2026-07-22T05:26:15Zhttps://repisalud.isciii.es/rest/oai/request
oai:repisalud.isciii.es:20.500.12105/236112024-11-28T23:45:41Zcom_20.500.12105_15322com_20.500.12105_2051col_20.500.12105_16967
Repisalud author Llinàs-Arias, Pere author Ensenyat-Mendez, Miquel author Íñiguez-Muñoz, Sandra author Orozco, Javier IJ author Valdez, Betsy author Salomon, Matthew P author Matsuba, Chikako author Solivellas-Pieras, Maria author Bedoya-López, Andrés F author Sesé, Borja author Mezger, Anja author Ormestad, Mattias author Unzueta, Fernando author Strand, Siri H author Boiko, Alexander D author Hwang, E Shelley author Cortés, Javier author DiNome, Maggie L author Esteller, Manel author Lupien, Mathieu author Marzese, Diego M 2024-10-09T06:33:42Z 2024-10-09T06:33:42Z 2023-11-28 Llinàs-Arias P, Ensenyat-Mendez M, Íñiguez-Muñoz S, Orozco JIJ, Valdez B, Salomon MP, et al. Chromatin insulation orchestrates matrix metalloproteinase gene cluster expression reprogramming in aggressive breast cancer tumors. Mol Cancer. 2023 Nov 28;22(1):190. 10.1186/s12943-023-01906-8 1476-4598 Molecular cancer https://hdl.handle.net/20.500.13003/20059 38017545 L2026846302 2-s2.0-85178059608 https://hdl.handle.net/20.500.12105/23611 1110529700002 Background: Triple-negative breast cancer (TNBC) is an aggressive subtype that exhibits a high incidence of distant metastases and lacks targeted therapeutic options. Here we explored how the epigenome contributes to matrix metalloprotease (MMP) dysregulation impacting tumor invasion, which is the first step of the metastatic process. Methods: We combined RNA expression and chromatin interaction data to identify insulator elements potentially associated with MMP gene expression and invasion. We employed CRISPR/Cas9 to disrupt the CCCTC-Binding Factor (CTCF) binding site on an insulator element downstream of the MMP8 gene (IE8) in two TNBC cellular models. We characterized these models by combining Hi-C, ATAC-seq, and RNA-seq with functional experiments to determine invasive ability. The potential of our findings to predict the progression of ductal carcinoma in situ (DCIS), was tested in data from clinical specimens. Results: We explored the clinical relevance of an insulator element located within the Chr11q22.2 locus, downstream of the MMP8 gene (IE8). This regulatory element resulted in a topologically associating domain (TAD) boundary that isolated nine MMP genes into two anti-correlated expression clusters. This expression pattern was associated with worse relapse-free (HR = 1.57 [1.06 - 2.33]; p = 0.023) and overall (HR = 2.65 [1.31 - 5.37], p = 0.005) survival of TNBC patients. After CRISPR/Cas9-mediated disruption of IE8, cancer cells showed a switch in the MMP expression signature, specifically downregulating the pro-invasive MMP1 gene and upregulating the antitumorigenic MMP8 gene, resulting in reduced invasive ability and collagen degradation. We observed that the MMP expression pattern predicts DCIS that eventually progresses into invasive ductal carcinomas (AUC = 0.77, p < 0.01). Conclusion: Our study demonstrates how the activation of an IE near the MMP8 gene determines the regional transcriptional regulation of MMP genes with opposing functional activity, ultimately influencing the invasive properties of aggressive forms of breast cancer. eng Chromatin insulation orchestrates matrix metalloproteinase gene cluster expression reprogramming in aggressive breast cancer tumors research article