BCMA (TNFRSF17) Induces APRIL and BAFF Mediated Breast Cancer Cell Stemness

Abstract

Recent advances in cancer immunology revealed immune-related properties of cancer cells as novel promising therapeutic targets. The two TNF superfamily members, APRIL (TNFSF13), and BAFF (TNFSF13B), which are type II membrane proteins, released in active forms by proteolytic cleavage and are primarily involved in B-lymphocyte maturation, have also been associated with tumor growth and aggressiveness in several solid tumors, including breast cancer. In the present work we studied the effect of APRIL and BAFF on epithelial to mesenchymal transition, migration, and stemness of breast cancer cells. Our findings show that both molecules increase epithelial to mesenchymal transition and migratory capacity of breast cancer cells, as well as cancer stem cell numbers, by increasing the expression of pluripotency genes such as ALDH1A1, KLF4, and NANOG. These effects are mediated by their common receptor BCMA (TNFRSF17) and the JNK signaling pathway. Interestingly, transcriptional data analysis from breast cancer cells and patients revealed that androgens can increase APRIL transcription and subsequently, in an autocrine/paracrine manner, enhance its pluripotency effect. In conclusion, our data suggest a possible role of APRIL and BAFF in breast cancer disease progression and provide evidence for a new possible mechanism of therapy resistance, that could be particularly relevant in aromatase inhibitors-treated patients, were local androgen is increased.

The TNFSF Members APRIL and BAFF and Their Receptors TACI, BCMA, and BAFFR in Oncology, With a Special Focus in Breast Cancer

“…This was further supported by the preferential expression of APRIL and its receptors in a small series of triple-negative human tumors as compared to luminal-type carcinomas (149). Finally, the authors reported a direct effect of APRIL on cell proliferation [reported also by other groups (150,151)] and the induction of tumor xenografts in an APRIL-rich environment. Interestingly, in a recent work (151), we have reported that APRIL is upregulated by membrane-acting androgen, and that induces breast cancer cell migration and epithelial-to-mesenchymal transition, together with mammosphere formation and induction of stemness.…”

Estrogen receptor-α regulation of microRNA-590 targets FAM171A1—a modifier of breast cancer invasiveness

“…Previous work suggests that FAM171 A1 may be associated with chemoresistance of cancer cells 2,3 . Data-mining studies suggest that FAM171A1 interacts with FAM171B, PCDHGB1, TNFRSF17, TMEM, CTDSPL, and NTRK1 4–7 , many of which have been implicated in various cancers 8–13 . Emerging reports suggest that FAM171A1 might be overexpressed in TNBC tumors 14–16 .…”

Identification of a prognostic gene signature of colon cancer using integrated bioinformatics analysis

“…The peroxisome proliferator-activated receptor-γ coactivator 1-α (PPARGC1A) gene also contributes to tumor growth and metastasis in several cancers [ 68 , 69 ]. In addition, studies have suggested that both the paired related homeobox 2 (PRRX2) gene [ 70 , 71 ] and the tumor necrosis factor receptor superfamily member 17 (TNFRSF17) gene [ 72 , 73 ] are associated with the development of several cancers, while the proprotein convertase subtilisin/kexin type 5 (PCSK5) gene and the WD repeat domain 78 (WDR78) gene have not been reported to be associated with pathogenesis and progression. Thus, the functions of these genes in colon cancer should be further investigated using preclinical and clinical experiments.…”