Abstract
Cancer-associated fibroblasts (CAFs) are major players in the development and spread of breast carcinomas through non-cell-autonomous signaling. These paracrine effects are under the control of several genes and microRNAs. We present here clear evidence that let-7b, a tumor suppressor microRNA, plays key roles in the persistent activation of breast stromal fibroblasts and their functional interplay with cancer cells. We have first shown that let-7b is down-regulated in CAFs as compared to their corresponding normal adjacent fibroblasts, and transient specific let-7b inhibition permanently activated breast fibroblasts through induction of the IL-6-related positive feedback loop. More importantly, let-7b-deficient cells promoted the epithelial-to-mesenchymal transition process in breast cancer cells in an IL-8-dependent manner, and also enhanced orthotopic tumor growth in vivo. On the other hand, overexpression of let-7b by mimic permanently suppressed breast myofibroblasts through blocking the positive feedback loop, which inhibited their paracrine pro-carcinogenic effects. Furthermore, we have shown that let-7b negatively controls IL-8, which showed higher expression in the majority of CAF cells as compared to their adjacent normal counterparts, indicating that IL-8 plays a major role in the carcinoma/stroma cross-talk. These findings support targeting active stromal fibroblasts through restoration of let-7b/IL-8 expression as a therapeutic option for breast carcinomas.
Highlights
Despite early detection and targeted therapies, breast cancer remains the most commonly diagnosed cancer and the leading cause of cancer death among women worldwide [1]
These results suggest that let-7b inhibition activated the IL-6-related positive feedback loop
Similar results were obtained when tumor counterpart fibroblasts (TCFs)-346c and TCF-346i cells were passaged once and were reincubated in let-7b inhibitorfree medium (Supplementary Figure 1). These results suggest that let-7b inhibition activates breast stromal fibroblasts
Summary
Despite early detection and targeted therapies, breast cancer remains the most commonly diagnosed cancer and the leading cause of cancer death among women worldwide [1]. Let-7 family members act as tumor suppressor in several types of malignant human tumors by www.oncotarget.com inhibiting the expression of oncogenes and key regulators of mitogenic pathways [6, 7]. The expression of let-7 family members has been found reduced in many types of cancers [8]. It has been shown that the restoration of let-7b expression effectively inhibited the growth of lung and breast cancer cells in vitro, as well as in mouse models of hepatocellular carcinoma [6, 9, 10]. It has been recently reported that let-7b expression was reduced in breast cancer tissues and was inversely associated with tumor lymph node metastasis, patient overall survival and relapse-free survival. Breast cancer patients with low let7b expression had poor prognoses, indicating that let-7b could act as tumor suppressor miRNA in breast cancer onset and spread [5, 11]
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