BCL9/STAT3 regulation of transcriptional enhancer networks promote DCIS progression

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.npj Breast Cancer (2020) 6:12 ; https://doi.

Progression from ductal carcinoma in situ to invasive breast cancer: molecular features and clinical significance

“…Studies using MIND models to investigate the DCIS-IDC transition have reported on the underlying mechanisms of DCIS progression by using candidate promoters or suppressors. 140 , 149 , 202 , 219 For instance, Elsarraj et al targeted the B cell lymphoma-9 in a MIND model and found that it acted as a promoter of DCIS. 219 Compared to other DCIS xenografts (such as xenotransplants of DCIS cell lines or patient-derived DCIS into the mammary fat pad), MIND models better mimic human DCIS lesions with recapitulation of the initial ductal environment.…”

“… 140 , 149 , 202 , 219 For instance, Elsarraj et al targeted the B cell lymphoma-9 in a MIND model and found that it acted as a promoter of DCIS. 219 Compared to other DCIS xenografts (such as xenotransplants of DCIS cell lines or patient-derived DCIS into the mammary fat pad), MIND models better mimic human DCIS lesions with recapitulation of the initial ductal environment. 152 , 221 – 223 However, all these models are limited by the failure to explore the immune effect in DCIS progression (due to their immunodeficient hosts); they do not therefore fully mimic the natural evolution of human DCIS.…”

Supplementary Methods S1 from SPOP Mutations Target STING1 Signaling in Prostate Cancer and Create Therapeutic Vulnerabilities to PARP Inhibitor–Induced Growth Suppression

“…Published STAT3 ChIP-seq datasets were downloaded and analyzed utilizing Integrative Genomics Viewer (IGV) (28)(29)(30)(31)(32)(33)(34). A public database for aggregated analysis of STAT3 ChIP-seq data ENCODE Transcription Factor Targets dataset (https://maayanlab.cloud/Harmonizome/ gene_set/STAT3/ENCODE+Transcription+Factor+Targets) was provided to predict STAT3 targets (35).…”

The interactions of Bcl9/Bcl9L with β-catenin and Pygopus promote breast cancer growth, invasion, and metastasis

“…In breast cancer, BCL9 has been identified as a prognostic biomarker for high-risk human ductal carcinoma in situ (DCIS) [ 21 ]. Subsequently, BCL9 has been found to form a complex with STAT3 and to enhance the expression of the genes encoding for integrin β3 and its associated metalloproteinase MMP16 [ 22 ]. Another study has shown that nuclear BCL9L is associated with high nuclear grade and the expression of ErbB2/HER-2 in both DCIS and invasive ductal carcinoma (IDC) [ 23 ].…”