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.
Highlights
It is currently believed that human Ductal carcinoma in situ (DCIS) is over diagnosed and over treated
Analysis of The Cancer Genome Atlas (TCGA) database showed significantly lower DNA methylation in the B Cell Lymphoma9 (BCL9) promoter region of luminal A and B breast cancers compared to control tissues (Supplementary Fig. 1e, f). These results suggest that aberrant elevated expression of BCL9 in breast cancers is driven by BCL9 genomic amplification and/or promoter hypomethylation
BCL9 protein expression by Western blot was investigated in five breast cancer cell lines including: MCF7 (ER+ PR+), T47D (ER+ PR+), CCH1 (DCIS Basal), DCIS.COM (DCIS Basal), SUM225 (DCIS HER2 + ) as well as MCF10A, and 293 T
Summary
It is currently believed that human Ductal carcinoma in situ (DCIS) is over diagnosed and over treated. DCIS is a non-obligate precursor to invasive breast cancer and due to recent advances in imaging technology and an increase in screening, there has been a significant increase in the rate of DCIS detection[1,2,3,4]. Despite this increase, the rate at which women present with late-stage invasive breast cancer has only marginally declined (~8%)[5]. DCIS is treated by surgery, mastectomy (for extensive disease) or lumpectomy plus radiation, and problematic anti-hormonal therapy for hormone receptor positive DCIS. There is a critical need for the discovery of cellular and molecular mechanisms by which some DCIS transition to invasive ductal carcinoma (IDC) which would elucidate biomarkers for DCIS risk stratification and help develop therapies for prevention of IDC
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