Delineating the Mechanisms of DANCR-Rac1 in Triple-negative Breast Cancer Invasion and Metastasis
DescriptionTriple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with poor prognosis, underlined by high rates of metastasis. Currently, treatments for TNBC are limited with unsatisfactory outcome, and identifying new therapeutic targets has become an urgent need. Noncoding RNAs of more than 200 nucleotides in length are termed long non-coding RNAs (lncRNAs), which have recently emerged as essential regulators in human health and diseases including TNBC. In particular, studies in TNBC cell lines and tissues have revealed overexpression of lncRNA DANCR (Differentiation Antagonizing Non-Protein Coding RNA), which plays an important role in driving the malignant behaviors of TNBC. However, the molecular mechanisms underlying the oncogenic activities of DANCR in TNBC remain poorly characterized. The interplay between lncRNA and RNA binding proteins (RBPs) plays a key role in mediating the functions of lncRNA. We have developed a CRISPR-Assisted RNA-Protein Interaction Detection (CARPID) method that dissects the molecular mechanisms of lncRNAs by illustrating their interactions with functional RBP partners in native cellular contexts. In preliminary studies, we have applied CARPID in TNBC cells and revealed that lncRNA DANCR interacts with Rac1, a small GTPase that plays essential roles in cell migration, invasion and metastasis. Functionally, silencing of DANCR expression disrupted Rac1 activation, which led to inhibited cell invasion and metastasis. Our preliminary results indicate a critical role of DANCR in regulating Rac1. To further dissect the molecular mechanism, we developed a CARPID-immunoprecipitation (CARPID-IP) platform in order to dissect the components and regulation of the DANCR-Rac1 complex. The overall goal of this grant is to elucidate the molecular mechanisms underlying the dynamic regulation of DANCR-Rac1 in TNBC progression, with a particular focus on invasion and metastasis. Results from our study will help identify new therapeutic strategies for TNBC.
|Effective start/end date||1/01/23 → …|