Abstract
Dysregulation of long non-codng RNA (lncRNA) expression has been found to contribute to tumorigenesis. However, the roles of lncRNAs in BRCA1-related breast cancer remain largely unknown. In this study, we delineate the role of the novel BRCA1/lncRNA NEAT1 signaling axis in breast tumorigenesis. BRCA1 inhibits NEAT1 expression potentially through binding to its genomic binding site upstream of the NEAT1 gene. BRCA1 deficiency in human normal/cancerous breast cells and mouse mammary glands leads to NEAT1 overexpression. Our studies show that NEAT1 upregulation resulting from BRCA1 deficiency stimulates in vitro and in vivo breast tumorigenicity. We have further identified molecular mediators downstream of the BRCA1/NEAT1 axis. NEAT1 epigenetically silences miR-129-5p expression by promoting the DNA methylation of the CpG island in the miR-129 gene. Silencing of miR-129-5p expression by NEAT1 results in upregulation of WNT4 expression, a target of miR-129-5p, which leads to activation of oncogenic WNT signaling. Our functional studies indicate that this NEAT1/miR-129-5p/WNT4 axis contributes to the tumorigenic effects of BRCA1 deficiency. Finally our in silico expression correlation analysis suggests the existence of the BRCA1/NEAT1/miR-129-5p axis in breast cancer. Our findings, taken together, suggest that the dysregulation of the BRCA1/NEAT1/miR-129-5p/WNT4 signaling axis is involved in promoting breast tumorigenesis.
Highlights
Breast cancers have been classified into several molecular subtypes including luminal-A, luminal-B, human epidermal growth factor receptor 2 (HER2)-positive, normal- and basal-like [1, 2]
We examined the correlation between Breast cancer susceptibility gene 1 (BRCA1) status and NEAT1 expression in the immortalized human mammary epithelial cell (HMEC) line MCF10A, BL- DCIS cell line MCF10DCIS [39,40,41] and Basal-like breast cancers (BLBCs) cell line HCC1937
To determine if NEAT1 upregulation in MCF10DCIS cells correlates with decreased BRCA1 expression levels, we examined the protein levels of BRCA1 in MCF10DCIS and MCF10A cells
Summary
Breast cancers have been classified into several molecular subtypes including luminal-A, luminal-B, HER2-positive, normal- and basal-like [1, 2]. Basal-like breast cancers (BLBCs) are frequently triple-negative for estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). BLBCs are an aggressive cancer with high tumor grade, increased proliferation rate, frequent recurrence, high metastatic rate, and the frequent presence of p53 mutations [2,3,4]. Patients with BLBCs have a poor prognosis and are difficult to treat [4]. Basal-like ductal carcinoma in situ (BL-DCIS) is known to be a potential precursor of invasive BLBCs [5, 6]. Breast cancer susceptibility gene 1 (BRCA1) encodes a multi-functional tumor suppressor protein that is necessary to maintain genomic integrity [7,8,9,10,11]
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