Abstract
microRNA-143 (miR-143) is a well-known tumor suppressive microRNA that exhibits anti-tumoral function by targeting KRAS signaling pathways in various malignancies. We hypothesized that miR-143 suppresses breast cancer progression by targeting KRAS and its effector molecules. We further hypothesized that high expression of miR-143 is associated with a favorable tumor immune microenvironment of estrogen receptor (ER)-positive breast cancer patients which result in improved survival. Two major publicly available breast cancer cohorts; The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) were used. The miR-143 high expression group was associated with increased infiltration of anti-cancer immune cells and decreased pro-cancer immune cells, as well as enrichment of the genes relating to T helper (Th1) cells resulting in improved overall survival (OS) in ER-positive breast cancer patients. To the best of our knowledge, this is the first study to demonstrate that high expression of miR-143 in cancer cells associates with a favorable tumor immune microenvironment, upregulation of anti-cancer immune cells, and suppression of the pro-cancer immune cells, associating with better survival of the breast cancer patients.
Highlights
Breast cancer is one of the most frequently diagnosed types of cancer and the leading cause of cancer death in women in both the United States and worldwide [1,2]. microRNA is short non-coding RNA, consisting of 19–25 nucleotides in length, which function as epigenetic regulators of gene expression via binding to the mRNA of target genes [3,4,5]. miRNAs can be categorized into two major types depending on their function: oncomiRs and tumor suppressor miRNAs
In order to assess whether miR-143 has a suppressive role in breast cancer, we initially investigated the expression levels of miR-143 in breast cancer cell lines compared with a normal breast cell line
Previous studies have demonstrated that KRAS/MAPK and PI3K/AKT signaling pathways play a critical role in breast cancer progression, growth, and survival [33,34]
Summary
Breast cancer is one of the most frequently diagnosed types of cancer and the leading cause of cancer death in women in both the United States and worldwide [1,2]. microRNA (miRNA) is short non-coding RNA, consisting of 19–25 nucleotides in length, which function as epigenetic regulators of gene expression via binding to the mRNA of target genes [3,4,5]. miRNAs can be categorized into two major types depending on their function: oncomiRs and tumor suppressor miRNAs. It is critical to investigate the mechanism of how the tumor immune microenvironment is shaped in the ER positive subtype (which encompasses the majority breast cancer cases) in order to increase the potential for utilization of immunotherapy for treatment. Th2 cells demonstrate pro-cancer function via the secretion of interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-10 (IL-10), and transforming growth factor-β (TGF-β) [25] Given this background, we hypothesized that miR-143 plays a suppressive role in breast cancer development by targeting KRAS and its associated molecules. 2020, 21, 3213 expression of miR-143 is associated with a favorable tumor immune microenvironment and may result in improved survival of patients with breast cancer Sci. 2020, 21, 3213 expression of miR-143 is associated with a favorable tumor immune microenvironment and may result in improved survival of patients with breast cancer
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