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Published in: Cancer Cell International 1/2019

Open Access 01-12-2019 | Breast Cancer | Primary research

High expression of metabolic enzyme PFKFB4 is associated with poor prognosis of operable breast cancer

Authors: Ling Yao, Lei Wang, Zhi-Gang Cao, Xin Hu, Zhi-Ming Shao

Published in: Cancer Cell International | Issue 1/2019

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Abstract

Background

Enhanced glycolysis in tumors, known as the Warburg effect, provides the metabolic basis of enhanced cancer cell proliferation and metastasis. The Warburg pathway enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) is a newly identified key kinase that regulates transcriptional reprogramming and cell proliferation. Here we show the prognostic value of PFKFB4 expression in patients with operable breast cancer.

Methods

PFKFB4 expression was evaluated by immunohistochemistry in surgical specimens retrospectively collected from 200 patients with histologically proven invasive ductal breast cancer. Kaplan–Meier survival analysis and Cox regression analysis were performed to assess the prognostic significance of PFKFB4 expression.

Results

Kaplan–Meier survival analysis revealed that breast cancer patients with high PFKFB4 expression demonstrated unfavorable disease-free survival (p = 0.008) and overall survival (p = 0.002). PFKFB4 had an hazard ratio (HR) of 7.38 (95% CI 1.69–32.3; p = 0.008) in univariate Cox analysis and retained prognostic power (HR 7.44, 95% CI 1.67–33.2; p = 0.009) when adjusted by tumor size, lymph node status, grade, estrogen receptor status, human epidermal growth factor receptor 2 status and subtype, which indicated PFKFB4 was an independent prognostic factor in breast cancer.

Conclusions

Together, our findings establish the prognostic value of metabolic enzyme PFKFB4 in patients with operable breast cancer.
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Literature
1.
go back to reference Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30.CrossRef Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30.CrossRef
2.
go back to reference Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66:115–32.CrossRef Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66:115–32.CrossRef
3.
go back to reference Curigliano G, Burstein HJ, Winer EP, Gnant M, Dubsky P, Loibl S, et al. De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen international expert consensus conference on the primary therapy of Early Breast Cancer 2017. Ann Oncol. 2017;28:1700–12.CrossRef Curigliano G, Burstein HJ, Winer EP, Gnant M, Dubsky P, Loibl S, et al. De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen international expert consensus conference on the primary therapy of Early Breast Cancer 2017. Ann Oncol. 2017;28:1700–12.CrossRef
4.
go back to reference Giuliano AE, Connolly JL, Edge SB, Mittendorf EA, Rugo HS, Solin LJ, et al. Breast cancer-major changes in the American joint committee on cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67:290–303.CrossRef Giuliano AE, Connolly JL, Edge SB, Mittendorf EA, Rugo HS, Solin LJ, et al. Breast cancer-major changes in the American joint committee on cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67:290–303.CrossRef
5.
go back to reference Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–33.CrossRef Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–33.CrossRef
6.
go back to reference Dasgupta S, Rajapakshe K, Zhu B, Nikolai BC, Yi P, Putluri N, et al. Metabolic enzyme PFKFB4 activates transcriptional coactivator SRC-3 to drive breast cancer. Nature. 2018;556:249–54.CrossRef Dasgupta S, Rajapakshe K, Zhu B, Nikolai BC, Yi P, Putluri N, et al. Metabolic enzyme PFKFB4 activates transcriptional coactivator SRC-3 to drive breast cancer. Nature. 2018;556:249–54.CrossRef
7.
go back to reference Ros S, Santos CR, Moco S, Baenke F, Kelly G, Howell M, et al. Functional metabolic screen identifies 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 as an important regulator of prostate cancer cell survival. Cancer Discov. 2012;2:328–43.CrossRef Ros S, Santos CR, Moco S, Baenke F, Kelly G, Howell M, et al. Functional metabolic screen identifies 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 as an important regulator of prostate cancer cell survival. Cancer Discov. 2012;2:328–43.CrossRef
8.
go back to reference Goidts V, Bageritz J, Puccio L, Nakata S, Zapatka M, Barbus S, et al. RNAi screening in glioma stem-like cells identifies PFKFB4 as a key molecule important for cancer cell survival. Oncogene. 2012;31:3235–43.CrossRef Goidts V, Bageritz J, Puccio L, Nakata S, Zapatka M, Barbus S, et al. RNAi screening in glioma stem-like cells identifies PFKFB4 as a key molecule important for cancer cell survival. Oncogene. 2012;31:3235–43.CrossRef
9.
go back to reference Zheng YZ, Cao ZG, Hu X, Shao ZM. The endoplasmic reticulum stress markers GRP78 and CHOP predict disease-free survival and responsiveness to chemotherapy in breast cancer. Breast Cancer Res Treat. 2014;145:349–58.CrossRef Zheng YZ, Cao ZG, Hu X, Shao ZM. The endoplasmic reticulum stress markers GRP78 and CHOP predict disease-free survival and responsiveness to chemotherapy in breast cancer. Breast Cancer Res Treat. 2014;145:349–58.CrossRef
10.
go back to reference Wang L, Yao L, Zheng YZ, Xu Q, Liu XP, Hu X, et al. Expression of autophagy-related proteins ATG5 and FIP200 predicts favorable disease-free survival in patients with breast cancer. Biochem Biophys Res Commun. 2015;458:816–22.CrossRef Wang L, Yao L, Zheng YZ, Xu Q, Liu XP, Hu X, et al. Expression of autophagy-related proteins ATG5 and FIP200 predicts favorable disease-free survival in patients with breast cancer. Biochem Biophys Res Commun. 2015;458:816–22.CrossRef
11.
go back to reference Qiu Y, Cai G, Zhou B, Li D, Zhao A, Xie G, et al. A distinct metabolic signature of human colorectal cancer with prognostic potential. Clin Cancer Res. 2014;20:2136–46.CrossRef Qiu Y, Cai G, Zhou B, Li D, Zhao A, Xie G, et al. A distinct metabolic signature of human colorectal cancer with prognostic potential. Clin Cancer Res. 2014;20:2136–46.CrossRef
12.
go back to reference Baek G, Tse YF, Hu Z, Cox D, Buboltz N, McCue P, et al. MCT4 defines a glycolytic subtype of pancreatic cancer with poor prognosis and unique metabolic dependencies. Cell Rep. 2014;9:2233–49.CrossRef Baek G, Tse YF, Hu Z, Cox D, Buboltz N, McCue P, et al. MCT4 defines a glycolytic subtype of pancreatic cancer with poor prognosis and unique metabolic dependencies. Cell Rep. 2014;9:2233–49.CrossRef
13.
go back to reference Wang JB, Erickson JW, Fuji R, Ramachandran S, Gao P, Dinavahi R, et al. Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell. 2010;18:207–19.CrossRef Wang JB, Erickson JW, Fuji R, Ramachandran S, Gao P, Dinavahi R, et al. Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell. 2010;18:207–19.CrossRef
14.
go back to reference Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature. 2008;452:230–3.CrossRef Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature. 2008;452:230–3.CrossRef
15.
go back to reference Ros S, Floter J, Kaymak I, Da Costa C, Houddane A, Dubuis S, et al. 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 is essential for p53-null cancer cells. Oncogene. 2017;36:3287–99.CrossRef Ros S, Floter J, Kaymak I, Da Costa C, Houddane A, Dubuis S, et al. 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 is essential for p53-null cancer cells. Oncogene. 2017;36:3287–99.CrossRef
16.
go back to reference Yun SJ, Jo SW, Ha YS, Lee OJ, Kim WT, Kim YJ, et al. PFKFB4 as a prognostic marker in non-muscle-invasive bladder cancer. Urol Oncol. 2012;30:893–9.CrossRef Yun SJ, Jo SW, Ha YS, Lee OJ, Kim WT, Kim YJ, et al. PFKFB4 as a prognostic marker in non-muscle-invasive bladder cancer. Urol Oncol. 2012;30:893–9.CrossRef
17.
go back to reference Dang CV. Cancer cell metabolism: there is no ROS for the weary. Cancer Discov. 2012;2:304–7.CrossRef Dang CV. Cancer cell metabolism: there is no ROS for the weary. Cancer Discov. 2012;2:304–7.CrossRef
18.
go back to reference Gao R, Liu Y, Li D, Xun J, Zhou W, Wang P, et al. PFKFB4 promotes breast cancer metastasis via induction of hyaluronan production in a p38-dependent manner. Cell Physiol Biochem. 2018;50:2108–23.CrossRef Gao R, Liu Y, Li D, Xun J, Zhou W, Wang P, et al. PFKFB4 promotes breast cancer metastasis via induction of hyaluronan production in a p38-dependent manner. Cell Physiol Biochem. 2018;50:2108–23.CrossRef
19.
go back to reference Wang Q, Zeng F, Sun Y, Qiu Q, Zhang J, Huang W, Huang J, Huang X, Guo L. Etk interaction with PFKFB4 modulates chemoresistance of small-cell lung cancer by regulating autophagy. Clin Cancer Res. 2018;24(4):950–62.CrossRef Wang Q, Zeng F, Sun Y, Qiu Q, Zhang J, Huang W, Huang J, Huang X, Guo L. Etk interaction with PFKFB4 modulates chemoresistance of small-cell lung cancer by regulating autophagy. Clin Cancer Res. 2018;24(4):950–62.CrossRef
Metadata
Title
High expression of metabolic enzyme PFKFB4 is associated with poor prognosis of operable breast cancer
Authors
Ling Yao
Lei Wang
Zhi-Gang Cao
Xin Hu
Zhi-Ming Shao
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2019
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-019-0882-2

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