The type 2 diabetes-associated Th17 cytokines IL-21 and IL-22 promote breast cancer cell survival.

Abstract

Abstract Obesity-induced inflammation has taken center stage as a driving force in metabolic disease and type 2 diabetes (T2D). As the epidemic of obesity deepens, it has become imperative to dissect mechanisms by which obesity-induced inflammation contributes to increased cancer morbidity. Recent studies have shown that increased breast cancer mortality rates are associated with obesity-related T2D. Our goal is to understand the immunological mechanisms in T2D that contribute to increased breast cancer risk. We previously showed that PBMCs treated with T cell-targeted stimuli produce a pro-inflammatory Th17 cytokine profile that differentiates T2D from obese non-T2D subjects. We therefore tested the hypothesis that Th17 cytokines support breast cancer cells. Proliferation assays showed that IL-21 and IL-22, but not IL-17A/F, or the Th1 cytokine IL-6, maintained the proliferation of MCF7 cells, an estrogen dependent breast cancer cell line, in the absence of estrogen. Building on this result, we tested the effect of IL-21/22 on MCF7 survival. Immunoblots and mRNA arrays demonstrated that IL-21 but not IL-22 upregulated steady-state expression of BCL-2 family survival mRNA/protein. Both IL-21 and IL-22 survival was blocked by JQ1, an inhibitor of the Bromodomain and ExtraTerminal (BET) family of chromatin regulating proteins. The inferred cross-talk between BET- and Th17 cytokine-triggered pathways implicate the Th17 cytokine signature from PBMCs of patients with T2D in the higher recurrence of post-menopausal breast cancer after tamoxifen treatment. The public health impact of these data is that monitoring Th17 cytokine production by PBMCs may inform risk assessment for relapse or recurrence in breast cancer patients with T2D.