TGFβ-mediated MMP13 secretion drives myoepithelial cell dependent breast cancer progression

Shayin V Gibson; Elena Tomas Bort; Lucía Rodríguez-Fernández; Michael D Allen; Jennifer J Gomm; Iain Goulding; Ulrich Auf dem Keller; Andrea Agnoletto; Cathrin Brisken; Barrie Peck; Angus J Cameron; John F Marshall; J Louise Jones; Edward P Carter; Richard P Grose

doi:10.1038/s41523-023-00513-6

TGFβ-mediated MMP13 secretion drives myoepithelial cell dependent breast cancer progression

Shayin V Gibson, Elena Tomas Bort, Lucía Rodríguez-Fernández, Michael D Allen, Jennifer J Gomm, Iain Goulding, Ulrich Auf dem Keller, Andrea Agnoletto, Cathrin Brisken, Barrie Peck, Angus J Cameron, John F Marshall, J Louise Jones, Edward P Carter, Richard P Grose

Department of Life Sciences

Research output: Contribution to journal › Article › peer-review

13 Citations (SciVal)

Abstract

Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer. Virtually all women with DCIS are treated, despite evidence suggesting up to half would remain with stable, non-threatening, disease. Overtreatment thus presents a pressing issue in DCIS management. To understand the role of the normally tumour suppressive myoepithelial cell in disease progression we present a 3D in vitro model incorporating both luminal and myoepithelial cells in physiomimetic conditions. We demonstrate that DCIS-associated myoepithelial cells promote striking myoepithelial-led invasion of luminal cells, mediated by the collagenase MMP13 through a non-canonical TGFβ - EP300 pathway. In vivo, MMP13 expression is associated with stromal invasion in a murine model of DCIS progression and is elevated in myoepithelial cells of clinical high-grade DCIS cases. Our data identify a key role for myoepithelial-derived MMP13 in facilitating DCIS progression and point the way towards a robust marker for risk stratification in DCIS patients.

Original language	English
Article number	9
Pages (from-to)	9
Journal	NPJ breast cancer
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41523-023-00513-6
Publication status	Published - 2 Mar 2023

Bibliographical note

Funding Information:
We thank Prof. Susana Godhino, Dr. Oliver Pearce and Prof. Jude Fitzgibbon for their comments on the manuscript and Nadia Rahman for her help with the histology. We also thank Dr. Ann-Marie Baker for her expert advice on RNAscope experiments and pathologists Dr. Fred John Nnaemeka Obiajulu and Dr. Philip Elliott for their guidance on analysis of clinical tissue. We would also like to acknowledge Dr. Charles Mein for his help with the RNA sequencing and the role of the Breast Cancer Now Tissue Bank in collecting and making available the samples used in the generation of this publication. This work was supported by Cancer Research UK (CRUK) (C10847/A27781), Breast Cancer Now (2017NovPR988), Barts Charity (MRC0173), Rosetrees Trust (M501-F1), CRUK Microscopy Core Service Grant (C16420/A18066) and by a CRUK UK Centre Grant to Barts Cancer Institute (C355/A25137).

Data availability
All RNAseq data generated during the study are publicly available and have been deposited in Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/) with the accession code GSE224401. Invasive Breast Carcinoma data are available on cBioportal (https://www.cbioportal.org) and were generated by the TCGA research Network (https://www.cancer.gov/tcga). EP300 Kaplan-Meier plots were generated with Kaplan-Meier Plotter (https://kmplot.com) using proteomic data available in the PRIDE Archive – proteomics data repository under the accession number PXD005692. All further datasets generated and analysed in this study are available from the corresponding author upon reasonable request.

ASJC Scopus subject areas

Pharmacology (medical)
Oncology
Radiology Nuclear Medicine and imaging

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41523-023-00513-6Licence: CC BY

Cite this

Gibson, S. V., Tomas Bort, E., Rodríguez-Fernández, L., Allen, M. D., Gomm, J. J., Goulding, I., Auf dem Keller, U., Agnoletto, A., Brisken, C., Peck, B., Cameron, A. J., Marshall, J. F., Jones, J. L., Carter, E. P., & Grose, R. P. (2023). TGFβ-mediated MMP13 secretion drives myoepithelial cell dependent breast cancer progression. NPJ breast cancer, 9(1), 9. Article 9. https://doi.org/10.1038/s41523-023-00513-6

Gibson, SV, Tomas Bort, E, Rodríguez-Fernández, L, Allen, MD, Gomm, JJ, Goulding, I, Auf dem Keller, U, Agnoletto, A, Brisken, C, Peck, B, Cameron, AJ, Marshall, JF, Jones, JL, Carter, EP & Grose, RP 2023, 'TGFβ-mediated MMP13 secretion drives myoepithelial cell dependent breast cancer progression', NPJ breast cancer, vol. 9, no. 1, 9, pp. 9. https://doi.org/10.1038/s41523-023-00513-6

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abstract = "Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer. Virtually all women with DCIS are treated, despite evidence suggesting up to half would remain with stable, non-threatening, disease. Overtreatment thus presents a pressing issue in DCIS management. To understand the role of the normally tumour suppressive myoepithelial cell in disease progression we present a 3D in vitro model incorporating both luminal and myoepithelial cells in physiomimetic conditions. We demonstrate that DCIS-associated myoepithelial cells promote striking myoepithelial-led invasion of luminal cells, mediated by the collagenase MMP13 through a non-canonical TGFβ - EP300 pathway. In vivo, MMP13 expression is associated with stromal invasion in a murine model of DCIS progression and is elevated in myoepithelial cells of clinical high-grade DCIS cases. Our data identify a key role for myoepithelial-derived MMP13 in facilitating DCIS progression and point the way towards a robust marker for risk stratification in DCIS patients.",

author = "Gibson, \{Shayin V\} and \{Tomas Bort\}, Elena and Luc{\'i}a Rodr{\'i}guez-Fern{\'a}ndez and Allen, \{Michael D\} and Gomm, \{Jennifer J\} and Iain Goulding and \{Auf dem Keller\}, Ulrich and Andrea Agnoletto and Cathrin Brisken and Barrie Peck and Cameron, \{Angus J\} and Marshall, \{John F\} and Jones, \{J Louise\} and Carter, \{Edward P\} and Grose, \{Richard P\}",

note = "Funding Information: We thank Prof. Susana Godhino, Dr. Oliver Pearce and Prof. Jude Fitzgibbon for their comments on the manuscript and Nadia Rahman for her help with the histology. We also thank Dr. Ann-Marie Baker for her expert advice on RNAscope experiments and pathologists Dr. Fred John Nnaemeka Obiajulu and Dr. Philip Elliott for their guidance on analysis of clinical tissue. We would also like to acknowledge Dr. Charles Mein for his help with the RNA sequencing and the role of the Breast Cancer Now Tissue Bank in collecting and making available the samples used in the generation of this publication. This work was supported by Cancer Research UK (CRUK) (C10847/A27781), Breast Cancer Now (2017NovPR988), Barts Charity (MRC0173), Rosetrees Trust (M501-F1), CRUK Microscopy Core Service Grant (C16420/A18066) and by a CRUK UK Centre Grant to Barts Cancer Institute (C355/A25137). Data availability All RNAseq data generated during the study are publicly available and have been deposited in Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/) with the accession code GSE224401. Invasive Breast Carcinoma data are available on cBioportal (https://www.cbioportal.org) and were generated by the TCGA research Network (https://www.cancer.gov/tcga). EP300 Kaplan-Meier plots were generated with Kaplan-Meier Plotter (https://kmplot.com) using proteomic data available in the PRIDE Archive – proteomics data repository under the accession number PXD005692. All further datasets generated and analysed in this study are available from the corresponding author upon reasonable request.",

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T1 - TGFβ-mediated MMP13 secretion drives myoepithelial cell dependent breast cancer progression

AU - Gibson, Shayin V

AU - Tomas Bort, Elena

AU - Rodríguez-Fernández, Lucía

AU - Allen, Michael D

AU - Gomm, Jennifer J

AU - Goulding, Iain

AU - Auf dem Keller, Ulrich

AU - Agnoletto, Andrea

AU - Brisken, Cathrin

AU - Peck, Barrie

AU - Cameron, Angus J

AU - Marshall, John F

AU - Jones, J Louise

AU - Carter, Edward P

AU - Grose, Richard P

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N2 - Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer. Virtually all women with DCIS are treated, despite evidence suggesting up to half would remain with stable, non-threatening, disease. Overtreatment thus presents a pressing issue in DCIS management. To understand the role of the normally tumour suppressive myoepithelial cell in disease progression we present a 3D in vitro model incorporating both luminal and myoepithelial cells in physiomimetic conditions. We demonstrate that DCIS-associated myoepithelial cells promote striking myoepithelial-led invasion of luminal cells, mediated by the collagenase MMP13 through a non-canonical TGFβ - EP300 pathway. In vivo, MMP13 expression is associated with stromal invasion in a murine model of DCIS progression and is elevated in myoepithelial cells of clinical high-grade DCIS cases. Our data identify a key role for myoepithelial-derived MMP13 in facilitating DCIS progression and point the way towards a robust marker for risk stratification in DCIS patients.

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TGFβ-mediated MMP13 secretion drives myoepithelial cell dependent breast cancer progression

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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