APRIL and BAFF increase 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 and BAFF even though were primarily studied in lymphocyte maturation, they have also been associated with tumor growth and aggressiveness in a number of solid tumors, including breast cancer. In the present work we studied the effect of APRIL and BAFF on epithelial to mesenchymal transition and migration of breast cancer cells, and their action on the sub-population of cancer stem cells identified by autofluorescence and ALDH activity. Their action on an number of pluripotency genes was examined and breast cancer stem cell ability to form mammospheres was also utilized. The receptor and the signaling pathway involved as well as the role of steroid hormones in their action were also investigated. Our findings show that both APRIL and BAFF increase epithelial to mesenchymal transition and migratory capacity of breast cancer cells, as well as cancer stem cell numbers, by inducing pluripotency genes such as KLF4 and NANOG. These effects are mediated by their common receptor BCMA and the JNK signaling pathway. Interestingly, androgens enhance APRIL transcription and subsequently its pluripotency effect. In conclusion, our data support the significant 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 role of BAFF and APRIL in rheumatoid arthritis

“…Groom et al, 2002;Han et al, 2018;Hegazy et al, 2010;Kamhieh-Milz et al, 2018;Li et al, 2014;Vosters et al, 2012;Xin et al, 2013). Research shows that BAFF and APRIL are also associated with increased tumor growth and invasion in certain solid tumors such as breast cancer (Pelekanou et al, 2017).…”

“…Overexpression of BAFF leads to the development of polyclonal B cell, hyperglobulinemia and autoimmunity diseases such as systemic lupus erythematosus (SLE), IgA nephropathy, membranous nephropathy, SS, immune thrombocytopenic purpura, and RA (Elbirt et al, ; J. Groom et al, ; Han et al, ; Hegazy et al, ; Kamhieh‐Milz et al, ; Li et al, ; Vosters et al, ; Xin et al, ). Research shows that BAFF and APRIL are also associated with increased tumor growth and invasion in certain solid tumors such as breast cancer (Pelekanou et al, ).…”

Immunomodulatory effects of BAFF and APRIL cytokines in post-pulmonary infection lung cancer

“… 27 Additionally, BAFF and APRIL have been found to induce pluripotency genes like KLF4 and NANOG, thereby enhancing breast cancer cell stemness and migration. 28 …”

“…These increased levels are liked with disease progression and therapy efficacy, as they augment the viability, proliferation, and invasiveness of cancer cells. 7 , 28 Notably, local androgens in breast cancer amplify APRIL expression, fostering the transformation cells into stem cells and potentially leading to resistance to aromatase inhibitors. 28 Additionally, increased levels of APRIL have been observed in breast cancer cells and patients, particularly in response to androgens, which promote APRIL transcription and tumour cell stemness, potently leading to therapeutic resistance in patients receiving aromatase inhibitors.…”

“… 7 , 28 Notably, local androgens in breast cancer amplify APRIL expression, fostering the transformation cells into stem cells and potentially leading to resistance to aromatase inhibitors. 28 Additionally, increased levels of APRIL have been observed in breast cancer cells and patients, particularly in response to androgens, which promote APRIL transcription and tumour cell stemness, potently leading to therapeutic resistance in patients receiving aromatase inhibitors. 29 Furthermore, BAFF and APRIL, along with their receptor genes, have been found to be expressed in MM cell lines, and elevated levels of these cytokines are correlated with poor outcomes and disease progression, promoting MM cells proliferation and survival.…”