IL-6 and Breast Cancer Risk: No More Than the Tip of an Iceberg?

Corresponding author: Raffaella Mormile, Division of Pediatrics and Neonatology, Moscati Hospital, Aversa, Campania 81031, Italy. E-mail: raffaellamormile@alice.it Breast cancer still represents the main cause of cancer-related death in women, although progress has been made in the treatment.1 Interleukin-6 (IL-6) levels have been connected with clinical disease stage and lymph node metastasis in breast cancer patients.2 IL-6 is a potent inflammatory cytokine that has been shown to play a key role in breast cancer growth and metastasis.2 Overexpression of IL-6 has been observed in the tumor microenvironment of several tumors, including breast cancer.1 Chronic inflammation in cancer microenvironment has been demonstrated to promote tumor growth and induce resistance toward chemo and radiotherapy.1 IL-6 and its signaling pathways have been linked to tumor growth, metastasis, and therapeutic resistance in breast cancer.1 Concordantly, inhibition of IL-6 signaling pathways has been suggested to suppress bone metastases in a breast cancer cell line.2 A significant down-regulation of microRNA-126 (miR-126) has been documented in human breast cancer tissues when compared with adjacent normal tissues.3 miRNAs deregulation is commonly detected in human malignancies and implicated in cancer metastasis.3 They have emerged to play crucial regulatory roles in cell growth, proliferation, differentiation, and cell death.3 Notably, miR-126 has been stated to act as a tumor suppressor in breast cancer.3 Increased expression levels of miR-126 have been shown to inhibit metastases in breast cancer.3 Overexpression of miR-126 has been proved to significantly counteract proinflammatory cytokines expression including IL-6.4 Reduced miR-126-3p expression has been reversely associated with increased IL-6.5 It has been indicated that miR-126 regulates inflammatory cytokine secretion via targeting tumor necrosis factor receptor-associated factor 6 (TRAF6).4 miR-126 has been found to significantly decrease TRAF6 expression.4 It represents a member of the TRAF superfamily.4,6 It is an endogenous adaptor of innate and adaptive immune responses that has been revealed to exert oncogenic activity.6 It is also involved in the development of several tissues including lymph nodes and mammary glands.6 It appears to function as a positive regulator of human breast tumorigenesisis.6 It has been proved that TRAF6 plays a critical role in cell proliferation related to human breast tumorigenesis.6 Expression levels of TRAF6 have been found to be upregulated in human breast carcinoma, compared with adjacent healthy tissues.6 However, the potential underlying mechanisms linking TRAF6 to human breast cancer progression still remains unclear.6 All these contentions led us to suppose that downstream signaling pathways related to IL-6 may lead to malignant transformation of breast tissues by perturbation of the expression of tumor suppressor miR126 through upregulation of TRAF6. We suggest that therapeutic strategies aimed at increasing or restoring the activity of miR-126 may be included among treatment options for breast cancer. Research studies are required to fully elucidate the therapeutic potential of inhibition of IL-6 and its signaling pathways in the fight against breast cancer, targeting the interaction between miR-126 and TRAF6.