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Expression of Monocarboxylate Transporter 1 in Immunosuppressive Macrophages Is Associated With the Poor Prognosis in Breast Cancer.

ABSTRACT: Monocarboxylate transporter 1 (MCT1) participates in the transport of lactate to facilitate metabolic reprogramming during tumor progression. Tumor-associated macrophages (TAMs) are also involved in the inflammatory adaptation of the tumor microenvironment (TME). This study aimed to determine the correlation between metabolite changes and the polarization of macrophages in the TME. We demonstrated that the expression of CD163 on macrophages was significantly higher in breast cancer tissues than in normal tissues, especially in the HER2 subtype, although it was not statistically associated with recurrence-free survival (RFS). The presence of MCT1+ and CD163+ macrophages in the invasive margin was significantly correlated with decreased RFS. A significant correlation existed between MCT1 and CD163 expression in the margin, and high infiltration of MCT1+CD163+ macrophages into the margin predicted rapid progression and poor survival outcomes for breast cancer patients. These data suggested that MCT1 at least partially promoted the alternative polarization of macrophages to inhibit antitumor immunity, and blocking this interaction may be a promising method for breast cancer therapy.

SUBMITTER: Li B

PROVIDER: S-EPMC7596686 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Expression of Monocarboxylate Transporter 1 in Immunosuppressive Macrophages Is Associated With the Poor Prognosis in Breast Cancer.

Li Bei B Yang Qian Q Li Zhiyu Z Xu Zhiliang Z Sun Si S Wu Qi Q Sun Shengrong S

Frontiers in oncology 20201016

Monocarboxylate transporter 1 (MCT1) participates in the transport of lactate to facilitate metabolic reprogramming during tumor progression. Tumor-associated macrophages (TAMs) are also involved in the inflammatory adaptation of the tumor microenvironment (TME). This study aimed to determine the correlation between metabolite changes and the polarization of macrophages in the TME. We demonstrated that the expression of CD163 on macrophages was significantly higher in breast cancer tissues than ...[more]

PMID: 33178603

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Project description:IntroductionProgrammed cell death through apoptosis plays an essential role in the hormone-regulated physiological turnover of mammary tissue. Failure of this active gene-dependent process is central both to the development of breast cancer and to the appearance of the therapy-resistant cancer cells that produce clinical relapse. Functional expression cloning in two independent laboratories has identified Finkel-Biskis-Reilly murine sarcoma virus-associated ubiquitously expressed gene (Fau) as a novel apoptosis regulator and candidate tumour suppressor. Fau modifies apoptosis-controller Bcl-G, which is also a key target for candidate oncoprotein maternal embryonic leucine zipper kinase (MELK).MethodsWe have used RNA interference to downregulate Fau and Bcl-G expression, both simultaneously and independently, in breast cancer cells in vitro to determine the importance of their roles in apoptosis. Expression of Fau, Bcl-G and MELK was measured by quantitative RT-PCR in breast cancer tissue and in matched breast epithelial tissue from the same patients. Expression data of these genes obtained using microarrays from a separate group of patients were related to patient survival in Kaplan-Meier analyses.ResultssiRNA-mediated downregulation of either Fau or Bcl-G expression inhibited apoptosis, and the inhibition produced by combining the two siRNAs was consistent with control of Bcl-G by Fau. Fau expression is significantly reduced in breast cancer tissue and this reduction is associated with poor patient survival, as predicted for a candidate breast cancer tumour suppressor. In addition, MELK expression is increased in breast cancer tissue and this increase is also associated with poor patient survival, as predicted for a candidate oncogene. Bcl-G expression is reduced in breast cancer tissue but decreased Bcl-G expression showed no correlation with survival, indicating that the most important factors controlling Bcl-G activity are post-translational modification (by Fau and MELK) rather than the rate of transcription of Bcl-G itself.ConclusionsThe combination of in vitro functional studies with the analysis of gene expression in clinical breast cancer samples indicates that three functionally interconnected genes, Fau, Bcl-G and MELK, are crucially important in breast cancer and identifies them as attractive targets for improvements in breast cancer risk prediction, prognosis and therapy.

Project description:BackgroundRECQL is a number of the RecQ DNA helicase family and plays an important role in maintaining genome stability. Although several studies have reported that RECQL mutations were correlated with the susceptibility to breast cancer, the effect on prognosis in breast cancer was not yet clarified. Here, we explored the association between RECQL expression level and survival in patients with breast cancer.MethodsIn the first cohort, the RECQL mRNA expression level was evaluated in 774 primary breast cancer patients using a quantitative real-time PCR assay. Then, in the second independent cohort, the level of RECQL protein expression was detected in 322 patients with breast cancer using immunohistochemistry assay. Survival curves of patients with RECQL expression were compared using the Kaplan-Meier method with log-rank test.ResultsIn the first cohort of 774 breast cancer patients, the low expression level of RECQL mRNA was significantly correlated with aggressive clinicopathological characteristics, including the positive lymph node status (P = 0.026), HER2 overexpression (P < 0.001), ER negative status (P = 0.047) and high tumor grade (P = 0.041). Moreover, the low expression level of RECQL mRNA was significantly associated with poor distant recurrence-free survival (DRFS, unadjusted hazard ratio (HR): 2.77, 95% confidence interval (CI): 1.88-4.09, P < 0.001) and disease-specific survival (DSS, unadjusted HR: 3.10, 95% CI: 1.84-5.20,P < 0.001), and it remained an independent unfavorable factor for DRFS and DSS (DRFS: adjusted HR: 3.04, 95% CI: 1.89-4.87, P < 0.001; DSS: adjusted HR: 4.25, 95% CI: 2.12-8.46, P < 0.001). In the second cohort of 322 breast cancer patients, low expression of RECQL protein was also subject to poor survival in breast cancer, and it was an independent prognosis factor of poor DRFS by multivariate analysis (DRFS: adjusted HR: 2.12, 95% CI: 1.16-3.88, P = 0.015).ConclusionsBreast cancer patients with low RECQL expression had a worse survival. The expression level of RECQL may be a potential prognosis factor for breast cancer.

Dataset Information

Expression of Monocarboxylate Transporter 1 in Immunosuppressive Macrophages Is Associated With the Poor Prognosis in Breast Cancer.

Publications

Expression of Monocarboxylate Transporter 1 in Immunosuppressive Macrophages Is Associated With the Poor Prognosis in Breast Cancer.

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