miR-205-5p-mediated downregulation of ErbB/HER receptors in breast cancer stem cells results in targeted therapy resistance

Abstract

The ErbB tyrosine kinase receptor family has been shown to have an important role in tumorigenesis, and the expression of its receptor members is frequently deregulated in many types of solid tumors. Various drugs targeting these receptors have been approved for cancer treatment. Particularly, in breast cancer, anti-Her2/EGFR molecules represent the standard therapy for Her2-positive malignancies. However, in a number of cases, the tumor relapses or progresses thus suggesting that not all cancer cells have been targeted. One possibility is that a subset of cells capable of regenerating the tumor, such as cancer stem cells (CSCs), may not respond to these therapeutic agents. Accumulating evidences indicate that miR-205-5p is significantly downregulated in breast tumors compared with normal breast tissue and acts as a tumor suppressor directly targeting oncogenes such as Zeb1 and ErbB3. In this study, we report that miR-205-5p is highly expressed in BCSCs and represses directly ERBB2 and indirectly EGFR leading to resistance to targeted therapy. Furthermore, we show that miR-205-5p directly regulates the expression of p63 which is in turn involved in the EGFR expression suggesting a miR-205/p63/EGFR regulation.

Decreased expression of microRNA-17 and microRNA-20b promotes breast cancer resistance to taxol therapy by upregulation of NCOA3

“…Several studies have linked high expression of miRNAs with resistance to chemotherapeutics in breast cancers. 15 On the other hand, loss of miRNAs was found in chemotherapy-resistant breast cancer. 17 One recent study shows that miR-17 and miR-20b were significantly downregulated in taxol-resistant breast cancer cells by miRNA array chips.…”

“…15, 16, 17 Numerous miRNAs are highly expressed or low expressed in tumor, contributing to the initiation and drugs resistance of the cancer. For instance, miRNA-451 high expression sensitizes breast cancer cells to adriamycin, 18 whereas upregulation of miRNA-21 promote cancer cell resistance to trastuzumab.…”

MiR-4638-5p inhibits castration resistance of prostate cancer through repressing Kidins220 expression and PI3K/AKT pathway activity

“…We found 30 underexpressed (Supplementary Table S2) and 32 overexpressed miRNAs (Supplementary Table S3) with >2 fold difference of mean value in the three CRPC samples compared with the ADPC samples (Figure 1A). 25 underexpressed and 16 overexpressed miRNAs have been previously reported in human cancers, including PCa, such as underexpression of miR-135a [17, 18], miR-143 [17, 19], miR-145 [17, 20], miR-205 [17, 21–24], miR-24-1 [17, 25], miR-146a [26, 27], miR-3607 [28], and overexpression of miR-1247 [29], miR-197 [20], miR-592 [30], miR-150 [31, 32]. Among the 30 underexpressed miRNAs in CRPC samples, miR-4638-5p, a miRNA that has not been previously reported in any human cancers, was expressed 2.4-fold higher in the ADPC than CRPC samples.…”

Molecular Network Pathway Of ERBB In Diffuse-Type Gastric Cancer, Mesenchymal Stem Cells And Epithelial-Mesenchymal Transition

“…Expression of ERBB3 is correlated with intestinal stem cell markers such as LGR5, EPHB2, CD44 in colorectal cancer, although ERBB3 expression is observed in the differentiated cell population at the top of the crypts [19]. Furthermore, ERBB3 is targeted by miR-205-5p, a tumor suppressor in breast cancer [20]. Knockdown of ERBB3 suppressed migration and invasion of bladder cancer cells [21].…”