MCT1 in Invasive Ductal Carcinoma: Monocarboxylate Metabolism and Aggressive Breast Cancer

Abstract

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.

Metabolic coupling and the Reverse Warburg Effect in cancer: Implications for novel biomarker and anticancer agent development

“…From a prognostic standpoint, markers of metabolism may be useful in predicting disease behavior and outcomes. For example: in triple negative breast cancer, high expression of MCT1 on carcinoma cells has been associated with decreased progression free survival and increased risk of recurrence [34]; in cytogenetically normal acute myeloid leukemia, high TIGAR expression has been correlated with decreased survival [69]; in multiple tumor types (melanoma, colorectal, prostate, breast, gastric) loss of stromal CAV1 has been shown to be an independent predictor of poor prognosis [71] [72] [73] [74] [75]. There is great interest in incorporating metabolic parameters into cancer prognostic models [2].…”

“…The same procedure was then performed for MCT1, which was found to be selectively upregulated on MCF7 breast cancer cells and absent on CAFs [28]. High MCT1 expression is found in the majority of carcinoma cells in human breast cancer while as high MCT4 is found in the majority of breast cancer-associated stroma [34] [35]. This supported the authors’ hypothesis that a lactate shuttle may exist in tumors to transfer lactate from the stroma to the cancer cells for utilization [28].…”

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

“…With this important impact on lactate metabolism in tumor cells, MCT1, MCT2, and MCT4 have been proposed as diagnostic biomarkers or prognostic factors for cancer outcome and survival. For instance, increasing MCT1 expression is observed along with tumor aggressiveness e.g., in cervical cancer or is described as a prognostic marker in invasive breast cancer 32, 33. In prostate cancer, MCT2 has been proposed as a biomarker for disease diagnosis, because the transporter is not expressed in normal prostate tissue, an increase in expression can be observed in adjacent non‐neoplastic tissue and strong MCT2 expression is found in primary prostate tumor tissue samples 34.…”

“…For instance, increasing MCT1 expression is observed along with tumor aggressiveness e.g., in cervical cancer or is described as a prognostic marker in invasive breast cancer. 32,33 In prostate cancer, MCT2 has been proposed as a biomarker for disease diagnosis, because the transporter is not expressed in normal prostate tissue, an increase in expression can be observed in adjacent non-neoplastic tissue and strong MCT2 expression is found in primary prostate tumor tissue samples. 34 The lactate exporter MCT4, which is overexpressed in glycolytic tumor cells, is a promising candidate for cancer prognosis in various cancer entities, such as pancreatic cancer, 35 clear cell renal cell carcinoma, 29 or hepatocellular carcinoma.…”

CAIX forms a transport metabolon with monocarboxylate transporters in human breast cancer cells

“…Despite substantial progress in early detection and tumor therapy, breast cancer is still the most commonly diagnosed form of cancer and leading cause of cancer death in women worldwide [1]. Like most solid tumors, breast tumor tissue displays a significant increase in glycolytic activity, as compared to healthy breast tissue [2]). This increase in glycolysis, which was discovered by Otto Warburg more than 90 years ago [3,4], is now considered an emerging hallmark of cancer [5].…”