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BCL9/STAT3 regulation of transcriptional enhancer networks promote DCIS progression

Authors
  • Elsarraj, Hanan S.1
  • Hong, Yan1
  • Limback, Darlene1
  • Zhao, Ruonan1
  • Berger, Jenna2
  • Bishop, Stephanie C.3
  • Sabbagh, Aria4
  • Oppenheimer, Linzi1
  • Harper, Haleigh E.5
  • Tsimelzon, Anna6
  • Huang, Shixia7
  • Hilsenbeck, Susan G.8
  • Edwards, Dean P.7
  • Fontes, Joseph1
  • Fan, Fang1
  • Madan, Rashna1
  • Fangman, Ben5
  • Ellis, Ashley5
  • Tawfik, Ossama9
  • Persons, Diane L.1
  • And 7 more
  • 1 The University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS, 66160, USA , Kansas City (United States)
  • 2 Warren Alpert Medical School of Brown University, Providence, RI, 02912, USA , Providence (United States)
  • 3 South University, 709 Mall Blvd, Savannah, GA, 31406, USA , Savannah (United States)
  • 4 The University of Texas Health Science Center, Houston, TX, 77030, USA , Houston (United States)
  • 5 University of Kansas School of Medicine, The University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS, 66160, USA , Kansas City (United States)
  • 6 Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA , Houston (United States)
  • 7 Dan L. Duncan Cancer Center and Department of Molecular & Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA , Houston (United States)
  • 8 Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, C30, USA , Houston (United States)
  • 9 MAWD Pathology Group, St Luke’s Health System of Kansas City, 2750 Clay Edwards Dr, Kansas City, MO, 64116, USA , Kansas City (United States)
  • 10 Department of Anatomy and Cell Biology, The University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS, 66160, USA , Kansas City (United States)
  • 11 Department of Biostatistics, The University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS, 66160, USA , Kansas City (United States)
  • 12 Department of Pathology and Laboratory Medicine, MS 3045, The University of Kansas Medical Center, Kansas City, KS, 66160, USA , Kansas City (United States)
Type
Published Article
Journal
npj Breast Cancer
Publisher
Nature Publishing Group UK
Publication Date
Apr 24, 2020
Volume
6
Issue
1
Identifiers
DOI: 10.1038/s41523-020-0157-z
Source
Springer Nature
License
Green

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.

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