CIAP1 regulates the EGFR/Snai2 axis in triple-negative breast cancer cells

Maria Teresa Majorini; Giacomo Manenti; Miguel Mano; Loris De Cecco; Annalisa Conti; Patrizia Pinciroli; Enrico Fontanella; Elda Tagliabue; Claudia Chiodoni; Mario Paolo Colombo; Domenico Delia; Daniele Lecis

doi:10.1038/s41418-018-0100-0

CIAP1 regulates the EGFR/Snai2 axis in triple-negative breast cancer cells

Maria Teresa Majorini, Giacomo Manenti, Miguel Mano, Loris De Cecco, Annalisa Conti, Patrizia Pinciroli, Enrico Fontanella, Elda Tagliabue, Claudia Chiodoni, Mario Paolo Colombo, Domenico Delia, Daniele Lecis^*

^*Corresponding author for this work

Cardiovascular Sciences

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

19 Citations (Scopus)

Abstract

Inhibitor of apoptosis (IAP) proteins constitute a family of conserved molecules that regulate both apoptosis and receptor signaling. They are often deregulated in cancer cells and represent potential targets for therapy. In our work, we investigated the effect of IAP inhibition in vivo to identify novel downstream genes expressed in an IAP-dependent manner that could contribute to cancer aggressiveness. To this end, immunocompromised mice engrafted subcutaneously with the triple-negative breast cancer MDA-MB231 cell line were treated with SM83, a Smac mimetic that acts as a pan-IAP inhibitor, and tumor nodules were profiled for gene expression. SM83 reduced the expression of Snai2, an epithelial-to-mesenchymal transition factor often associated with increased stem-like properties and metastatic potential especially in breast cancer cells. By testing several breast cancer cell lines, we demonstrated that Snai2 downregulation prevents cell motility and that its expression is promoted by cIAP1. In fact, the chemical or genetic inhibition of cIAP1 blocked epidermal growth factor receptor (EGFR)-dependent activation of the mitogen-activated protein kinase (MAPK) pathway and caused the reduction of Snai2 transcription levels. In a number of breast cancer cell lines, cIAP1 depletion also resulted in a reduction of EGFR protein levels which derived from the decrease of its gene transcription, though, paradoxically, the silencing of cIAP1 promoted EGFR protein stability rather than its degradation. Finally, we provided evidence that IAP inhibition displays an anti-tumor and anti-metastasis effect in vivo. In conclusion, our work indicates that IAP-targeted therapy could contribute to EGFR inhibition and to the reduction of its downstream mediators. This approach could be particularly effective in tumors characterized by high levels of EGFR and Snai2, such as triple-negative breast cancer.

Original language	English
Pages (from-to)	2147-2164
Number of pages	18
Journal	CELL DEATH AND DIFFERENTIATION
Volume	25
Issue number	12
DOIs	https://doi.org/10.1038/s41418-018-0100-0
Publication status	Published - 19 Apr 2018

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10.1038/s41418-018-0100-0

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@article{8a86a9720b8b464da53e4670f05f7a2c,

title = "CIAP1 regulates the EGFR/Snai2 axis in triple-negative breast cancer cells",

abstract = "Inhibitor of apoptosis (IAP) proteins constitute a family of conserved molecules that regulate both apoptosis and receptor signaling. They are often deregulated in cancer cells and represent potential targets for therapy. In our work, we investigated the effect of IAP inhibition in vivo to identify novel downstream genes expressed in an IAP-dependent manner that could contribute to cancer aggressiveness. To this end, immunocompromised mice engrafted subcutaneously with the triple-negative breast cancer MDA-MB231 cell line were treated with SM83, a Smac mimetic that acts as a pan-IAP inhibitor, and tumor nodules were profiled for gene expression. SM83 reduced the expression of Snai2, an epithelial-to-mesenchymal transition factor often associated with increased stem-like properties and metastatic potential especially in breast cancer cells. By testing several breast cancer cell lines, we demonstrated that Snai2 downregulation prevents cell motility and that its expression is promoted by cIAP1. In fact, the chemical or genetic inhibition of cIAP1 blocked epidermal growth factor receptor (EGFR)-dependent activation of the mitogen-activated protein kinase (MAPK) pathway and caused the reduction of Snai2 transcription levels. In a number of breast cancer cell lines, cIAP1 depletion also resulted in a reduction of EGFR protein levels which derived from the decrease of its gene transcription, though, paradoxically, the silencing of cIAP1 promoted EGFR protein stability rather than its degradation. Finally, we provided evidence that IAP inhibition displays an anti-tumor and anti-metastasis effect in vivo. In conclusion, our work indicates that IAP-targeted therapy could contribute to EGFR inhibition and to the reduction of its downstream mediators. This approach could be particularly effective in tumors characterized by high levels of EGFR and Snai2, such as triple-negative breast cancer.",

author = "Majorini, {Maria Teresa} and Giacomo Manenti and Miguel Mano and {De Cecco}, Loris and Annalisa Conti and Patrizia Pinciroli and Enrico Fontanella and Elda Tagliabue and Claudia Chiodoni and Colombo, {Mario Paolo} and Domenico Delia and Daniele Lecis",

note = "Funding Information: FFPE samples were prepared and stained by the Immunohistochemistry facility of INT, SM83 was designed and synthesized in collaboration with the University of Milan, and in particular with Pierfausto Seneci, Leonardo Manzoni, and Carmelo Drago. MCF10A bearing mutated EGFR were provided by Alberto Bardelli, c-Cbl-expressing plasmid was a kind gift from Pier Paolo Di Fiore. We are grateful to Matteo Dugo for continuous bioinformatic support and TCGA analysis, and to Mads Gyrd-Hansen for helpful discussion of the data. Laura Botti provided invaluable help during the revision of this manuscript. This study was supported by the Italian Association for Cancer Research (AIRC, MCO-9998, DD) and by the Italian Ministry of Health (5 ? 1000 Funds-2013). Funding Information: Acknowledgements FFPE samples were prepared and stained by the Immunohistochemistry facility of INT, SM83 was designed and synthesized in collaboration with the University of Milan, and in particular with Pierfausto Seneci, Leonardo Manzoni, and Carmelo Drago. MCF10A bearing mutated EGFR were provided by Alberto Bardelli, c-Cbl-expressing plasmid was a kind gift from Pier Paolo Di Fiore. We are grateful to Matteo Dugo for continuous bioinformatic support and TCGA analysis, and to Mads Gyrd-Hansen for helpful discussion of the data. Laura Botti provided invaluable help during the revision of this manuscript. This study was supported by the Italian Association for Cancer Research (AIRC, MCO-9998, DD) and by the Italian Ministry of Health (5 × 1000 Funds - 2013). Publisher Copyright: {\textcopyright} The Author(s) 2018.",

year = "2018",

month = apr,

day = "19",

doi = "10.1038/s41418-018-0100-0",

language = "English",

volume = "25",

pages = "2147--2164",

journal = "CELL DEATH AND DIFFERENTIATION",

issn = "1350-9047",

publisher = "Nature Publishing Group",

number = "12",

}

TY - JOUR

T1 - CIAP1 regulates the EGFR/Snai2 axis in triple-negative breast cancer cells

AU - Majorini, Maria Teresa

AU - Manenti, Giacomo

AU - Mano, Miguel

AU - De Cecco, Loris

AU - Conti, Annalisa

AU - Pinciroli, Patrizia

AU - Fontanella, Enrico

AU - Tagliabue, Elda

AU - Chiodoni, Claudia

AU - Colombo, Mario Paolo

AU - Delia, Domenico

AU - Lecis, Daniele

N1 - Funding Information: FFPE samples were prepared and stained by the Immunohistochemistry facility of INT, SM83 was designed and synthesized in collaboration with the University of Milan, and in particular with Pierfausto Seneci, Leonardo Manzoni, and Carmelo Drago. MCF10A bearing mutated EGFR were provided by Alberto Bardelli, c-Cbl-expressing plasmid was a kind gift from Pier Paolo Di Fiore. We are grateful to Matteo Dugo for continuous bioinformatic support and TCGA analysis, and to Mads Gyrd-Hansen for helpful discussion of the data. Laura Botti provided invaluable help during the revision of this manuscript. This study was supported by the Italian Association for Cancer Research (AIRC, MCO-9998, DD) and by the Italian Ministry of Health (5 ? 1000 Funds-2013). Funding Information: Acknowledgements FFPE samples were prepared and stained by the Immunohistochemistry facility of INT, SM83 was designed and synthesized in collaboration with the University of Milan, and in particular with Pierfausto Seneci, Leonardo Manzoni, and Carmelo Drago. MCF10A bearing mutated EGFR were provided by Alberto Bardelli, c-Cbl-expressing plasmid was a kind gift from Pier Paolo Di Fiore. We are grateful to Matteo Dugo for continuous bioinformatic support and TCGA analysis, and to Mads Gyrd-Hansen for helpful discussion of the data. Laura Botti provided invaluable help during the revision of this manuscript. This study was supported by the Italian Association for Cancer Research (AIRC, MCO-9998, DD) and by the Italian Ministry of Health (5 × 1000 Funds - 2013). Publisher Copyright: © The Author(s) 2018.

PY - 2018/4/19

Y1 - 2018/4/19

N2 - Inhibitor of apoptosis (IAP) proteins constitute a family of conserved molecules that regulate both apoptosis and receptor signaling. They are often deregulated in cancer cells and represent potential targets for therapy. In our work, we investigated the effect of IAP inhibition in vivo to identify novel downstream genes expressed in an IAP-dependent manner that could contribute to cancer aggressiveness. To this end, immunocompromised mice engrafted subcutaneously with the triple-negative breast cancer MDA-MB231 cell line were treated with SM83, a Smac mimetic that acts as a pan-IAP inhibitor, and tumor nodules were profiled for gene expression. SM83 reduced the expression of Snai2, an epithelial-to-mesenchymal transition factor often associated with increased stem-like properties and metastatic potential especially in breast cancer cells. By testing several breast cancer cell lines, we demonstrated that Snai2 downregulation prevents cell motility and that its expression is promoted by cIAP1. In fact, the chemical or genetic inhibition of cIAP1 blocked epidermal growth factor receptor (EGFR)-dependent activation of the mitogen-activated protein kinase (MAPK) pathway and caused the reduction of Snai2 transcription levels. In a number of breast cancer cell lines, cIAP1 depletion also resulted in a reduction of EGFR protein levels which derived from the decrease of its gene transcription, though, paradoxically, the silencing of cIAP1 promoted EGFR protein stability rather than its degradation. Finally, we provided evidence that IAP inhibition displays an anti-tumor and anti-metastasis effect in vivo. In conclusion, our work indicates that IAP-targeted therapy could contribute to EGFR inhibition and to the reduction of its downstream mediators. This approach could be particularly effective in tumors characterized by high levels of EGFR and Snai2, such as triple-negative breast cancer.

AB - Inhibitor of apoptosis (IAP) proteins constitute a family of conserved molecules that regulate both apoptosis and receptor signaling. They are often deregulated in cancer cells and represent potential targets for therapy. In our work, we investigated the effect of IAP inhibition in vivo to identify novel downstream genes expressed in an IAP-dependent manner that could contribute to cancer aggressiveness. To this end, immunocompromised mice engrafted subcutaneously with the triple-negative breast cancer MDA-MB231 cell line were treated with SM83, a Smac mimetic that acts as a pan-IAP inhibitor, and tumor nodules were profiled for gene expression. SM83 reduced the expression of Snai2, an epithelial-to-mesenchymal transition factor often associated with increased stem-like properties and metastatic potential especially in breast cancer cells. By testing several breast cancer cell lines, we demonstrated that Snai2 downregulation prevents cell motility and that its expression is promoted by cIAP1. In fact, the chemical or genetic inhibition of cIAP1 blocked epidermal growth factor receptor (EGFR)-dependent activation of the mitogen-activated protein kinase (MAPK) pathway and caused the reduction of Snai2 transcription levels. In a number of breast cancer cell lines, cIAP1 depletion also resulted in a reduction of EGFR protein levels which derived from the decrease of its gene transcription, though, paradoxically, the silencing of cIAP1 promoted EGFR protein stability rather than its degradation. Finally, we provided evidence that IAP inhibition displays an anti-tumor and anti-metastasis effect in vivo. In conclusion, our work indicates that IAP-targeted therapy could contribute to EGFR inhibition and to the reduction of its downstream mediators. This approach could be particularly effective in tumors characterized by high levels of EGFR and Snai2, such as triple-negative breast cancer.

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DO - 10.1038/s41418-018-0100-0

M3 - Article

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AN - SCOPUS:85045735884

SN - 1350-9047

VL - 25

SP - 2147

EP - 2164

JO - CELL DEATH AND DIFFERENTIATION

JF - CELL DEATH AND DIFFERENTIATION

IS - 12

ER -

CIAP1 regulates the EGFR/Snai2 axis in triple-negative breast cancer cells

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