A SRC-slug-TGFβ2 signaling axis drives poor outcomes in triple-negative breast cancers

Charlotte Zoe Angel; Shannon Beattie; Ezanee Azlina Mohamad Hanif; Micheal P Ryan; Francisco D C Guerra Liberal; Shu-Dong Zhang; Scott Monteith; Niamh E Buckley; Emma Parker; Shannon Haynes; Alexander J McIntyre; Paula Haddock; Madina Sharifova; Cristina M Branco; Paul B Mullan

doi:10.1186/s12964-024-01793-6

A SRC-slug-TGFβ2 signaling axis drives poor outcomes in triple-negative breast cancers

Charlotte Zoe Angel, Shannon Beattie, Ezanee Azlina Mohamad Hanif, Micheal P Ryan, Francisco D C Guerra Liberal, Shu-Dong Zhang, Scott Monteith, Niamh E Buckley, Emma Parker, Shannon Haynes, Alexander J McIntyre, Paula Haddock, Madina Sharifova, Cristina M Branco, Paul B Mullan

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Abstract

BACKGROUND: Treatment options for the Triple-Negative Breast Cancer (TNBC) subtype remain limited and the outcome for patients with advanced TNBC is very poor. The standard of care is chemotherapy, but approximately 50% of tumors develop resistance.

METHODS: We performed gene expression profiling of 58 TNBC tumor samples by microarray, comparing chemosensitive with chemoresistant tumors, which revealed that one of the top upregulated genes was TGFβ2. A connectivity mapping bioinformatics analysis predicted that the SRC inhibitor Dasatinib was a potential pharmacological inhibitor of chemoresistant TNBCs. Claudin-low TNBC cell lines were selected to represent poor-outcome, chemoresistant TNBC, for in vitro experiments and in vivo models.

RESULTS: In vitro, we identified a signaling axis linking SRC, AKT and ERK2, which in turn upregulated the stability of the transcription factors, Slug and Snail. Slug was shown to repress TGFβ2-antisense 1 to promote TGFβ2 signaling, upregulating cell survival via apoptosis and DNA-damage responses. Additionally, an orthotopic allograft in vivo model demonstrated that the SRC inhibitor Dasatinib reduced tumor growth as a single agent, and enhanced responses to the TNBC mainstay drug, Epirubicin.

CONCLUSION: Targeting the SRC-Slug-TGFβ2 axis may therefore lead to better treatment options and improve patient outcomes in this highly aggressive subpopulation of TNBCs.

Original language	English
Article number	454
Journal	Cell communication and signaling : CCS
Volume	22
Issue number	1
Early online date	26 Sept 2024
DOIs	https://doi.org/10.1186/s12964-024-01793-6
Publication status	Published online - 26 Sept 2024

Bibliographical note

Keywords

Triple Negative Breast Neoplasms/genetics
Humans
Signal Transduction/drug effects
Transforming Growth Factor beta2/metabolism
src-Family Kinases/metabolism
Cell Line, Tumor
Snail Family Transcription Factors/metabolism
Female
Animals
Dasatinib/pharmacology
Mice
Gene Expression Regulation, Neoplastic/drug effects
Drug Resistance, Neoplasm/genetics

UN SDGs

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

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10.1186/s12964-024-01793-6Licence: CC BY

2024-0926-Angel-etal-Cell-Commu-SRC-TGFB2-TNBC-s12964-024-01793-6Final published version, 7.39 MBLicence: CC BY

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Angel, C. Z., Beattie, S., Hanif, E. A. M., Ryan, M. P., Guerra Liberal, F. D. C., Zhang, S.-D., Monteith, S., Buckley, N. E., Parker, E., Haynes, S., McIntyre, A. J., Haddock, P., Sharifova, M., Branco, C. M., & Mullan, P. B. (2024). A SRC-slug-TGFβ2 signaling axis drives poor outcomes in triple-negative breast cancers. Cell communication and signaling : CCS, 22(1), Article 454. Advance online publication. https://doi.org/10.1186/s12964-024-01793-6

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title = "A SRC-slug-TGFβ2 signaling axis drives poor outcomes in triple-negative breast cancers",

abstract = "BACKGROUND: Treatment options for the Triple-Negative Breast Cancer (TNBC) subtype remain limited and the outcome for patients with advanced TNBC is very poor. The standard of care is chemotherapy, but approximately 50% of tumors develop resistance.METHODS: We performed gene expression profiling of 58 TNBC tumor samples by microarray, comparing chemosensitive with chemoresistant tumors, which revealed that one of the top upregulated genes was TGFβ2. A connectivity mapping bioinformatics analysis predicted that the SRC inhibitor Dasatinib was a potential pharmacological inhibitor of chemoresistant TNBCs. Claudin-low TNBC cell lines were selected to represent poor-outcome, chemoresistant TNBC, for in vitro experiments and in vivo models.RESULTS: In vitro, we identified a signaling axis linking SRC, AKT and ERK2, which in turn upregulated the stability of the transcription factors, Slug and Snail. Slug was shown to repress TGFβ2-antisense 1 to promote TGFβ2 signaling, upregulating cell survival via apoptosis and DNA-damage responses. Additionally, an orthotopic allograft in vivo model demonstrated that the SRC inhibitor Dasatinib reduced tumor growth as a single agent, and enhanced responses to the TNBC mainstay drug, Epirubicin.CONCLUSION: Targeting the SRC-Slug-TGFβ2 axis may therefore lead to better treatment options and improve patient outcomes in this highly aggressive subpopulation of TNBCs.",

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Angel, CZ, Beattie, S, Hanif, EAM, Ryan, MP, Guerra Liberal, FDC, Zhang, S-D, Monteith, S, Buckley, NE, Parker, E, Haynes, S, McIntyre, AJ, Haddock, P, Sharifova, M, Branco, CM & Mullan, PB 2024, 'A SRC-slug-TGFβ2 signaling axis drives poor outcomes in triple-negative breast cancers', Cell communication and signaling : CCS, vol. 22, no. 1, 454. https://doi.org/10.1186/s12964-024-01793-6

TY - JOUR

T1 - A SRC-slug-TGFβ2 signaling axis drives poor outcomes in triple-negative breast cancers

AU - Angel, Charlotte Zoe

AU - Beattie, Shannon

AU - Hanif, Ezanee Azlina Mohamad

AU - Ryan, Micheal P

AU - Guerra Liberal, Francisco D C

AU - Zhang, Shu-Dong

AU - Monteith, Scott

AU - Buckley, Niamh E

AU - Parker, Emma

AU - Haynes, Shannon

AU - McIntyre, Alexander J

AU - Haddock, Paula

AU - Sharifova, Madina

AU - Branco, Cristina M

AU - Mullan, Paul B

PY - 2024/9/26

Y1 - 2024/9/26

N2 - BACKGROUND: Treatment options for the Triple-Negative Breast Cancer (TNBC) subtype remain limited and the outcome for patients with advanced TNBC is very poor. The standard of care is chemotherapy, but approximately 50% of tumors develop resistance.METHODS: We performed gene expression profiling of 58 TNBC tumor samples by microarray, comparing chemosensitive with chemoresistant tumors, which revealed that one of the top upregulated genes was TGFβ2. A connectivity mapping bioinformatics analysis predicted that the SRC inhibitor Dasatinib was a potential pharmacological inhibitor of chemoresistant TNBCs. Claudin-low TNBC cell lines were selected to represent poor-outcome, chemoresistant TNBC, for in vitro experiments and in vivo models.RESULTS: In vitro, we identified a signaling axis linking SRC, AKT and ERK2, which in turn upregulated the stability of the transcription factors, Slug and Snail. Slug was shown to repress TGFβ2-antisense 1 to promote TGFβ2 signaling, upregulating cell survival via apoptosis and DNA-damage responses. Additionally, an orthotopic allograft in vivo model demonstrated that the SRC inhibitor Dasatinib reduced tumor growth as a single agent, and enhanced responses to the TNBC mainstay drug, Epirubicin.CONCLUSION: Targeting the SRC-Slug-TGFβ2 axis may therefore lead to better treatment options and improve patient outcomes in this highly aggressive subpopulation of TNBCs.

AB - BACKGROUND: Treatment options for the Triple-Negative Breast Cancer (TNBC) subtype remain limited and the outcome for patients with advanced TNBC is very poor. The standard of care is chemotherapy, but approximately 50% of tumors develop resistance.METHODS: We performed gene expression profiling of 58 TNBC tumor samples by microarray, comparing chemosensitive with chemoresistant tumors, which revealed that one of the top upregulated genes was TGFβ2. A connectivity mapping bioinformatics analysis predicted that the SRC inhibitor Dasatinib was a potential pharmacological inhibitor of chemoresistant TNBCs. Claudin-low TNBC cell lines were selected to represent poor-outcome, chemoresistant TNBC, for in vitro experiments and in vivo models.RESULTS: In vitro, we identified a signaling axis linking SRC, AKT and ERK2, which in turn upregulated the stability of the transcription factors, Slug and Snail. Slug was shown to repress TGFβ2-antisense 1 to promote TGFβ2 signaling, upregulating cell survival via apoptosis and DNA-damage responses. Additionally, an orthotopic allograft in vivo model demonstrated that the SRC inhibitor Dasatinib reduced tumor growth as a single agent, and enhanced responses to the TNBC mainstay drug, Epirubicin.CONCLUSION: Targeting the SRC-Slug-TGFβ2 axis may therefore lead to better treatment options and improve patient outcomes in this highly aggressive subpopulation of TNBCs.

KW - Triple Negative Breast Neoplasms/genetics

KW - Humans

KW - Signal Transduction/drug effects

KW - Transforming Growth Factor beta2/metabolism

KW - src-Family Kinases/metabolism

KW - Cell Line, Tumor

KW - Snail Family Transcription Factors/metabolism

KW - Female

KW - Animals

KW - Dasatinib/pharmacology

KW - Mice

KW - Gene Expression Regulation, Neoplastic/drug effects

KW - Drug Resistance, Neoplasm/genetics

U2 - 10.1186/s12964-024-01793-6

DO - 10.1186/s12964-024-01793-6

M3 - Article

C2 - 39327614

SN - 1478-811X

VL - 22

JO - Cell communication and signaling : CCS

JF - Cell communication and signaling : CCS

IS - 1

M1 - 454

ER -

A SRC-slug-TGFβ2 signaling axis drives poor outcomes in triple-negative breast cancers

Abstract

Bibliographical note

Keywords

UN SDGs

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