The EGFR/miR-338-3p/EYA2 axis controls breast tumor growth and lung metastasis

Abstract

Dysregulation of the epidermal growth factor receptor (EGFR) promotes cancer cell growth, invasion and metastasis. However, its relevant downstream effectors are still limited. Here, we show that EGFR promotes breast tumor growth and metastasis by downregulating the tumor suppressor micoRNA-338-3p (miR-338-3p) and activating the EYA2 (EYA transcriptional coactivator and phosphatase 2) oncoprotein. EGFR represses miR-338-3p expression largely through HIF1α transcription factor. miR-338-3p inhibits EYA2 expression by binding to the 3′-untranslated region of EYA2. EGFR increases EYA2 expression via HIF1α repression of miR-338-3p. Through the miR-338-3p/EYA2 pathway, EGFR increases breast cancer cell growth, epithelial-to-mesenchymal transition, migration, invasion and lung metastasis in vitro and in a allograft tumor mouse model in vivo. In breast cancer patients, miR-338-3p expression negatively correlates with the expression of EGFR and EYA2, EGFR status positively associates with EYA2 expression, and miR-338-3p and EYA2 predict breast cancer lung metastasis when expressed in primary breast cancers. These data suggest that the miR-338-3p/ EYA2 axis contributes to EGFR-mediated tumor growth and lung metastasis and that miR-338-3p activation or EYA2 inhibition or combination therapy targeting EGFR/miR-338-3p/EYA2 axis may be a promising way to treat patients with metastatic cancer. Cell Death and Disease (2017) 8, e2928; doi:10.1038/cddis.2017.325; published online 13 July 2017The epidermal growth factor receptor (EGFR) is a member of the ErbB (avian erythroblastosis oncogene B) family of receptors and activates multiple signaling pathways, including mitogen-activated protein kinase (MAPK)/extracellular signalregulated kinases (ERK) and phosphoinositide-3-kinase (PI3K)/V-AKT murine thymoma viral oncogene homolog (AKT) pathways. 1-3 EGFR activation regulates many biological processes, such as cell proliferation, invasion, metastasis and apoptosis. [4][5][6] EGFR is overexpressed in various human cancers, including lung cancer, breast cancer, colon cancer and glioblastoma, and is associated with tumor malignancy and poor prognosis. 7-10 Thus, EGFR and its downstream signaling effectors have become targets for cancer therapy. 11 Approximately 90% of deaths associated with cancer are due to distant metastases. 12 Many cancers can metastasize anywhere in body but primarily metastasizes to some organs or tissues. For instance, lungs and bones are frequent sites of breast cancer metastasis. Although EGFR dysregulation enhances cancer metastasis, the relevant downstream effectors are largely unknown.MicroRNAs (miRNAs) are small noncoding RNA molecules (about 22 nucleotides in length), which function in RNA silencing and post-transcriptional regulation of gene expression. miRNAs participate in many biological processes, such as cell proliferation, invasion, metastasis, and apoptosis. 13 Recently, EGFR has been shown to promote prostate cancer bone metastasis by decreasing the expression of miR-1, a tumor suppressor, and inc...

Breast cancer lung metastasis: Molecular biology and therapeutic implications

“…Of note, BLBC markers such as EGFR and FOXC1 have been shown to control and correlate with lung metastasis. [11][12][13] In this review, we seek to provide an overview of the recent advances in understanding the molecular basis of lung metastasis of breast cancer with a special emphasis on cancer stem cell pathways and microenvironment. In addition to presenting the clinical characteristics of breast cancer lung metastasis, we discuss the potential therapeutic approaches that may improve the prognosis of breast cancer patients with lung metastasis.…”

Distinct co-expression networks using multi-omic data reveal novel interventional targets in HPV-positive and negative head-and-neck squamous cell cancer

“…Transcription factors were also overexpressed in the HPV+ Blue network, such as YBX2, DMRTA2 and EYA2. Most of these TF have been described as overexpressed in different types of cancers, including ovarian, testis and breast cancer in the case of YBX2 (37, 38), and breast cancer, lung cancer and acute myeloid leukemia in the case of EYA2 (39,40). DMRTA2, on the other hand, is also expressed in the spermatogenesis of the testis, and regulates the cyclin-dependent kinase CDKN2c (41), in addition to maintaining neuroprogenitor cells in the cell cycle (42).…”

Implications of SARS-CoV-2 mutations for genomic RNA structure and host microRNA targeting

“…The miR-338-3p target in the S-gene is removed by the C24034U conserved mutation identified early January in multiple countries ( Figure S1). The miR-338-3p miRNA acts as tumor suppressor in liver, lung and gastric cancers [73][74][75]. The expression level of miR-338-3p declines during HBV infection [76,77] and miR-338-3p has a recognition site within Vaccinia virus genome [78].…”