TY  - JOUR
T1  - CTCF-Mediated Insulator Dynamics Reprogram MMP Gene Expression Driving Aggressive Breast Cancer Invasion
A1  - Patrick Aidan Murphy
A1  - Ciara Louise Nolan
A1  - Brian Thomas Walsh
A1  - Kevin Michael Doyle
A1  - Declan Seamus Ryan
A1  - Eoin Patrick Brennan
JF  - Archive of International Journal of Cancer and Allied Science
JO  - Arch Int J Cancer Allied Sci
SN  - 3108-4834
Y1  - 2024
VL  - 4
IS  - 2
DO  - 10.51847/IjUQf9AsYu
SP  - 81
EP  - 95
N2  - Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer, marked by frequent metastasis and limited targeted therapies. The mechanisms by which epigenomic regulation influences matrix metalloprotease (MMP) activity—and thereby tumor invasiveness—remain incompletely understood. We integrated transcriptomic and chromatin conformation datasets to identify candidate insulator elements that might coordinate MMP gene expression and invasive potential. Using CRISPR/Cas9, we specifically disrupted a CTCF binding site within an insulator element downstream of MMP8 (IE8) in two TNBC cell models. The resulting cells were profiled through Hi-C, ATAC-seq, and RNA-seq, alongside functional assays to assess invasion. We also evaluated the prognostic relevance of these regulatory elements in clinical ductal carcinoma in situ (DCIS) samples. We characterized a functional insulator at the Chr11q22.2 locus (IE8) that establishes a TAD boundary, partitioning nine MMP genes into two inversely regulated clusters. This MMP expression architecture was linked to shorter relapse-free (HR = 1.57 [1.06–2.33]; p = 0.023) and overall survival (HR = 2.65 [1.31–5.37]; p = 0.005) in TNBC patients. CRISPR-mediated IE8 disruption reshaped the MMP expression landscape, suppressing the pro-invasive MMP1 while inducing the anti-tumorigenic MMP8, leading to reduced invasion and collagen degradation. Furthermore, this MMP signature predicted DCIS progression to invasive carcinoma (AUC = 0.77, p 
UR  - https://smerpub.com/article/ctcf-mediated-insulator-dynamics-reprogram-mmp-gene-expression-driving-aggressive-breast-cancer-inva-pib198kn7ixkacl
ER  -