Abstract
Interleukin-12 (IL-12) is a proinflammatory cytokine that links innate and adaptive immune responses against tumor cells. Single Nucleotide Polymorphisms (SNPs) in IL-12 genes have been associated with cancer risk. However, limited studies have assessed the role of IL-12 in breast cancer (BC) risk comprehensively, and these were done in European and Asian populations. Here, we evaluated the association of the IL-12 signaling pathway and BC risk in Puerto Rican women. A genetic association study was completed with 461 BC cases and 463 non-BC controls. By logistic regression, IL-12 signaling SNPs were associated with an increased BC risk, including rs2243123 (IL12A), rs3761041, rs401502 and rs404733 (IL12RB1), rs7849191 (JAK2), rs280500 (TYK2) and rs4274624 (STAT4). Conversely, other SNPs were associated with reduced BC risk including rs438421 (IL12RB1), rs6693065 (IL12RB2), rs10974947, and rs2274471 (JAK2), rs10168266 and rs925847 (STAT4), and rs2069718 (IFNG). Analyses based in hormone receptors such as estrogen (ER) and progesterone (PR) receptors also revealed protective (for SNPs rs3212227-IL12B; rs3024896 and rs3821236-STAT4) and predisposing (for rs2069705-IFNG SNP) BC associations. Haplotype analysis showed a decreased BC risk for IL12B and STAT4 SNPs, whereas increased risk for IL12RB1 SNPs. This study suggests a role of the IL-12 signaling axis and BC risk. SNPs in this pathway may alter IL-12 induced anti-tumor responses and modulate BC predisposition in a population-specific context. Functional studies will be necessary to confirm these findings, which potentially may benefit IL-12 related immunotherapeutic approaches towards BC.
Highlights
breast cancer (BC) is one of the leading causes of cancer-related deaths among women and constitutes a significant public health burden worldwide [1,2,3,4]
IL-12 is a strong proinflammatory cytokine that induces a signaling pathway in which STAT4 and interferon gamma (IFNG) are key for anti-tumor responses [12, 34, 35]
No comprehensive analyses focusing on the role of genetic variation in IL-12 signaling genes in relation to BC risk exists
Summary
BC is one of the leading causes of cancer-related deaths among women and constitutes a significant public health burden worldwide [1,2,3,4]. The relevant roles of the immune system in BC have been progressively unveiled [7,8,9,10]. Cytokines are the major cell-signaling proteins of both B and T cells Cytokines are the key modulators of immune system responses against cancer cells. Many studies have directed their efforts to elucidate the role of these proteins in cancer [11]. Interleukin-12 (IL-12) is an important proinflammatory cytokine for the development of effective anti-tumor immune responses [12, 13]. The main anti-tumor actions of IL-12 are promoted by a specific signaling pathway that includes STAT4 and interferon gamma (IFNG) [14,15,16]. Despite abundant IL12 cancer-related research, the roles of IL-12 in the BC carcinogenesis process remains unclear
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