Chronic
inflammation has been recognized as a risk factor for the development and maintenance of malignant disease.
Cytokines such as
interleukin-6 (IL-6),
oncostatin M (OSM), and
interleukin-1 beta (IL-1β) promote the development of both acute and chronic
inflammation while promoting in vitro metrics of
breast cancer metastasis. However, anti-IL-6 and anti-IL-1β
therapeutics have not yielded significant results against solid
tumors in clinical trials. Here we show that these three
cytokines are interrelated in expression. Using the Curtis TCGA™ dataset, we have determined that there is a correlation between expression levels of OSM,
IL-6, and IL-1β and reduced
breast cancer patient survival (r = 0.6, p = 2.2 x 10-23). Importantly, we confirm that OSM induces at least a 4-fold increase in
IL-6 production from
estrogen receptor-negative (ER-)
breast cancer cells in a manner that is dependent on STAT3 signaling. Furthermore, OSM induces STAT3 phosphorylation and IL-1β promotes p65 phosphorylation to synergistically induce
IL-6 secretion in ER- MDA-MB-231 and to a lesser extent in ER+ MCF7 human
breast cancer cells. Induction may be reduced in the ER+ MCF7 cells due to a previously known suppressive interaction between ER and STAT3. Interestingly, we show in MCF7 cells that ER's interaction with STAT3 is reduced by 50% through both OSM and IL-1β treatment, suggesting a role for ER in mitigating STAT3-mediated inflammatory cascades. Here, we provide a rationale for a
breast cancer treatment regime that simultaneously suppresses multiple targets, as these
cytokines possess many overlapping functions that increase
metastasis and worsen patient survival.