Investigating the Role of LncRNA-75 in TGF-β Signaling and Breast Cancer Progression

Abstract

The progression of breast cancer to the metastatic stage has severe clinical implications and accounts for the majority of cancer-related deaths. Understanding the molecular mechanisms that drive metastasis is therefore essential to improving diagnosis and treatment. Of the many pathways involved in cancer pathogenesis, the transforming growth β (TGF-β)/SMAD signaling pathway plays critical yet disparate roles by suppressing proliferation while promoting the epithelial-mesenchymal transition (EMT), a major hallmark of metastasis. Recent research has also implicated long noncoding RNAs (lncRNAs)—noncoding RNA transcripts greater than 200 nucleotides in length—in the development and progression of cancer, although relatively few transcripts are well-characterized. Using microarray gene expression data, our lab identified a number of lncRNAs that are differentially expressed in cancerous cells and may function in the context of the TGF-β signaling pathway. From this screen, the TGF-β-induced lncRNA-75 was selected for further study. We show that knocking down lncRNA-75 induces senescence, promotes cell cycle arrest, suppresses proliferation, and enhances the epithelial gene expression signature. We also explore whether lncRNA-75 functions with the oncogenic Y-box-binding protein 1 (YB-1) to enhance the TGF-β signaling response by disrupting the interaction between SMAD7 and the TGF-β type I receptor. Taken together, our findings indicate that lncRNA-75 functions in a context-dependent manner to oppose TGF-β’s growth inhibitory effect, as well as prolong the TGF-β signaling response and promote EMT. Further clarifying the role of lncRNA-75 in cancer progression and developing it as a therapeutic target may help improve the current standard of cancer care, which we discuss in the context of breast cancer disparities across the United States.