Supplementary MaterialsAdditional file 1: Physique S1. DFS and OS using KaplanCMeier survival analysis. As shown in Fig.?2a, b, patients with high PFKFB4 expression showed unfavorable DFS (valueno data, confidence interval, estrogen receptor, human epidermal growth factor receptor 2, hazard ratio, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4, progesterone receptor aDefinitions of subtypes: luminal (ER- and/or PR-positive), HER-2-enriched (ER- and PR-negative, HER-2-positive), and triple-negative (ER-negative, PR-negative, and HER-2-negative) Table?3 presents the association between OS and the clinicopathological variables analyzed using univariate and multivariate Cox regression. PFKFB4 had an HR of 7.38 (95% CI 1.69C32.3; no data, confidence interval, estrogen receptor, human epidermal growth factor receptor 2, hazard ratio, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4, progesterone receptor aDefinitions of subtypes: luminal (ER- and/or PR-positive), HER-2-enriched (ER- and BMS-790052 pontent inhibitor PR-negative, HER-2-positive), and triple-negative (ER-negative, PR-negative, and HER-2-unfavorable) Discussion Increasing recognition of the active role of cancer metabolism in tumorigenesis has led to the identification of novel markers for prognostic prediction [11, 12]. Enzymes participating in core metabolic pathways have proven to be essential for the proliferation and survival of cancer cells [6, 7, 13, 14]. In this study, we evaluated the relationship of the cancer metabolic enzyme PFKFB4 with the risk of recurrence, metastasis and death in operable breast malignancy. We exhibited that elevated PFKFB4 expression from immunohistochemistry analysis is usually associated with shorter DFS and OS in breast malignancy. Our results established that PFKFB4 is an impartial prognostic factor in breast malignancy. Dasgupta et al. found that PFKFB4 can phosphorylate steroid receptor coactivator-3 (SRC3) and lead to increased ER co-activation and cell proliferation. The authors examined 80 samples from the Malignancy Genome Atlas and exhibited that breast cancer patients with high SRC3 and mRNA expression have unfavorable prognosis . Using public high-throughput expression data, Ros et al. reported that a high level of mRNA predicted reduced survival in patients with breast malignancy and non-small cell lung cancer . mRNA expression has been proven to be a prognostic marker in non-muscle-invasive bladder cancer . However, quantification of mRNA expression is not easy to perform in routine clinical settings. In this study, we confirmed the prognostic value of PFKFB4 protein in breast malignancy using immunochemistry, which can be BMS-790052 pontent inhibitor easily performed in FFPE samples. To the best of our knowledge, this is BMS-790052 pontent inhibitor the first study supporting the prognostic value of PFKFB4 protein in breast cancer. PFKFB4 plays an important role in regulating glucose metabolism and directing metabolic pathways required for biosynthesis of macromolecules to maintain malignancy cell proliferation . Several groups independently identified PFKFB4 as a key metabolic enzyme in cancer using high-content screening [6C8]. PFKFB4 is required to maintain the balance of glycolytic activity for energy generation and cellular redox in prostate cancer . Using an unbiased RNA interference genome-wide screening assay, Dasgupta et al. discovered PFKFB4 as a dominant modulator of SRC3-dependent malignancy cell proliferation . PFKFB4 and SRC-3, an ER co-activator, can hyperactivate ER activity in the presence of estradiol , which may explain the correlation between reduced DFS and high PFKFB4 observed in luminal and ER-positive breast malignancy. PFKFB4 and SRC-3 are drivers of the growth of basal-subtype breast cancer . This may partially explain the prognostic significance of PFKFB4 in triple-negative and ER-negative subgroups. Further study is needed to determine the expression pattern of PFKFB4 and SRC-3 and the activated status of the PFKFB4-SRC-3 axis in breast cancer. Besides, it is also worthy to note the non-metabolic function of PFKFB4 that are relevant in cancer development. Gao et al. reported that PFKFB4 enhances breast malignancy migration by induction of hyaluronan production in a p38-dependent manner . Moreover, PFKFB4 can interact with endothelial tyrosine kinase to modulate chemoresistance of small-cell lung cancer by regulating autophagy . Recent studies reported PFKFB4 as a potential target in cancer. Silencing of PFKFB4 induced apoptosis in p53-deficient malignancy cells and inhibited tumor growth . A selective PFKFB4 inhibitor, 5-( em n /em -(8-methoxy-4-quinolyl)amino)pentyl nitrate, suppressed the glycolysis process and proliferation in human malignancy cell lines rather non-transformed epithelial cells in vitro, suggesting that targeting PFKFB4 may be a promising therapeutic strategy against breast malignancy. Our study revealed that almost half (49.0%, 98/200) of the breast cancer cases in our study had a score 3 (the highest) for PFKFB4 staining, which indicate a large population of breast cancer patients deposit the potential Rabbit polyclonal to ITLN2 therapeutic target. This study has some.