Expression of the hypoxia-inducible monocarboxylate transporter MCT4 is increased in triple negative breast cancer and correlates independently with clinical outcome

Doyen, J.; Trastour, C.; Ettore, F.; Peyrottes, Isabelle; Toussant, N.; Gal, Jocelyn; Ilc, Karine; Roux, Damien; Parks, Scott K.; Ferrero, Jean-­Marc; Pouysségur, Jacques

doi:10.1016/j.bbrc.2014.07.050

Cited by 98 publications

(92 citation statements)

References 25 publications

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“…Importantly, their expression levels correlate with worse clinical outcome. In particular, MCT4 was suggested to be a new independent prognostic factor in breast cancer (39). Our data implies that AI-resistant patients are characterized by enhanced MCT4 and GLUT1 expression (i.e., hyperglycolytic phenotype) and therefore may have a potential value in predicting AI response.…”

Section: Discussionmentioning

confidence: 66%

miR-155 Drives Metabolic Reprogramming of ER+ Breast Cancer Cells Following Long-Term Estrogen Deprivation and Predicts Clinical Response to Aromatase Inhibitors

et al. 2016

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Aromatase inhibitors (AI) have become the first-line endocrine treatment of choice for postmenopausal estrogen receptor-positive (ER þ ) breast cancer patients, but resistance remains a major challenge. Metabolic reprogramming is a hallmark of cancer and may contribute to drug resistance. Here, we investigated the link between altered breast cancer metabolism and AI resistance using AI-resistant and sensitive breast cancer cells, patient tumor samples, and AI-sensitive human xenografts. We found that long-term estrogen deprivation (LTED), a model of AI resistance, was associated with increased glycolysis dependency. Targeting the glycolysis-priming enzyme hexokinase-2 (HK2) in combination with the AI, letrozole, synergistically reduced cell viability in AI-sensitive models. Conversely, MCF7-LTED cells, which displayed a high degree of metabolic plasticity, switched to oxidative phosphorylation when glycolysis was impaired. This effect was ER dependent as breast cancer cells with undetectable levels of ER failed to exhibit metabolic plasticity. MCF7-LTED cells were also more motile than their parental counterparts and assumed amoeboid-like invasive abilities upon glycolysis inhibition with 2-deoxyglucose (2-DG). Mechanistic investigations further revealed an important role for miR-155 in metabolic reprogramming. Suppression of miR-155 resulted in sensitization of MCF7-LTED cells to metformin treatment and impairment of 2-DG-induced motility. Notably, high baseline miR-155 expression correlated with poor response to AI therapy in a cohort of ER þ breast cancers treated with neoadjuvant anastrozole. These findings suggest that miR-155 represents a biomarker potentially capable of identifying the subset of breast cancers most likely to adapt to and relapse on AI therapy. Cancer Res; 76(6); 1615-26. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 66%

miR-155 Drives Metabolic Reprogramming of ER+ Breast Cancer Cells Following Long-Term Estrogen Deprivation and Predicts Clinical Response to Aromatase Inhibitors

et al. 2016

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“…High levels of tumor lactate in cervical cancers (40) as well as high expression of MCT4, a major lactate transporter in breast cancers (17), are reported to be associated with a high frequency of metastases, tumor recurrence, and low survival. High lactate levels also signal "pseudo hypoxia" by increasing HIF1a stability (41), which promotes or enhances tumor hypoxia.…”

Section: Inhibition Of Mcts Maintains Cell Survival By Reactivating Omentioning

confidence: 99%

“…However, the high glycolytic rate associated with a production of lactic acid rapidly creates a hostile acidic and hypoxic microenvironment that induces dissemination of metastatic variants (11). Hypoxia via HIF1 controls intracellular pH (pHi) by inducing the membrane-bound carbonic anhydrases IX and XII (12)(13)(14) and a major H þ /lactate À symporter, MCT4 (15)(16)(17). Considering the key role of glycolysis in "glucoseaddicted" tumors, targeting this bioenergetic and anabolic pathway represents an attractive therapeutic approach (18)(19)(20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

“…Transport of lactate across the plasma membrane is carried out by a family of solute carrier family 16 (SLC16), or monocarboxylate transporters (MCT) in which four (MCT1-4) catalyze bidirectional proton-coupled transport of lactate. MCT1 is induced by Myc and MCT4 by HIF1, and are upregulated in several cancers (17,24). These two transporters require an accessory glycoprotein CD147/BASIGIN (BSG) for proper folding, stability, and trafficking to the cell surface (25,26).…”

Section: Introductionmentioning

confidence: 99%

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Genetic Disruption of Lactate/H+ Symporters (MCTs) and Their Subunit CD147/BASIGIN Sensitizes Glycolytic Tumor Cells to Phenformin

et al. 2015

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Rapidly growing glycolytic tumors require energy and intracellular pH (pHi) homeostasis through the activity of two major monocarboxylate transporters, MCT1 and the hypoxia-inducible MCT4, in intimate association with the glycoprotein CD147/ BASIGIN (BSG). To further explore and validate the blockade of lactic acid export as an anticancer strategy, we disrupted, via zinc finger nucleases, MCT4 and BASIGIN genes in colon adenocarcinoma (LS174T) and glioblastoma (U87) human cell lines. First, we showed that homozygous loss of MCT4 dramatically sensitized cells to the MCT1 inhibitor AZD3965. Second, we demonstrated that knockout of BSG leads to a decrease in lactate transport activity of MCT1 and MCT4 by 10-and 6-fold, respectively. Consequently, cells accumulated an intracellular pool of lactic and pyruvic acids, magnified by the MCT1 inhibitor decreasing further pHi and glycolysis. As a result, we found that these glycolytic/MCT-deficient cells resumed growth by redirecting their metabolism toward OXPHOS. Third, we showed that in contrast with parental cells, BSG-null cells became highly sensitive to phenformin, an inhibitor of mitochondrial complex I. Phenformin addition to these MCT-disrupted cells in normoxic and hypoxic conditions induced a rapid drop in cellular ATP-inducing cell death by "metabolic catastrophe." Finally, xenograft analysis confirmed the deleterious tumor growth effect of MCT1/MCT4 ablation, an action enhanced by phenformin treatment. Collectively, these findings highlight that inhibition of the MCT/BSG complexes alone or in combination with phenformin provides an acute anticancer strategy to target highly glycolytic tumors. This genetic approach validates the anticancer potential of the MCT1 and MCT4 inhibitors in current development.

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“…48 MCT expression is increased in cancers including triple-negative breast cancer, 49 renal cancer 50 and These bone-modifying factors further stimulate osteoclastic bone resorption via activation of receptor activator of the nuclear factor-kB (RANKL)/RANK pathway in osteoblasts and osteoclasts, thereby further increasing the release of bone-stored growth factors, thus establishing 'vicious cycle' between bone-resorbing osteoclasts and bone-colonizing cancer cells. [3][4][5][6] Some bone-colonizing cancer cells reside in stromal cell niche via cell-cell contact mediated by cell adhesion molecules (CAMs) and stay dormant or undergo EMT and acquire further aggressiveness.…”

Section: Proton Release By Cancer Cells In Cabpmentioning

confidence: 99%

Acidic microenvironment and bone pain in cancer-colonized bone

Yoneda¹,

Hiasa²,

Nagata³

et al. 2015

BoneKEy Reports

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Solid cancers and hematologic cancers frequently colonize bone and induce skeletal-related complications. Bone pain is one of the most common complications associated with cancer colonization in bone and a major cause of increased morbidity and diminished quality of life, leading to poor survival in cancer patients. Although the mechanisms responsible for cancer-associated bone pain (CABP) are poorly understood, it is likely that complex interactions among cancer cells, bone cells and peripheral nerve cells contribute to the pathophysiology of CABP. Clinical observations that specific inhibitors of osteoclasts reduce CABP indicate a critical role of osteoclasts. Osteoclasts are proton-secreting cells and acidify extracellular bone microenvironment. Cancer cell-colonized bone also releases proton/lactate to avoid intracellular acidification resulting from increased aerobic glycolysis known as the Warburg effect. Thus, extracellular microenvironment of cancer-colonized bone is acidic. Acidosis is algogenic for nociceptive sensory neurons. The bone is densely innervated by the sensory neurons that express acid-sensing nociceptors. Collectively, CABP is evoked by the activation of these nociceptors on the sensory neurons innervating bone by the acidic extracellular microenvironment created by bone-resorbing osteoclasts and bone-colonizing cancer cells. As current treatments do not satisfactorily control CABP and can elicit serious side effects, new therapeutic interventions are needed to manage CABP. Understanding of the cellular and molecular mechanism by which the acidic extracellular microenvironment is created in cancer-colonized bone and by which the expression and function of the acid-sensing nociceptors on the sensory neurons are regulated would facilitate to develop novel therapeutic approaches for the management of CABP.

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Expression of the hypoxia-inducible monocarboxylate transporter MCT4 is increased in triple negative breast cancer and correlates independently with clinical outcome

Cited by 98 publications

References 25 publications

miR-155 Drives Metabolic Reprogramming of ER+ Breast Cancer Cells Following Long-Term Estrogen Deprivation and Predicts Clinical Response to Aromatase Inhibitors

miR-155 Drives Metabolic Reprogramming of ER+ Breast Cancer Cells Following Long-Term Estrogen Deprivation and Predicts Clinical Response to Aromatase Inhibitors

Genetic Disruption of Lactate/H+ Symporters (MCTs) and Their Subunit CD147/BASIGIN Sensitizes Glycolytic Tumor Cells to Phenformin

Acidic microenvironment and bone pain in cancer-colonized bone

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