MicroRNA regulation of progesterone receptor in breast cancer
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Avital Gilam1,*, Ayelet Shai2,3,*, Itamar Ashkenazi4, Liat Appel Sarid2,3, Assi Drobot2, Amitai Bickel2,3 and Noam Shomron1
1 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
2 Oncology Department, Galilee Medical Center, Nahariya, Israel
3 Faculty of Medicine, Bar Illan University, Zefad, Israel
4 Hillel Yaffe Medical Center, Hedera, Israel
* These authors have contributed equally to this work
Noam Shomron, email:
Keywords: breast cancer, progesterone receptor, microRNA, miR-181a, miR-23a
Received: January 17, 2017 Accepted: January 25, 2017 Published: February 23, 2017
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.
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