APRIL and BAFF increase breast cancer cell stemness

Abstract

Background: Recent advances in cancer immunology revealed immune-related properties of the cancer cell as a promising new therapeutic target. The two TNF superfamily members, APRIL and BAFF even though were primarily studied for their role in lymphocyte maturation, their presence in a number of normal and cancer solid tumors including breast cancer revealed an association with tumor growth and aggressiveness. Methods: In the present work, we have explored the role of APRIL and BAFF in breast tumor development, progression and metastasis as well as resistance to therapy. We studied their effect on the epithelial to mesenchymal transition and migration of breast cancer cells, and their action on the important 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 were also investigated as well as the role of steroid hormones in their action. Results: Our findings show that in breast cancer both APRIL and BAFF increase epithelial to mesenchymal transition and migratory capacity, as well as cancer stem cell numbers, by inducing pluripotency genes such as KLF4 and NANOG. These effects were mediated by their common receptor BCMA and the JNK signaling pathway. Interestingly, androgens enhance APRIL transcription and subsequently its pluripotency effect. Conclusions: All these 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, especially in aromatase inhibitors-treated patients, were local androgen is increased.