Abstract 3769: Intracellular miR-1290 promotes breast cancer stemness in HER2-enriched and triple-negative breast cancer

Abstract

Abstract HER2-enriched breast cancer and triple-negative breast cancer (TNBC) have the highest propensity to metastasize to the brain; patients with breast cancer brain metastasis (BCBM) survive only 6-18 months after diagnosis. Mechanisms that drive brain metastasis remain unclear, contributing to limited effective treatments and poor prognoses for HER2-enriched breast cancer and TNBC patients. Our lab recently reported that breast cancer with truncated glioma-associated oncogene homolog 1, a BCBM-promoting transcription factor, secretes high levels of extracellular vesicle (EV)-derived miR-1290 (Cancer Letters 540:215726, 2022). EV-miR-1290 activates astrocytes in the brain microenvironment. Using mammosphere assays, which enrich breast cancer stem cells (BCSCs), we found conditioned media from miR-1290-activated astrocytes promotes mammosphere formation of breast cancer cells. Furthermore, miR-1290-activated astrocytes secrete high levels of ciliary neurotrophic factor (CNTF) to promote the progression of brain metastases through the novel EV-miR-1290-FOXA2-CNTF signaling axis. However, it remains unknown whether intratumoral miR-1290 promotes BCSCs and BCBM. To help fill this knowledge gap, we first examined whether a miR-1290 mimic enhanced expression of known BCSC markers in SKBR3, HER2-enriched breast cancer, and CN34, TNBC, cells. Our results showed that overexpression of miR-1290 significantly increased the expression of stemness genes, CD44, Nanog, and OCT4, in both cell lines. Furthermore, we determined whether miR-1290 promotes formation of mammospheres that are enriched with BCSCs, and the results indicated that ectopic miR-1290 expression significantly enriched BCSCs in SKBR3 and CN34 cells. Conversely, inhibition of miR-1290 suppressed mammosphere-forming ability of SKBRM and CN34-BRM cells, two brain metastatic breast cancer cell lines derived from SKBR3 and CN34 cells, respectively. We further observed that miR-1290 overexpression in SKBR3 cells significantly increased the percentage of CD44+/CD24− cells, indicative of the BCSCs. Analysis of Gene Expression Omnibus breast cancer patient datasets revealed that miR-1290 expression is significantly increased in HER2-positive and basal subtypes of breast cancer patient tumors. Using the publicly available miR-1290 gene signature, we performed Gene Set Enrichment Analysis and found that high miR-1290 gene activation signature is positively enriched with multiple pathway gene signatures that are known to be upregulated in breast cancer, such as EGFR, MAPK, PI3K, and STAT3 pathways. Furthermore, the miR-1290 gene signature is upregulated in HER2-positive breast cancer and TNBC tumors, and is correlated with worse metastasis-free survival (MFS) and brain-MFS in breast cancer patients. In summary, our study suggests an important role for intratumoral miR-1290 in BCSCs and BCBM. Citation Format: Grace L. Wong, Mariana Najjar, Yoshua Esquenazi, Nitin Tandon, Angelina T. Regua, Hui-Wen Lo. Intracellular miR-1290 promotes breast cancer stemness in HER2-enriched and triple-negative breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3769.