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.
Highlights
Monocarboxylate transporter 1 (MCT1) is an importer of monocarboxylates such as lactate and pyruvate and a marker of mitochondrial metabolism
For human epidermal growth factor receptor 2 (HER2) status, the current guidelines of 3+ staining by immunohistochemistry with >30% of invasive tumor cells showing staining, in-situ hybridization (ISH) positive based on single probe average HER2 copy number of >= 6 signals/cell, or ISH positive based on dual probe HER2 to CEP17 ratio >= 2.0 were used as cut-offs
We further investigated triple negative breast cancer (TNBC) (ER negative, PR negative, and HER2 negative tumors) and found an association between high MCT1 expression and TNBC compared to the other subtypes with an estimated difference of 27% (p < 0.001; Table 2)
Summary
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. Tumors frequently have very high levels of lactate in their microenvironment, produced by aerobic glycolysis. Otto Warburg hypothesized that cancer cells contained dysfunctional mitochondria leading to their inability to utilize oxidative phosphorylation to generate ATP and forcing them to use aerobic glycolysis (Koppenol et al, 2011). We know that in many cases of human breast cancer, mitochondria are not dysfunctional and some cancer cells have very high mitochondrial oxidative phosphorylation (OXPHOS) (MartinezOutschoorn et al, 2017). Glycolysis is more energetically inefficient compared to OXPHOS and why cells within tumors would utilize glycolysis has remained a paradox (Vander Heiden et al, 2009)
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