Date of Award

Spring 5-2022

Document Type

Honors Thesis

Degree Name

Bachelor of Science

Department

Biological Science

Advisor/Committee Chair

Ali S. Ropri

Committee Member

Jason I. Herschkowitz

Committee Member

Thomas Begley

Abstract

Triple negative breast cancer (TNBC) is defined by the lack of estrogen receptors (ER), the lack of progesterone receptors (PR), and normal human epidermal growth factor 2 (HER2) protein levels in breast tumors. Therefore, TNBC is an aggressive type of breast cancer due to limited treatment options for patients. Determining genes that regulate the progression of tumors to TNBC may help develop new therapeutic techniques. Many super-enhancer long noncoding RNAs (SElncRNAs) are found to be differentially expressed in cancer cells. Super-enhancer activity heavily influences target gene transcription and is often augmented through cis-acting SE-lncRNA activity. Therefore, we hypothesize cis-acting SE-lncRNAs may be significant in controlling the expression of neighboring genes with implications in triple negative breast cancer progression. To determine SE-lncRNAs with potential cis-acting mechanisms in controlling target gene expression and influencing progression, differential gene expression analysis of RNA-Seq data from 42 TNBC and 21 paired normal patient samples was performed. SE-lncRNAs with |log2 fold changes| ≥ 2 and adjusted p-values ≤ 0.05 were considered to be significantly differentially expressed. Furthermore, the genomic regions of the SE-lncRNAs were intersected with the genomic coordinates of super-enhancers classified in breast cancer progression: from normal to atypical ductal hyperplasia (AT1), ductal carcinoma in situ (DCIS), and finally, invasive ductal carcinoma (CA1). Six SE-lncRNAs; RBMS3-AS3, AL121906.1, SLC2A1-AS1, AC126696.3, AC126696.1, and TFAP2A-AS1; were selected as the top candidate cis-acting SE-lncRNAs with neighboring genes having implications in breast cancer. The neighboring genes have roles in regulating different canonical cancer pathways, such as the cell cycle, apoptosis, glucose transport, and amino acid transport. These SE-lncRNAs may serve as biomarkers and potential therapeutic targets against breast tumor progression, specifically for TNBC. Here, we knockdown two SE-lncRNAs, SLC2A1-AS1 and TFAP2A-AS1, in the MCF10A-CA1 (CA1) cell line to determine the effects on neighboring protein-coding genes, SLC2A1 and TFAP2A, respectively.

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