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      Hyperglycemia and Chemoresistance in Breast Cancer: From Cellular Mechanisms to Treatment Response


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          Female breast cancer is a complex, multifactorial disease. Studies have shown that hyperglycemia is one of the most important contributing factors to increasing the risk of breast cancer that also has a major impact on the efficacy of chemotherapy. At the cellular level, hyperglycemia can promote the proliferation, invasion, and migration of breast cancer cells and can also induce anti-apoptotic responses to enhance the chemoresistance of tumors via abnormal glucose metabolism. In this article, we focus on the latest progress in defining the mechanisms of chemotherapy resistance in hyperglycemic patients including the abnormal behaviors of cancer cells in the hyperglycemic microenvironment and the impact of abnormal glucose metabolism on key signaling pathways. To better understand the advantages and challenges of breast cancer treatments, we explore the causes of drug resistance in hyperglycemic patients that may help to better inform the development of effective treatments.

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            LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells.

            Elevated lactate dehydrogenase A (LDHA) expression is associated with poor outcome in tumor patients. Here we show that LDHA-associated lactic acid accumulation in melanomas inhibits tumor surveillance by T and NK cells. In immunocompetent C57BL/6 mice, tumors with reduced lactic acid production (Ldha(low)) developed significantly slower than control tumors and showed increased infiltration with IFN-γ-producing T and NK cells. However, in Rag2(-/-)γc(-/-) mice, lacking lymphocytes and NK cells, and in Ifng(-/-) mice, Ldha(low) and control cells formed tumors at similar rates. Pathophysiological concentrations of lactic acid prevented upregulation of nuclear factor of activated T cells (NFAT) in T and NK cells, resulting in diminished IFN-γ production. Database analyses revealed negative correlations between LDHA expression and T cell activation markers in human melanoma patients. Our results demonstrate that lactic acid is a potent inhibitor of function and survival of T and NK cells leading to tumor immune escape.
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              Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer.

              Population studies have suggested that metformin use in diabetic patients decreases cancer incidence and mortality. Metformin inhibits the growth of cancer cells in vitro and tumors in vivo. However, there is little clinical data to support this. Our purpose was to determine whether metformin use was associated with a change in pathologic complete response (pCR) rates in diabetic patients with breast cancer receiving neoadjuvant chemotherapy. We identified 2,529 patients who received neoadjuvant chemotherapy for early-stage breast cancer between 1990 and 2007. Patients were compared by groups: 68 diabetic patients taking metformin, 87 diabetic patients not taking metformin, and 2,374 nondiabetic patients. pCR rates were compared between the three groups using chi(2) tests of independence and compared pair- wise using a binomial test of proportions. Factors predictive of pCR were assessed using a multivariate logistic regression model. The rate of pCR was 24% in the metformin group, 8.0% in the nonmetformin group, and 16% in the nondiabetic group (P = .02). Pairwise comparisons between the metformin and nonmetformin groups (P = .007) and the nonmetformin and nondiabetic groups (P = .04) were significant. Comparison of the pCR rates between the metformin and nondiabetic groups trended toward but did not meet significance (P = .10). Metformin use was independently predictive of pCR (odds ratio, 2.95; P = .04) after adjustment for diabetes, body mass index, age, stage, grade, receptor status, and neoadjuvant taxane use. Diabetic patients with breast cancer receiving metformin and neoadjuvant chemotherapy have a higher pCR rate than do diabetics not receiving metformin. Additional studies to evaluate the potential of metformin as an antitumor agent are warranted.

                Author and article information

                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                25 February 2021
                : 11
                1 Zhejiang Chinese Medical University , Hangzhou, China
                2 Department of Breast Surgery, Zhejiang Provincial People’s Hospital , Hangzhou, China
                Author notes

                Edited by: Xiaosong Chen, Shanghai Jiao Tong University, China

                Reviewed by: Chuangui Song, Fujian Medical University, China; Chaochen Wang, Zhejiang University, China

                *Correspondence: Xuli Meng, mxlmail@ 123456126.com

                This article was submitted to Women’s Cancer, a section of the journal Frontiers in Oncology

                †These authors have contributed equally to this work

                Copyright © 2021 Qiu, Zheng and Meng

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 4, Tables: 2, Equations: 0, References: 101, Pages: 12, Words: 5316


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