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Bcl11a Marks Mammary Progenitor Cells and Promotes Early Cellular Changes Associated with TNBC by Recruiting Chd8

57 Pages Posted: 2 Aug 2018   Sneak Peek Status: Under Review

Sara Pensa

University of Cambridge - Department of Pharmacology

Kyren A. Lazarus

University of Cambridge - Department of Pharmacology

Karsten Bach

University of Cambridge - Department of Pharmacology

Maria Francesca Santolla

University of Cambridge - Department of Pharmacology

Marcello Maggiolini

Università degli Studi della Calabria - Department of Pharmacy, Health and Nutritional Sciences

John Cassidy

University of Cambridge - Cancer Research UK Cambridge Institute

Ankita Sati Batra

University of Cambridge - Cancer Research UK Cambridge Institute

Alejandra Bruna

University of Cambridge - Cancer Research UK Cambridge Institute

Hisham Mohammed

University of Cambridge - Cancer Research UK Cambridge Institute

Pentao Liu

The University of Hong Kong - School of Biomedical Sciences

Jason S. Carroll

University of Cambridge - Cancer Research UK Cambridge Institute

Carlos Caldas

University of Cambridge - Cancer Research UK Cambridge Institute

John C. Marioni

University of Cambridge - Cancer Research UK Cambridge Institute

Walid T. Khaled

University of Cambridge - Department of Pharmacology

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Abstract

The transcription factor Bcl11a is an oncogene in triple negative breast cancer (TNBC), the subtype with the poorest prognostic outcome. Here we perform lineage-tracing combined with single-cell RNA-sequencing (scRNAseq) to show that Bcl11a is expressed in long lived luminal progenitor cells that expand in response to MPA/DMBA mediated oncogenesis. Moreover, we find that the deletion of Bcl11a protects mice from developing tumours in the Brca1/p53 mouse model of TNBC. scRNAseq of pre-cancerous mammary epithelial cells revealed that the deletion fully reverses an aberrant differentiation behaviour of the luminal progenitor compartment associated with Brca1 loss-of-function. Finally, we show that BCL11A interacts with and recruits the chromatin remodeller CHD8, which, we demonstrate is essential for mediating the oncogenic effects of BCL11A. In summary, BCL11A promotes early stages of TNBC via its formation of context specific protein interactions making them ideal candidate for drug development.

Suggested Citation

Pensa, Sara and Lazarus, Kyren A. and Bach, Karsten and Santolla, Maria Francesca and Maggiolini, Marcello and Cassidy, John and Batra, Ankita Sati and Bruna, Alejandra and Mohammed, Hisham and Liu, Pentao and Carroll, Jason S. and Caldas, Carlos and Marioni, John C. and Khaled, Walid T., Bcl11a Marks Mammary Progenitor Cells and Promotes Early Cellular Changes Associated with TNBC by Recruiting Chd8 (2018). Available at SSRN: https://ssrn.com/abstract=3224558 or http://dx.doi.org/10.2139/ssrn.3224558
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Sara Pensa

University of Cambridge - Department of Pharmacology

Trinity Ln
Cambridge, CB2 1TN
United Kingdom

Kyren A. Lazarus

University of Cambridge - Department of Pharmacology

Trinity Ln
Cambridge, CB2 1TN
United Kingdom

Karsten Bach

University of Cambridge - Department of Pharmacology

Trinity Ln
Cambridge, CB2 1TN
United Kingdom

Maria Francesca Santolla

University of Cambridge - Department of Pharmacology

Trinity Ln
Cambridge, CB2 1TN
United Kingdom

Marcello Maggiolini

Università degli Studi della Calabria - Department of Pharmacy, Health and Nutritional Sciences

Ponte Bucci, Cubo 3C
Rende, Cosenza 87036
Italy

John Cassidy

University of Cambridge - Cancer Research UK Cambridge Institute

Li Ka Shing Centre
Robinson Way
Cambridge, CB2 0RE
United Kingdom

Ankita Sati Batra

University of Cambridge - Cancer Research UK Cambridge Institute

Li Ka Shing Centre
Robinson Way
Cambridge, CB2 0RE
United Kingdom

Alejandra Bruna

University of Cambridge - Cancer Research UK Cambridge Institute

Li Ka Shing Centre
Robinson Way
Cambridge, CB2 0RE
United Kingdom

Hisham Mohammed

University of Cambridge - Cancer Research UK Cambridge Institute

Li Ka Shing Centre
Robinson Way
Cambridge, CB2 0RE
United Kingdom

Pentao Liu

The University of Hong Kong - School of Biomedical Sciences

Pokfulam Road
Hong Kong, Pokfulam HK
China

Jason S. Carroll

University of Cambridge - Cancer Research UK Cambridge Institute

Li Ka Shing Centre
Robinson Way
Cambridge, CB2 0RE
United Kingdom

Carlos Caldas

University of Cambridge - Cancer Research UK Cambridge Institute

Li Ka Shing Centre
Robinson Way
Cambridge, CB2 0RE
United Kingdom

John C. Marioni

University of Cambridge - Cancer Research UK Cambridge Institute

Li Ka Shing Centre
Robinson Way
Cambridge, CB2 0RE
United Kingdom

Walid T. Khaled (Contact Author)

University of Cambridge - Department of Pharmacology ( email )

Trinity Ln
Cambridge, CB2 1TN
United Kingdom