MiR-148a functions to suppress metastasis and serves as a prognostic indicator in triple-negative breast cancer

Abstract

Triple-negative breast cancer (TNBC) presents a major challenge in the clinic due to its lack of reliable prognostic markers and targeted therapies. Accumulating evidence strongly supports the notion that microRNAs (miRNAs) are involved in tumorigenesis and could serve as biomarkers for diagnostic purposes. To identify miRNAs that functionally suppress metastasis of TNBC, we employed a concerted approach with selecting miRNAs that display differential expression profiles from bioinformatic analyses of breast cancer patient databases and validating top candidates with functional assays using breast cancer cell lines and mouse models. We have found that miR-148a exhibits properties as a tumor suppressor as its expression is inversely correlated with the ability of both human and mouse breast cancer cells to colonize the lung in mouse xenograft tumor models. Mechanistically, miR-148a appears to suppress the extravasation process of cancer cells, likely by targeting two genes WNT1 and NRP1 in a cell non-autonomous manner. Importantly, lower expression of miR-148a is detected in higher-grade tumor samples and correlated with increased likelihood to develop metastases and poor prognosis in subsets of breast cancer patients, particularly those with TNBC. Thus, miR-148a is functionally defined as a suppressor of breast cancer metastasis and may serve as a prognostic biomarker for this disease.

MicroRNA-148a suppresses proliferation and invasion potential of non-small cell lung carcinomas via regulation of STAT3

“…Numerous miRNAs have been found to be dysregulated under the pathological condition of NSCLC 18,19. Recently, studies have found that miR-148a functions to suppress NSCLC 20–22. However, the mechanism underlying the inhibitory effect of miR-148a on NSCLC is still not completely known.…”

The Role of micro RNAs in Breast Cancer Metastasis: Preclinical Validation and Potential Therapeutic Targets

“…miR-148a was identified by bioinformatic analysis of BC patient databases. There is a correlation between the low expression of miR-148a in higher grade tumors and a higher likelihood to develop metastases and poor prognosis especially in BC patients with basal and luminal B subtypes (94). In 4T1 and MDA-MB-231 BC cells, ectopic expression of miR-148a did not affect cell growth, viability in culture or in vitro migration (94).…”

“…There is a correlation between the low expression of miR-148a in higher grade tumors and a higher likelihood to develop metastases and poor prognosis especially in BC patients with basal and luminal B subtypes (94). In 4T1 and MDA-MB-231 BC cells, ectopic expression of miR-148a did not affect cell growth, viability in culture or in vitro migration (94). However, for both cell lines there was a reduction of lung metastases (≥50%) observed after fat pad implantation of cells ectopically expressing miR-148a.…”

“…However, for both cell lines there was a reduction of lung metastases (≥50%) observed after fat pad implantation of cells ectopically expressing miR-148a. It was shown that the extravasation process of circulating tumor cells (CTC) and therefore the access to lung parenchyma was suppressed by miR-148a (94). Wingless/integrated1 (Wnt1) and neuropilin-1 (NRP1) were identified as direct targets for miR-148a (94).…”

“…It was shown that the extravasation process of circulating tumor cells (CTC) and therefore the access to lung parenchyma was suppressed by miR-148a (94). Wingless/integrated1 (Wnt1) and neuropilin-1 (NRP1) were identified as direct targets for miR-148a (94). Wnt-1 induced Wnt signaling can promote EMT and metastasis (95,96) and NRP1 functions as mediator of cell growth, survival and metastasis (97,98).…”