PFKFB4 facilitates palbociclib resistance in oestrogen receptor‐positive breast cancer by enhancing stemness

Abstract

Background ER+ breast cancer (ER+ BC) is the most common subtype of BC. Recently, CDK4/6 inhibitors combined with aromatase inhibitors have been approved by FDA as the first‐line therapy for patients with ER+ BC, and showed promising therapeutic efficacy in clinical treatment. However, resistance to CDK4/6 inhibitors is frequently observed. A better understanding of the drug resistance mechanism is beneficial to improving therapeutic strategies by identifying optimal combinational treatments. Methods Western blotting, qPCR, flow cytometry and a series of cell experiments were performed to evaluate the phenotype of MCF‐7/R cells. RNA sequencing, non‐targeted metabolomics, shRNA knockdown and tumour cell‐bearing mouse models were used to clarify the drug resistance mechanism. Results Here, we found that ER+ BC cells have shown an adaptive resistance to palbociclib‐induced cell cycle arrest by activating an alternative signal pathway, independent of the CDK4/6‐RB signal transduction. Continuing treatment of palbociclib evoked cellular senescence of ER+ BC cells. Subsequently, the senescence‐like phenotype promoted stemness of ER+ BC cells, accompanied by increased chemoresistance and tumour‐initiating potential. Based on transcriptome analysis, we found that PFKFB4 played an important role in stemness transformation and drug resistance. A close correlation was determined between PFKFB4 expression by ER+ BC cells and cell senescence and stemness. Mechanistically, metabolomic profiling revealed that PFKFB4 reprogramed glucose metabolism and promoted cell stemness by enhancing glycolysis. Strikingly, diminishing PFKFB4 levels improved drug sensitivity and overcame chemoresistance during palbociclib treatment in ER+ BC. Conclusions These findings not only demonstrated the novel mechanism underlying which ER+ BC cells resisted to palbociclib, but also provided a possible therapeutic strategy in the intervention of ER+ BC to overcome drug resistance.

Self-Renewal Inhibition in Breast Cancer Stem Cells: Moonlight Role of PEDF in Breast Cancer

“…The co-administration with chemotherapy would lead to a less resistant population because TICs would have lost their stemness characteristics, as we discuss in the following paragraphs. The regulation of breast cancer progression through regulation of breast cancer stem cell-like properties has been recently described, probably mediated by the NF-κB cell signaling pathway [82,83], and the connection between chemoresistance, mesenchymal plasticity, and cancer stem cells in metastasis origin [84][85][86][87][88].…”

Comparative clinical significance and biological roles of PFKFB family members in oral squamous cell carcinoma

“…PFKFB4 enhances cancer stemness and contributes to chemoresistance to palbociclib in estrogen receptor–positive breast cancer [ 7 ]. PFKFB4 is involved in chemoresistance to sunitinib in clear-cell renal cell carcinoma [ 23 ].…”

“…Phosphofructokinase-fructose bisphosphatases (PFKFBs), a family of bidirectional glycolytic enzymes, modulate the formation and degradation of fructose-2,6-bisphosphate (F-2,6-BP), thereby regulating glycolysis [ 7 ]. PFKFBs is encoded by four genes ( PFKFB1 , PFKFB2 , PFKFB3 , and PFKFB4 ) in humans [ 8 ].…”

Senescence Promotes the Recovery of Stemness among Cancer Cells via Reprograming

“…CD36 has been shown to be involved in the regulation of the SASP [ 81 ]. Furthermore, in a study of ER+ breast cancer, Pingping Shen et al [ 82 ] reported that MCF-7 breast cancer cell lines treated with CDK4/6 inhibitors generally experience senescence and subsequently exhibit increased expression of stemness-related genes. Moreover, they established the relationship between PFKFB4 (a rate-limiting enzyme involved in the cell glycolysis metabolic pathway, with dual functional activities of kinase and phosphatase) and breast cancer cell stemness.…”