Oncotarget

Research Papers:

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

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Oncotarget. 2019; 10:2068-2085. https://doi.org/10.18632/oncotarget.26699

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Ken Tawara, Hannah Scott, Jacqueline Emathinger, Cody Wolf, Dollie LaJoie, Danielle Hedeen, Laura Bond, Paul Montgomery, Cheryl Jorcyk

Abstract

Ken Tawara1, Hannah Scott2, Jacqueline Emathinger2, Cody Wolf1,2, Dollie LaJoie2,3, Danielle Hedeen2,3, Laura Bond4, Paul Montgomery5 and Cheryl Jorcyk1,2

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.