AUTHOR=Johnson Jennifer M. , Cotzia Paolo , Fratamico Roberto , Mikkilineni Lekha , Chen Jason , Colombo Daniele , Mollaee Mehri , Whitaker-Menezes Diana , Domingo-Vidal Marina , Lin Zhao , Zhan Tingting , Tuluc Madalina , Palazzo Juan , Birbe Ruth C. , Martinez-Outschoorn Ubaldo E. 

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

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=5

YEAR=2017

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2017.00027

DOI=10.3389/fcell.2017.00027

ISSN=2296-634X

ABSTRACT=<p><bold>Introduction:</bold> 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.</p><p><bold>Methods:</bold> 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.</p><p><bold>Results:</bold> High MCT1 expression was more commonly found in TNBC compared to ER+ and/or PR+ and compared to HER-2+ (<italic>p</italic> &lt; 0.001). Tumors with an <italic>in-situ</italic> component were less likely to stain strongly for MCT1 (<italic>p</italic> &lt; 0.05). High nuclear grade was associated with higher MCT1 staining (<italic>p</italic> &lt; 0.01). Higher T stage tumors were noted to have a higher expression of MCT1 (<italic>p</italic> &lt; 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 (<italic>p</italic> &lt; 0.05).</p><p><bold>Conclusion:</bold> 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.</p>