MicroRNA regulation of progesterone receptor in breast cancer

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.

Progesterone receptor A promotes invasiveness and metastasis of luminal breast cancer by suppressing regulation of critical microRNAs by estrogen

“…In the case of luminal breast cancer, our studies show that the ability of progesterone plus PR-A to prevent suppression of miR-26b-5p by estrogen leads to increased invasion and metastasis, again underscoring cell type-specific differences in the actions of miR-26b-5p. We note that in a recent report (46), the authors suggest that PR may be a target of miR-26b and suggest a negative correlation between miR-26b expression and total PR mRNA in breast tumors, whereas we have observed a positive correlation between miR-26b and the PR isoform A and regulatory effects consistent with a positive correlation. The functional studies reported (46), which were only performed in MCF-7 cells, only showed a modest decrease in PR mRNA (ϳ20%) upon ectopic overexpression of miR-26b (at an undetermined level), and the study did not measure PR protein or function and did not examine the effect of depleting endogenous miR-26b.…”

“…We note that in a recent report (46), the authors suggest that PR may be a target of miR-26b and suggest a negative correlation between miR-26b expression and total PR mRNA in breast tumors, whereas we have observed a positive correlation between miR-26b and the PR isoform A and regulatory effects consistent with a positive correlation. The functional studies reported (46), which were only performed in MCF-7 cells, only showed a modest decrease in PR mRNA (ϳ20%) upon ectopic overexpression of miR-26b (at an undetermined level), and the study did not measure PR protein or function and did not examine the effect of depleting endogenous miR-26b. Additionally, the correlative analysis was performed using data from only 10 of 19 tumor specimens, and the arbitrary criteria for selecting this small sample subset were not unbiased.…”

MicroRNA-26a: An Emerging Regulator of Renal Biology and Disease

“…Moreover, miRNAs have been shown to be involved in the development of many human diseases [22-25]. For example, miRNAs play essential roles in cancer progress [26, 27], cardiovascular diseases, kidney diseases and improper immune responses in macrophages [28-32]. Several miRNAs (e.g., miR-21, miR-29a, miR-30s, miR-146a, miR-192, miR-193, and miR-200) are exploited as important biomarkers of renal diseases [33-39].…”

Progesterone Effects in the Nervous System

“…In line with this, the lifespan of patients with low amounts of miR‐200c is significantly reduced because of the missing impact of miR‐200c on PR expression (Tuomarila et al, 2014; http://targetcan.org). Other miRNAs strongly connected to the downregulation of PR in breast cancer are miR‐23a, miR‐26b, miR‐129‐2, and miR‐181a (Gilam et al, ; Godbole et al, ). Since some of these miRNAs are already described as tumor suppressor factors known to target the classical PR (http://targetscan.org), the use of miRNA mimics could potentially lead to a decreased tumor cell invasion in PR‐positive breast cancer.…”