IL-6 secreted by cancer-associated fibroblasts induces tamoxifen resistance in luminal breast cancer

Abstract

Cancer-associated fibroblasts (CAFs) have been implicated in the development of resistance to anticancer drugs; however, the role and mechanism underlying CAFs in luminal breast cancer (BrCA) tamoxifen resistance are unclear. We found that stromal fibroblasts isolated from the central or peripheral area of BrCA have similar CAF phenotype and activity. In vitro and in vivo experiments showed that CAFs derived from clinical-luminal BrCAs induce tamoxifen resistance through decreasing estrogen receptor-α (ER-α) level when cultured with luminal BrCA cell lines MCF7 and T47D. CAFs promoted tamoxifen resistance through interleukin-6 (IL-6) secretion, which activates Janus kinase/signal transducers and activators of transcription (JAK/STAT3) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways in tumor cells, followed by induction of epithelial-mesenchymal transition and upregulation of E3 ubiquitin ligase anaphase-promoting complex 10 activity, which targeted ER-α degradation through the ubiquitin-proteasome pathway. Inhibition of proteasome activity, IL-6 activity or either the JAK/STAT3 or PI3K/AKT pathways markedly reduced CAF-induced tamoxifen resistance. In xenograft experiments of CAFs mixed with MCF7 cells, CAF-specific IL-6 knockdown inhibited tumorigenesis and restored tamoxifen sensitivity. These findings indicate that CAFs mediate tamoxifen resistance through IL-6-induced degradation of ER-α in luminal BrCAs.Oncogene advance online publication, 9 June 2014; doi:10.1038/onc.2014.158.

Cancer-associated fibroblasts: A multifaceted driver of breast cancer progression

“…It is also reported that mCAFs induce high mobility group box 1 and contribute to resistance to doxorubicin in breast cancer cells [120]. A previous study indicated co-culture with breast cancerderived fibroblasts decreased tamoxifen sensitivity in cancer cells and protected them from tamoxifen-induced death; the fibroblastinduced tamoxifen resistance was ascribed to soluble stromal factors such as IL6, MMPs and ECM components including fibronectin [122,124,125]. Notably, significant association was observed between CAF presence and endocrine resistance in several clinical series, as previously mentioned (Table 1).…”

“…Therefore, much effort has been focused on this area. Interestingly, increasing evidence revealed that mCAFs are a cause of endocrine/chemotherapy and target therapeutic resistance in breast cancer treatment [120][121][122]. Collagen type I secreted by CAFs was demonstrated to decrease chemotherapeutic drug uptake in tumors, and thus plays a significant role in regulating tumor sensitivity to a variety of chemotherapies.…”

LNA aptamer based multi-modal, Fe 3 O 4 -saturated lactoferrin (Fe 3 O 4 -bLf) nanocarriers for triple positive (EpCAM, CD133, CD44) colon tumor targeting and NIR, MRI and CT imaging

“…Upregulation in IL-6 was also observed. IL-6 is reported to impart drug resistance and cancer progression by Janus kinase/signal transducers and activators of transcription (JAK/STAT3) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways in tumor cells [65]. ITAC levels were highly upregulated in treatments when compared to control.…”

Extracellular matrix in obesity – cancer interactions

“…For a long time, it has been suspected that elevated estrogen levels are associated with an increased risk in breast cancer. A recent study Brought to you by | New York University Bobst Library Technical Services Authenticated Download Date | 6/25/15 10:38 AM on breast cancer showed that CAF conferred tamoxifen resistance through interleukin-6 (IL-6) [47]. Similarly, in prostate cancer, CAF exerts a mandatory role in prostate cancer progression and favors metastatic dissemination of aggressive lesions [48].…”