Variation in IL6ST cytokine family function and the potential of IL6 trans-signalling in ERa positive breast cancer cells

High expression of the transmembrane receptor IL6ST (gp130) has been identified as a predictive biomarker of endocrine treatment response in ERa-positive breast cancers. To investigate its function further in this disease, this study evaluated the expression, function and signalling of IL6ST in ERa-positive breast cancer cell lines and investigated crosstalk between ERa and IL6ST. IL6ST was differentially expressed in ERa-positive breast cancer cell lines (low in MCF-7, high in ZR751 and T47D), while multiple soluble isoforms of IL6ST were identified. IL6ST is the common signal transducing receptor component for the IL6ST family of cytokines and the effects of seven IL6ST cytokines on these cell lines were studied. These cytokines caused differential growth and migration effects in these cell lines e.g. MCF-7 cells were growth-stimulated, while ZR751 cells were inhibited by IL6 and OSM.. Activation of the STAT and ERK pathways is associated with these responses. Evidence to support trans-signalling involved in cell growth and migration was obtained in both MCF-7 and ZR751 models. Interaction between cytokines and estrogen on ERa-positive cell lines growth were analysed. High expression of IL6ST (in ZR751) may lead to growth inhibition by interacting cytokines while lower expression (in MCF-7) appears associated with proliferation. High IL6ST expression is consistent with a more beneficial clinical outcome if cytokine action contributes to anti-estrogen action.