through our tumor bank. Two hundred and fifty-seven cases were analyzed: 180 cases were estrogen receptor and/or progesterone receptor positive (ER+ and/or PR+), 62 cases were human epidermal growth factor receptor 2 positive (HER2+), and 56 cases were triple negative breast cancers (TNBC). MCT1 expression was quantified by digital pathology with Aperio software. The intensity of the staining was measured on a continuous scale (0-black to 255-bright white) using a co-localization algorithm. Statistical analysis was performed using a linear mixed model. Results: High MCT1 expression was more commonly found in TNBC compared to ER+ and/or PR+ and compared to HER-2+ (p < 0.001). Tumors with an in-situ component were less likely to stain strongly for MCT1 (p < 0.05). High nuclear grade was associated with higher MCT1 staining (p < 0.01). Higher T stage tumors were noted to have a higher expression of MCT1 (p < 0.05). High MCT1 staining in cancer cells was associated with shorter progression free survival, increased risk of recurrence, and larger size independent of TNBC status (p < 0.05). Conclusion: MCT1 expression, which is a marker of high catabolite uptake and mitochondrial metabolism, is associated with recurrence in breast invasive ductal carcinoma. MCT1 expression as quantified with digital image analysis may be useful as a prognostic biomarker and to design clinical trials using MCT1 inhibitors.