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^*

^*Corresponding author for this work

Department of Biotechnology and Biomedicine

Research output: Contribution to journal › Journal article › Research › peer-review

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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.

Original language	English
Article number	9
Journal	npj Breast Cancer
Volume	9
Number of pages	15
ISSN	2374-4677
DOIs	https://doi.org/10.1038/s41523-023-00513-6
Publication status	Published - 2023

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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, Article 9. https://doi.org/10.1038/s41523-023-00513-6

@article{3fd7e2a252e046a083cf2b97c2fa66db,

title = "TGFβ-mediated MMP13 secretion drives myoepithelial cell dependent breast cancer progression",

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.}",

year = "2023",

doi = "10.1038/s41523-023-00513-6",

language = "English",

volume = "9",

journal = "npj Breast Cancer",

issn = "2374-4677",

publisher = "Nature Publishing Group",

}

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, 9. https://doi.org/10.1038/s41523-023-00513-6

TY - JOUR

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.

PY - 2023

Y1 - 2023

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.

AB - 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.

U2 - 10.1038/s41523-023-00513-6

DO - 10.1038/s41523-023-00513-6

M3 - Journal article

C2 - 36864079

SN - 2374-4677

VL - 9

JO - npj Breast Cancer

JF - npj Breast Cancer

M1 - 9

ER -

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

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