microRNA-205 Regulates HER3 in Human Breast Cancer

Abstract

An increasing amount of experimental evidence shows that microRNAs can have a causal role in breast cancer tumorigenesis as a novel class of oncogenes or tumor suppressor genes, depending on the targets they regulate. HER2 overexpression is a hallmark of a particularly aggressive subset of breast tumors, and its activation is strictly dependent on the trans-interaction with other members of HER family; in particular, the activation of the PI3K/Akt survival pathway, so critically important in tumorigenesis, is predominantly driven through phosphorylation of the kinase-inactive member HER3. Here, we show that miR-205, down-modulated in breast tumors compared with normal breast tissue, directly targets HER3 receptor, and inhibits the activation of the downstream mediator Akt. The reintroduction of miR-205 in SKBr3 cells inhibits their clonogenic potential and increases the responsiveness to tyrosine-kinase inhibitors Gefitinib and Lapatinib, abrogating the HER3-mediated resistance and restoring a potent proapoptotic activity. Our data describe miR-205 as a new oncosuppressor gene in breast cancer, able to interfere with the proliferative pathway mediated by HER receptor family. Our study also provides experimental evidence suggesting that miR-205 can improve the responsiveness to specific anticancer therapies.

MicroRNA expression profiling identifies decreased expression of miR-205 in inflammatory breast cancer

“…Its functions in cancer appear to be tissue type specific. MiR-205 expression level is reportedly upregulated in human samples of lung cancer, 69 bladder cancer, 70 and endometrioid adenocarcinoma, 71 and downregulated in breast cancer, [72][73][74] prostate cancer, 75 and melanoma. 76 It has been reported that in a cohort of early breast cancer patients, decreased miR-205 is associated with worse disease-free interval and overall survival.…”

“…26 Identified direct targets of miR-205 in breast cancer include VEGF-A, a key regulator of angiogenesis and tumor metastasis, 72 E2F1, LAMC1, 79 and HER3. 72,73 Heterodimerization of HER2-HER3 leads to the activation of PI3K/Akt survival pathway, critical for HER2-mediated tumorigenesis. It was found that enforced expression of miR-205 in cultured breast cancer cells increases the responsiveness to EGFR inhibitor Gefitinib and EGFR/HER2 inhibitor Lapatinib.…”

“…It was found that enforced expression of miR-205 in cultured breast cancer cells increases the responsiveness to EGFR inhibitor Gefitinib and EGFR/HER2 inhibitor Lapatinib. 73 It is conceivable that miR-205 may affect tumor growth and metastasis by simultaneously targeting multiple genes. Additional targets of miR-205 identified in other tissue types have not been validated in breast cancer.…”

Recent trends in microRNA research into breast cancer with particular focus on the associations between microRNAs and intrinsic subtypes

“…Ichikawa et al also found that miR-26a and miR-30b mediate the effects of trastuzumab. 79,80 Furthermore, Iorio et al 81 demonstrated that miR-205, which targets HER3 and impairs the downstream Akt-mediated survival pathway, not only has an oncosuppressive role in breast cancer, but also increases its responsiveness to lapatinib and gefitinib.…”

miR-205 is frequently downregulated in prostate cancer and acts as a tumor suppressor by inhibiting tumor growth

“…9,10 microRNA205 (miR-205) has previously been cited as targeting HER3, SHIP2, VEGF-A, MED1, SIP1 and ZEB1 for repression. [11][12][13][14][15] In addition, miR-205 has been shown to activate IL24 and IL32 by targeting sites on their promoters. 16 In PCa, miR-205 exerts a tumorsuppressive effect by counteracting the epithelial-to-mesenchymal transition and reducing cell migration/invasion, in part through the down-regulation of protein kinase C epsilon.…”