Role of 3D Chromatin Architecture in Breast Cancer Endocrine Resistance

Project Description Narrative:

Breast cancer is the second most common cancer among American women. In Wisconsin, it is estimated that 5,380 new breast cancer patients are diagnosed every year, 720 of whom are estimated to die from the disease. Although endocrine therapy, including tamoxifen (Tam) and aromatase inhibitors (AIs), is currently a standard and effective treatment for estrogen receptor α (ER) breast cancer patients, about one third of patients eventually develop acquired resistance to this hormonal therapy. The mechanisms of endocrine resistance may include loss of ER expression, alterations in cell cycle and cell survival signaling molecules, altered metabolism, crosstalk between ER and other signaling pathways.

This project’s research team has recently revealed three-dimensional (3D) chromatin organization might be linked to acquired tamoxifen resistance. In a new preliminary study, they examined a gained enhancer-promoter loop (EPL) of FOXN2 in a Tam-resistant (TR) breast cancer cell line, MCF7TR and found CRISPR/Cas9 deletion of such loop reduced FOXN2 gene expression, leading to impeding MCF7TR cell migration and invasion. This prompts them to hypothesize that these altered genome domains and looping genes are responsible for driving acquired tamoxifen resistance. Based on their published studies and preliminary data, project team members hypothesize that altered 3D chromatin domains/loops are responsible for driving acquired tamoxifen resistance. To test the hypothesis, they plan to conduct an integrative biology approach combining omics-seq profiling, computational analysis, functional and mechanistic characterization.