Abstract
Background 6-Phosphofructo-2-kinase/fructose-2,6-biphosphate-4 (PFKFB4) is a key factor that plays an important role in tumorigenesis. However, its role in triple-negative breast cancer (TNBC) progression needs to be further validated. We investigated whether PFKFB4 is directly involved in the oncogenic signaling networks of TNBC. Methods First, we assessed the expression level of PFKFB4 in tumor tissue specimens by immunohistochemistry and evaluated its prognostic value. Next, the effect of PFKFB4 on TNBC cell growth and associated mechanisms were investigated. Finally, the results were further verified in vivo. Results We found that PFKFB4 overexpression was associated with an unfavorable prognosis in TNBC patients. PFKFB4 was overexpressed in TNBC cell lines in hypoxic environments, and its overexpression promoted tumor progression in vitro and in vivo. Further analyses demonstrated that the possible mechanism might be that PFKFB4 overexpression facilitates TNBC progression by enhancing the G1/S phase transition by increasing the protein level of CDK6 and phosphorylation of Rb. Conclusions These data suggest that PFKFB4 plays significant roles in the tumorigenesis and development of TNBC.
Highlights
Breast cancer is a global disease and one of the main causes of female morbidity and mortality [1, 2]
15% of breast cancers are defined as triple-negative breast cancer (TNBC), which lacks expression of the estrogen receptor (ER) and progesterone receptor (PR) and lacks overexpression of human epidermal growth factor 2 (HER2) [3, 4]
Since previous studies have demonstrated that the PFKFB4 gene is expressed in many tumor cell lines derived from different tissues [18, 19, 22], we provide consistent evidence that the testis isoform of the PFKFB protein is expressed in TNBC cells
Summary
Breast cancer is a global disease and one of the main causes of female morbidity and mortality [1, 2]. 15% of breast cancers are defined as triple-negative breast cancer (TNBC), which lacks expression of the estrogen receptor (ER) and progesterone receptor (PR) and lacks overexpression of human epidermal growth factor 2 (HER2) [3, 4]. The most common feature of all cancer cells is the production of large amounts of lactate and pyruvate, which is due to enhanced glycolysis despite the presence of oxygen. This phenomenon was first described by Warburg [5]. HIF-1α is known to be hyperactivated in TNBC [7, 8], while the mechanism and the target genes involved in the process by which HIF-1α regulates growth and metastasis in TNBC remain to be elucidated
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