Date of Award
Doctor of Philosophy (PhD)
Breast cancer is a prevalent disease. Metastatic disease accounts for the majority of deaths from breast cancer, as patients with distant metastatic disease have a much worse prognosis than those with localized disease. In order to better understand why some breast cancers metastasize and others do not, it is critical to identify and elucidate the determinants of breast cancer progression. Post-transcriptional control of gene expression plays a central role in modulating transcriptional output. The interactions between messenger RNA cis-regulatory elements and trans-factors control coordinated gene expression states. Posttranscriptional regulatory programs that enhance metastatic capacity are selected for during cancer progression. In this study, the RNA binding protein Muscleblind-like 1 (MBNL1) is identified as a novel suppressor of breast cancer metastasis. MBNL1 loss-of-function contributes to the pathogenesis of myotonic dystrophy, a human genetic disease, but has no reported role in tumorigenesis or cancer progression. In this study, MBNL1 is identified as a suppressor of breast cancer metastasis. MBNL1 was found to suppress metastasis of human breast cancer cells in a xenograft mouse model. Additionally, MBNL1 transcript levels are significantly correlated with metastasis-free survival of breast cancer patients. MBNL1 depletion was also found to enhance the invasion and trans-endothelial migration capacity of breast cancer cells. Identification of endogenous MBNL1 protein-RNA interactions in breast cancer cells was carried out using HITS-CLIP. Transcriptome-wide analysis of MBNL1-dependent transcript stability and MBNL1 HITS-CLIP data revealed that globally, transcripts directly bound by MBNL1 are stabilized by MBNL1. Two transcripts, DBNL and TACC1, were identified as transcripts that were bound by MBNL1 and also destabilized upon MBNL1 depletion. Both DBNL and TACC1, when overexpressed in breast cancer cells depleted of MBNL1, were found to reverse the pro-invasive and metastatic colonization phenotypes observed upon MBNL1 depletion. Therefore, DBNL and TACC1 were identified as modulators of the metastasis suppressive effect of MBNL1 in breast cancer.
Fish, Lisa, "Investigating the Role of Muscleblind-Like 1 in the Suppression of Breast Cancer Progression" (2016). Student Theses and Dissertations. 421.