Role of LBH in the Etiology of Basal-Subtype Triple-Negative Breast Cancer
Abstract
Basal-like Triple Negative Breast Cancers (B-TNBC) are highly lethal; yet effective treatments are lacking. The purpose of this grant is to investigate if Limb-Bud-and-Heart (LBH), a basal mammary stem cell transcriptional regulator and WNT target aberrantly overexpressed in 50 percent of B-TNBC, is a new molecular determinant driving the development of this aggressive breast cancer (BrCa) subtype. We are testing the hypothesis that LBH drives basal-like TNBC, which are highly metastatic and endocrine-resistant, by: (Aim 1) reprogramming luminal cells of-origin into basal stem-like cancer cells; (Aim 2) increasing the abundance of tumor/metastasis-initiating cancer stem cells (CSC); and (Aim3) promoting hormone receptor negativity. During year 1, we generated multiple LBH-dependent BrCa cell models, including patient-derived TNBC cells with inducible LBH knockdown and luminal MCF7 cells with inducible ectopic LBH expression. Focusing on Aim 2, we found LBH upregulates CSC abundance, sphere formation, and tumorigenicity in both B-TNBC and luminal BrCa, demonstrating LBH is a potent CSC driver. Ongoing RNA-Seq transcriptomic analysis (Aim 1) indicates LBH activates basal stem cell programs but represses luminal lineage/epithelial differentiation genes. Importantly, LBH downregulation decreases tumor initiation and metastasis of B-TNBC cells in vivo. This identifies LBH as B-TNBC oncogene and putative molecular target for anti-CSC therapy.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2020
- Accession Number
- AD1114477
Entities
People
- Karoline Briegel
Organizations
- University of Miami