Blockade of Fas Signaling in Breast Cancer Cells Suppresses Tumor Growth and Metastasis via Disruption of Fas Signaling-initiated Cancer-related Inflammation (Publication with Expression of Concern. See vol. 295, pg. 8886, 2020) (Withdrawn Publication. See vol. 296, 2021) (Withdrawn Publication. See vol. 296, 2021)

Background: The non-apoptotic functions of Fas signaling have been proposed to play an important role in promoting tumor progression. Results: Blockade of Fas signaling suppresses tumor growth and metastasis via disruption of Fas signaling-initiated cancer-related inflammation. Conclusion: Fas signaling-initiated cancer-related inflammation in breast cancer cells may be a potential target for cancer treatment. Significance: This study provides mechanistic insight into the role of Fas signaling in cancer-related inflammation. Mechanisms for cancer-related inflammation remain to be fully elucidated. Non-apoptotic functions of Fas signaling have been proposed to play an important role in promoting tumor progression. It has yet to be determined if targeting Fas signaling can control tumor progression through suppression of cancer-related inflammation. In the current study we found that breast cancer cells with constitutive Fas expression were resistant to apoptosis induction by agonistic anti-Fas antibody (Jo2) ligation or Fas ligand cross-linking. Higher expression of Fas in human breast cancer tissue has been significantly correlated with poorer prognosis in breast cancer patients. To determine whether blockade of Fas signaling in breast cancer could suppress tumor progression, we prepared an orthotopic xenograft mouse model with mammary cancer cells 4T1 and found that blockade of Fas signaling in 4T1 cancer cells markedly reduced tumor growth, inhibited tumor metastasis in vivo, and prolonged survival of tumor-bearing mice. Mechanistically, blockade of Fas signaling in cancer cells significantly decreased systemic or local recruitment of myeloid derived suppressor cells (MDSCs) in vivo. Furthermore, blockade of Fas signaling markedly reduced IL-6, prostaglandin E2 production from breast cancer cells by impairing p-p38, and activity of the NFB pathway. In addition, administration of a COX-2 inhibitor and anti-IL-6 antibody significantly reduced MDSC accumulation in vivo. Therefore, blockade of Fas signaling can suppress breast cancer progression by inhibiting proinflammatory cytokine production and MDSC accumulation, indicating that Fas signaling-initiated cancer-related inflammation in breast cancer cells may be a potential target for treatment of breast cancer.