miR-21 Induces Myofibroblast Differentiation and Promotes the Malignant Progression of Breast Phyllodes Tumors

Abstract

Phyllodes tumors of breast, even histologically diagnosed as benign, can recur locally and have metastatic potential. Histologic markers only have limited value in predicting the clinical behavior of phyllodes tumors. It remains unknown what drives the malignant progression of phyllodes tumors. We found that the expression of myofibroblast markers, a-smooth muscle actin (a-SMA), fibroblast activation protein (FAP), and stromal cell-derived factor-1 (SDF-1), is progressively increased in the malignant progression of phyllodes tumors. Microarray showed that miR-21 was one of the most significantly upregulated microRNAs in malignant phyllodes tumors compared with benign phyllodes tumors. In addition, increased miR-21 expression was primarily localized to a-SMA-positive myofibroblasts. More importantly, a-SMA and miR-21 are independent predictors of recurrence and metastasis, with their predictive value of recurrence better than histologic grading. Furthermore, miR-21 mimics promoted, whereas miR-21 antisense oligos inhibited, the expression of a-SMA, FAP, and SDF-1, as well as the proliferation and invasion of primary stromal cells of phyllodes tumors. The ability of miR-21 to induce myofibroblast differentiation was mediated by its regulation on Smad7 and PTEN, which regulate the migration and proliferation, respectively. In breast phyllodes tumor xenografts, miR-21 accelerated tumor growth, induced myofibroblast differentiation, and promoted metastasis. This study suggests an important role of myofibroblast differentiation in the malignant progression of phyllodes tumors that is driven by increased miR-21. Cancer Res; 74(16); 4341-52. Ó2014 AACR.

The novel role of miRNAs for tamoxifen resistance in human breast cancer

“…Mechanistically, upregulation of miR-21 expression leads to the suppression of several key tumor suppressor genes, such as p57 Kip2 , tropomyosin 1 (TPM1), programmed cell death protein 4 (PDCD4) and PTEN [71][72][73][74]. Indeed, it was also confirmed that miR-21 antisense oligos inhibited the proliferation and invasion of primary stromal cells of phyllodes tumors [70]. Therefore, miR-21 inhibition may have therapeutic benefits for treating breast cancer and a miR-21 inhibitor is currently being developed by Regulus Therapeutics.…”

“…Interestingly, miR-21 was identified as one of the oncomiRs whose expression was found to be upregulated in many types of cancer, including both solid tumors and breast cancer [70]. Mechanistically, upregulation of miR-21 expression leads to the suppression of several key tumor suppressor genes, such as p57 Kip2 , tropomyosin 1 (TPM1), programmed cell death protein 4 (PDCD4) and PTEN [71][72][73][74].…”

Comparison of skeletal muscle miRNA and mRNA profiles among three pig breeds

“…miR-21, miR-24, miR-26a, miR-27a, and miR-486 were expressed at the lowest levels in Wuzhishan pigs in our results. miR-21 induces the expression of myofibroblast markers in the stromal cells of phyllodes tumors (Gong et al 2014) and regulates PI3 K/Akt/mTOR signaling by targeting TGFβI during skeletal muscle development in pigs (Bai et al 2015). Knockdown of miR-24 leads to reduced expression of myogenic differentiation markers in C2C12 cells, while ectopic expression of miR-24 enhances differentiation (Sun et al 2008).…”

MiR-142-3p Suppresses SOCS6 Expression and Promotes Cell Proliferation in Nasopharyngeal Carcinoma

“…MicroRNAs (miRNAs) are small (20-25 nucleotides) noncoding RNAs that function as negative regulators of gene expression via binding to the 3′-untranslated region (3′-UTR) of their target messenger RNAs (mRNAs) [4]. miRNAs play vital roles in many fundamental biological processes including cell proliferation, differentiation, apoptosis, migration, and invasion by suppressing their target genes [5][6][7][8][9][10]. Numerous studies have demonstrated that deregulation of specific miRNAs is associated with cancer initiation and progression in many malignancies including NPC, and miRNAs can function as oncogenes or oncosuppressors depending on their targets [11][12][13][14][15].…”