BCL9/STAT3 regulation of transcriptional enhancer networks promote DCIS progression

Year: 2020

Type: article

Abstract: The molecular processes by which some human ductal carcinoma in situ (DCIS) lesions advance to the more aggressive form, while others remain indolent, are largely unknown. Experiments utilizing a patient-derived (PDX) DCIS Mouse INtraDuctal (MIND) animal model combined with ChIP-exo and RNA sequencing revealed that the formation of protein complexes between B Cell Lymphoma-9 (BCL9), phosphoserine 727 STAT3 (PS-727-STAT3) and non-STAT3 transcription factors on chromatin enhancers lead to subsequent transcription of key drivers of DCIS malignancy. Downregulation of two such targets, integrin β3 and its associated metalloproteinase, MMP16, resulted in a significant inhibition of DCIS invasive progression. Finally, in vivo targeting of BCL9, using rosemary extract, resulted in significant inhibition of DCIS malignancy in both cell line and PDX DCIS MIND animal models. As such, our studies provide compelling evidence for future testing of rosemary extract as a chemopreventive agent in breast cancer.

Source: npj Breast Cancer

DOI: 10.1038/s41523-020-0157-z

Institutions: University of Kansas Medical Center, Brown University, South University, The University of Texas Health Science Center at Houston, University of Kansas, Baylor College of Medicine, Dan L Duncan Comprehensive Cancer Center, Saint Luke's Health System

Language: English

Topic: Cytokine Signaling Pathways and Interactions

Subfield: Oncology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,990

Funders: Breast Cancer Research Foundation, Kansas IDeA Network of Biomedical Research Excellence, National Institutes of Health, Cancer Center, University of Kansas, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Environmental Health Sciences

Awards: Role of Cancer Stem Cells in Malignant Progression of Ductal Carcinoma in Situ., G1423423360, Identifying the Molecular and Cellular Basis of Invasive Phenotype in Human DCIS, G2198094389, G2458811206, G2921881625, G3120329307, G5465708471, (PQC3) Essential Role of BCL9 in Promotion of Human DCIS to Invasive Ductal Carci, G8271546232, G835355920, G862694305, G9000240210, G9000248580, Kansas IDeA Network of Biomedical Research Excellence 5, Gulf Coast Center for Precision Environmental Health, The Kansas Institute for Precision Medicine, Baylor College of Medicine Cancer Center - Cancer Center Support Grant, The University of Kansas Cancer Center

OpenAlex ID: W3020694770