Posted August 11, 2020

Pradeep Chaluvally-Raghavan, Ph.D., Medical College of Wisconsin

Current strategies to treat and prevent metastatic breast cancer suffer from poor understanding of the cellular mechanisms underlying metastasis initiation and progression. Evaluation of microRNAs (small non-coding RNAs that regulate gene expression) offers a unique strategy to examine subtype-specific mechanisms of metastasis and discover new therapeutic targets for breast cancer. The microRNA551b-3p (miRNA551b-3p) is frequently overexpressed in breast cancer, as well as other cancers (e.g., cervical, head and neck, prostate). Dr. Chaluvally-Raghavan’s previous work demonstrated that miRNA551b-3p mediates breast cancer progression through increased and persistent expression of the well-known oncogenic transcription factor Signal transducer and activator of transcription 3 (STAT3). STAT3-induced expression of various growth factors, cytokines, and cell surface receptors initiates a feed-forward signaling loop whereby excreted cytokines induce STAT3 expression by binding to receptors on the originating cell, thus resulting in signaling addiction and disease progression. A Fiscal Year 2017 Breast Cancer Research Program Breakthrough Award – Funding Level 1 enabled Dr. Chaluvally-Raghavan’s research team to explore the mechanisms by which miRNA551b-3p contributes to signaling addiction and metastatic activity in TNBC, an aggressive subtype of breast cancer, with implications for new therapeutic strategies.

In a recent Cell Reports article, Dr. Chaluvally-Raghavan and his team described the “oncostatin signaling module” as a mechanism by which miRNA551b-3p signaling addiction provides metastatic growth and proliferative advantages to TNBC cells. They also demonstrated that disruption of this pathway via blocking miRNA511b-3p reduced migration and invasion activities (key features of metastasis) in TNBC cell models, as well as reduced tumor growth in a mouse model of TNBC.

Dr. Chaluvally-Raghavan and his team first examined the role of miRNA551b-3p in vitro using a panel of cell lines representing different subtypes of breast cancer. Gene expression analysis revealed that basal-like TNBC cells exhibited high levels of miRNA551b-3p compared to cells that were estrogen receptor (ER)-positive or human epidermal growth factor receptor 2 (HER2)-positive. Moreover, the addition of miRNA551b-3p to TNBC cell lines resulted in accelerated growth, while blocking miRNA551b-3p reduced migration and invasion. miRNA551b-3p expression patterns correlated with oncogene STAT3 protein levels in both TNBC cell lines and in clinical breast cancer samples from the Danish Breast Cancer Cohort. Upon analysis of STAT3 transcriptional targets, the team determined that STAT3-induced activation of an “oncostatin signaling module,” which includes cytokines and their receptors, generates a persistent signaling loop that drives signaling addiction. To evaluate the therapeutic potential of targeting miRNA551b-3p, the research team examined the impact of miRNA551b-3p inhibition on breast cancer growth in an orthotopic mouse model of TNBC. Treatment of TNBC tumors with anti-miRNA551b-3p resulted in reduced tumor growth compared to control microRNA, as well as reduced levels of STAT3 in the tumor tissue. Importantly, treatment with anti-miRNA551b-3p revealed no toxic effects in serum or major organs of the mice. 

Dr. Chaluvally-Raghavan’s studies of miRNA551b-3p provide a mechanistic explanation for metastatic disease progression in TNBC. His team’s identification of the “oncostatin signaling module” and demonstration of anti-miRNA551b-3p activity in a mouse model also provide new opportunities for therapeutic approaches to treat TNBC and other cancers employing this pathway in metastasis.

Publication:

Parashar D, Geethadevi A, Aure MR, et al. 2019. miRNA551b-3p activates an oncostatin signaling module for the progression of triple-negative breast cancer. Cell Reports 29:4389-4406.

Link:

Public and Technical Abstracts: Targeting miR551b to Prevent Tumor Formation and Metastasis of Triple-Negative Breast Cancer