BCL9/STAT3 regulation of transcriptional enhancer networks promote DCIS progression
| Autor: | Cristian Coarfa, Ruonan Zhao, Fariba Behbod, Aria Sabbagh, Ossama Tawfik, Katherine I. Swenson-Fields, Rashna Madan, Diane L. Persons, Shixia Huang, Darlene Limback, Haleigh E. Harper, Timothy A. Fields, Yan Hong, Hanan S. Elsarraj, Susan G. Hilsenbeck, Joseph D. Fontes, Andrew K. Godwin, Dean P. Edwards, Linzi Oppenheimer, Stephanie C Bishop, Ashley L. Ellis, Ben Fangman, Jenna Berger, Anna Tsimelzon, Jeffrey Thompson, Fang Fan, Christy R. Hagan |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Biology Ductal carcinoma lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens lcsh:RC254-282 Article Chromatin Cancer prevention 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Breast cancer Oncology BCL9 Downregulation and upregulation 030220 oncology & carcinogenesis biology.protein Cancer research Pharmacology (medical) Radiology Nuclear Medicine and imaging MMP16 Enhancer STAT3 skin and connective tissue diseases Transcription factor |
| Zdroj: | NPJ Breast Cancer npj Breast Cancer, Vol 6, Iss 1, Pp 1-14 (2020) |
| ISSN: | 2374-4677 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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