Rationale:

MicroRNAs (miRNAs) are recently described novel small non-coding endogenous RNAs which critically regulate cancer progression, invasion and metastasis. Altered expression of miRNAs has been proposed to control the invasive capability of cancer cells. Modulating altered miRNAs is a novel approach for targeted therapy for cancer. Breast cancer is the most common cancer among women in the US. Breast cancer-related mortality and morbidity are primarily due to metastatic disease especially brain metastasis which also impacts patients’ quality of life. Molecular mechanisms of brain metastasis of breast cancer are largely unknown.

Study Objectives:

Identifying molecular miRNA signatures in breast cancers which metastasize to the brain can assist in designing novel targeted therapies to prevent and eliminate brain metastasis.

Design:

RNA was extracted from formalin fixed paraffin embedded tumor tissues from a cohort of breast cancer patients with brain metastasis, and age, stage and follow-up matched breast cancer cases without brain metastasis. miRNA expression profiling was done using EQIXON microarray. Quantitative real-time PCR (qRT-PCR) was used to validate abnormal expression of miRNAs. Data was statistically analyzed using Kruskal-Wallis test to determine the clinical significance of the findings.

Results:

Over 2000 unique miRNA sequences were profiled in each case. The upregulated miRNAs included miR-3927-5p, miR-216b and miR-10b and the down regulated miRNAs were miR-4280, miR-3174 and miR-1244 and miR20b. Validation of the deregulated miRNAs by q RT-PCR showed statistically significant difference in the expression levels in the breast cancers with brain metastasis compared to breast cancers without brain metastasis (Kruskal-Wallis test; p < 0.001).

Conclusions:

A unique set of miRNAs were deregulated in breast cancers with brain metastasis. This panel of altered miRNAs have clinical relevance since they can be silenced by antagomirs (chemically modified anti-miRNA oligonucleotides) to treat and prevent brain metastasis. These molecular microRNA signature-based novel targeted prophylactic and therapeutic strategies could improve patients’ quality of life and overall survival in the era of personalized and precision medicine.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-15-07.