Abstract
Hormone receptor status is of significant value when deciding on anti-estrogenic adjuvant therapy for breast cancer tumors. However, while estrogen receptor (ER) regulation was intensively studied, the regulation of progesterone receptor (PR) levels has not been extensively investigated. MicroRNAs (miRNAs, miRs) are post-transcriptional negative regulators of gene expression involved in diverse cellular processes. The aim of this study was to identify miRNAs that regulate PR in breast cancer.We mapped potential miRNA binding sites for miR-181a, miR-23a and miR-26b on PR mRNA and demonstrated a direct regulation of PR by these three miRNAs by in-vitro Luciferase binding assays. Over-expression of each miRNA in MCF-7 cells resulted in a reduction in the expression levels of PR mRNA. Then, expression levels of these miRNAs were measured in Formalin-Fixed, Paraffin-Embedded (FFPE) samples of 29 ER-positive breast cancer tumors and adjacent normal breast tissues. A significant reciprocal correlation between PR mRNA and the miRNA levels were identified suggesting a role for miR-181a, miR-23a and miR-26b in PR regulation in breast cancer. Moreover, the average expression fold-changes of the three miRNAs between cancerous and normal tissues displayed an opposite trend when analyzing according to Immuno-histochemistry(IHC) status. Furthermore, miR-181a and miR-26b were found to be over-expressed in most tumor tissues supporting their role in ER-positive breast cancer development. We conclude that miR-181a, miR-23a and miR-26b act as negative regulators of PR expression in ER-positive breast cancer. The diagnostic and prognostic potential of these miRNAs in breast cancer should be further evaluated.
Highlights
Breast cancer is the most frequent cancer in women, with more than 200,000 cases diagnosed per year in the USA
The estrogen receptor (ER) status has long been recognized as an important factor in prognosis and management of breast cancer and breast tumors that express the ER are often treated with anti-estrogenic drugs in the adjuvant and metastatic setting
In this study we focused on miR181a, miR-23a and miR-26b, and tested their relevance to the regulation of progesterone receptor (PR) in breast cancer
Summary
Breast cancer is the most frequent cancer in women, with more than 200,000 cases diagnosed per year in the USA. Hormone receptor status is of paramount importance when deciding on breast cancer treatment. The estrogen receptor (ER) status has long been recognized as an important factor in prognosis and management of breast cancer and breast tumors that express the ER are often treated with anti-estrogenic drugs in the adjuvant and metastatic setting. During the last four decades studies have tested the importance of progesterone receptor (PR) status in the decision making regarding the therapy for breast cancer patients [1, 2]. PR nuclear staining correlated with the likelihood of benefit from anti-estrogenic therapies [2,3,4,5]. Exposure to progesterone is a well-recognized risk factor for postmenopausal breast cancer [6]
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