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

High expression of the transmembrane receptor IL6ST (gp130) has been identified as a predictive biomarker of endocrine treatment response in ERα-positive breast cancers. To investigate its function further in this disease, this study evaluated the expression, function and signalling of IL6ST in ERα-positive breast cancer cell lines and investigated crosstalk between ERα and IL6ST. IL6ST was differentially expressed in ERα-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 ERα-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.

Breast cancer gene expression datasets do not reflect the disease at the population level.

Publicly available tumor gene expression datasets are widely reanalyzed, but it is unclear how representative they are of clinical populations. Estimations of molecular subtype classification and prognostic gene signatures were calculated for 16,130 patients from 70 breast cancer datasets. Collated patient demographics and clinical characteristics were sparse for many studies. Considerable variations were observed in dataset size, patient/tumor characteristics, and molecular composition. Results were compared with Surveillance, Epidemiology, and End Results Program (SEER) figures. The proportion of basal subtype tumors ranged from 4 to 59%. Date of diagnosis ranged from 1977 to 2013, originating from 20 countries across five continents although European ancestry dominated. Publicly available breast cancer gene expression datasets are a great resource, but caution is required as they tend to be enriched for high grade, ER-negative tumors from European-ancestry patients. These results emphasize the need to derive more representative and annotated molecular datasets from diverse populations.