Harnessing the Role of ESR1 in Breast Cancer: Correlation with microRNA, lncRNA, and Methylation

Abstract

Breast cancer (BC) is a multifactorial condition and it primarily expresses the estrogen receptor α (ERα) that is encoded by the gene estrogen receptor 1 (ESR1), which modulates estrogen signaling. ESR1, by facilitating estrogen overproduction, plays an indispensable role in the progression and survival of the majority of BCs. To obtain molecular insights into these phenomena, we analyzed The Cancer Genome Atlas (TCGA) breast invasive carcinoma (BRCA) RNA-Seq datasets for the expression of ESR1 and its correlation to microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), along with its methylation patterns. Regulation of ESR1 was also assessed with a total of 43 cancerous and non-cancerous breast cell lines. Analyses of both TCGA BRCA and breast cell line RNA-Seq data revealed that specific lncRNAs, i.e., MEG3, BIK, MLL, and FAS are negatively correlated with the ESR1, in which PARP1 demonstrates a positive association. Additionally, both miR-30a and miR-145 showed negative correlations with the ESR1 expression. Of the 54 ESR1 methylation loci analyzed, the majority of them exhibited a negative correlation with the ESR1 expression, highlighting a potentially modifiable regulatory mechanism. These findings underscore the complex regulatory events influencing ESR1 expression and its interaction with diverse signaling pathways, demonstrating novel insights into breast pathogenesis and its potential therapeutics.

Keywords: ESR1; breast cancer; gene expression; lncRNA; methylation; microRNA.

Figure 1

Boxplot analysis of the ESR1 expression using TCGA BRCA RNA-Seq datasets under three different categories: Normal (114), ER+/PR+ (611), and Other BCs (164), with sample numbers in parentheses. ***, p < 0.001 vs. Normal, as indicated.

Figure 2

Analyses of the Spearman’s correlation coefficients between ESR1 and specific lncRNAs (H19, XIST, RMRP, MEG3, BIK, FAS, MALAT1, HOTAIR, LIN28B, NEAT1, PARP1, KCNQ10T1, and MLL) using TCGA BRCA RNA-Seq data (A). The colors used were normal tissue—red; ER+/PR+ samples—green; and other BC subtypes—blue. (B) The Spearman’s correlation coefficients between ESR1 and target lncRNAs (MEG3, BIK, FAS, LIN 28B, PARP1, and MLL) with 43 breast cell line RNA-Seq data. Colors used were ER+ samples—green; ER− samples—blue; and other subtypes—gray.

Figure 3

Analyses of RNA-Seq data for relative expression of ESR1, BIK, and MLL mRNAs in a total of 43 different cancerous and non-cancerous breast cell lines. Shown are the names of various breast cell lines under the ER− and ER+ categories.

Figure 4

The Spearman’s correlation coefficients between ESR1 and miRNAs (miR-145, miR-29b, miR-30c, miR-155, and miR-30a) using TCGA BRCA RNA-Seq data. Colors used were normal tissue—red; ER/PR+ samples—green; and other BC subtypes—blue.

Figure 5

A heatmap illustrating the correlation matrix among lncRNA, miRNA, and ESR1. The genes included on the correlation map that influence diverse signaling pathways were the following: miR-30a, FAS, MEG3, miR-145, MALAT1, NEAT1, XIST, KCNQ10T1, MLL, STAR, H19, miR-29b, RMRP, HOTAIR, miR-155, LIN288, miR-30c, ESR1, BIK, and RARP1. p-values are provided in the correlation map in the format of “*” 0.01 ≤ p < 0.05; “**” 0.001 ≤ p < 0.01; and “***” p < 0.001.