HIGH expression of OSM and IL-6 are associated with decreased breast cancer survival: synergistic induction of IL-6 secretion by OSM and IL-1β

Abstract

// Ken Tawara 1 , Hannah Scott 2 , Jacqueline Emathinger 2 , Cody Wolf 1 , 2 , Dollie LaJoie 2 , 3 , Danielle Hedeen 2 , 3 , Laura Bond 4 , Paul Montgomery 5 and Cheryl Jorcyk 1 , 2 1 Boise State University, Biomolecular Sciences Program, Boise, ID, USA 2 Boise State University, Department of Biological Sciences, Boise, ID, USA 3 University of Utah, Department of Oncological Sciences, Salt Lake City, UT, USA 4 Boise State University, Biomolecular Research Center, Boise, ID, USA 5 St. Luke’s Mountain State Tumor Institute, Boise, ID, USA Correspondence to: Cheryl Jorcyk, email: cjorcyk@boisestate.edu Keywords: oncostatin M; interleukin-6 and oncostatin M; interleukin-1β; breast cancer; metastasis Received: October 12, 2018     Accepted: January 31, 2019     Published: March 12, 2019 ABSTRACT 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.