NOTCH3 inactivation increases triple negative breast cancer sensitivity to gefitinib by promoting EGFR tyrosine dephosphorylation and its intracellular arrest

Giulia Diluvio; Francesca Del Gaudio; Maria Valeria Giuli; Giulia Franciosa; Eugenia Giuliani; Rocco Palermo; Zein Mersini Besharat; Maria Gemma Pignataro; Alessandra Vacca; Giulia d'Amati; Marella Maroder; Claudio Talora; Carlo Capalbo; Diana Bellavia; Saula Checquolo

doi:10.1038/s41389-018-0051-9

NOTCH3 inactivation increases triple negative breast cancer sensitivity to gefitinib by promoting EGFR tyrosine dephosphorylation and its intracellular arrest

Giulia Diluvio, Francesca Del Gaudio, Maria Valeria Giuli, Giulia Franciosa, Eugenia Giuliani, Rocco Palermo, Zein Mersini Besharat, Maria Gemma Pignataro, Alessandra Vacca, Giulia d'Amati, Marella Maroder, Claudio Talora, Carlo Capalbo, Diana Bellavia, Saula Checquolo

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Abstract

Notch dysregulation has been implicated in numerous tumors, including triple-negative breast cancer (TNBC), which is the breast cancer subtype with the worst clinical outcome. However, the importance of individual receptors in TNBC and their specific mechanism of action remain to be elucidated, even if recent findings suggested a specific role of activated-Notch3 in a subset of TNBCs. Epidermal growth factor receptor (EGFR) is overexpressed in TNBCs but the use of anti-EGFR agents (including tyrosine kinase inhibitors, TKIs) has not been approved for the treatment of these patients, as clinical trials have shown disappointing results. Resistance to EGFR blockers is commonly reported. Here we show that Notch3-specific inhibition increases TNBC sensitivity to the TKI-gefitinib in TNBC-resistant cells. Mechanistically, we demonstrate that Notch3 is able to regulate the activated EGFR membrane localization into lipid rafts microdomains, as Notch3 inhibition, such as rafts depletion, induces the EGFR internalization and its intracellular arrest, without involving receptor degradation. Interestingly, these events are associated with the EGFR tyrosine dephosphorylation at Y1173 residue (but not at Y1068) by the protein tyrosine phosphatase H1 (PTPH1), thus suggesting its possible involvement in the observed Notch3-dependent TNBC sensitivity response to gefitinib. Consistent with this notion, a nuclear localization defect of phospho-EGFR is observed after combined blockade of EGFR and Notch3, which results in a decreased TNBC cell survival. Notably, we observed a significant correlation between EGFR and NOTCH3 expression levels by in silico gene expression and immunohistochemical analysis of human TNBC primary samples. Our findings strongly suggest that combined therapies of TKI-gefitinib with Notch3-specific suppression may be exploited as a drug combination advantage in TNBC treatment.

Original language	English
Article number	42
Journal	Critical Reviews in Oncogenesis
Volume	7
Pages (from-to)	1-15
ISSN	0893-9675
DOIs	https://doi.org/10.1038/s41389-018-0051-9
Publication status	Published - 2018

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NOTCH3 inactivation increases triple negative breast cancer sensitivity to gefitinib by promoting EGFR tyrosine dephosphorylation and its intracellular arrestFinal published version, 2.09 MB

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Diluvio, G., Del Gaudio, F., Giuli, M. V., Franciosa, G., Giuliani, E., Palermo, R., Besharat, Z. M., Pignataro, M. G., Vacca, A., d'Amati, G., Maroder, M., Talora, C., Capalbo, C., Bellavia, D., & Checquolo, S. (2018). NOTCH3 inactivation increases triple negative breast cancer sensitivity to gefitinib by promoting EGFR tyrosine dephosphorylation and its intracellular arrest. Critical Reviews in Oncogenesis, 7, 1-15. [42]. https://doi.org/10.1038/s41389-018-0051-9

NOTCH3 inactivation increases triple negative breast cancer sensitivity to gefitinib by promoting EGFR tyrosine dephosphorylation and its intracellular arrest. / Diluvio, Giulia; Del Gaudio, Francesca; Giuli, Maria Valeria et al.

In: Critical Reviews in Oncogenesis, Vol. 7, 42, 2018, p. 1-15.

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

Diluvio, G, Del Gaudio, F, Giuli, MV, Franciosa, G, Giuliani, E, Palermo, R, Besharat, ZM, Pignataro, MG, Vacca, A, d'Amati, G, Maroder, M, Talora, C, Capalbo, C, Bellavia, D & Checquolo, S 2018, 'NOTCH3 inactivation increases triple negative breast cancer sensitivity to gefitinib by promoting EGFR tyrosine dephosphorylation and its intracellular arrest', Critical Reviews in Oncogenesis, vol. 7, 42, pp. 1-15. https://doi.org/10.1038/s41389-018-0051-9

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title = "NOTCH3 inactivation increases triple negative breast cancer sensitivity to gefitinib by promoting EGFR tyrosine dephosphorylation and its intracellular arrest",

abstract = "Notch dysregulation has been implicated in numerous tumors, including triple-negative breast cancer (TNBC), which is the breast cancer subtype with the worst clinical outcome. However, the importance of individual receptors in TNBC and their specific mechanism of action remain to be elucidated, even if recent findings suggested a specific role of activated-Notch3 in a subset of TNBCs. Epidermal growth factor receptor (EGFR) is overexpressed in TNBCs but the use of anti-EGFR agents (including tyrosine kinase inhibitors, TKIs) has not been approved for the treatment of these patients, as clinical trials have shown disappointing results. Resistance to EGFR blockers is commonly reported. Here we show that Notch3-specific inhibition increases TNBC sensitivity to the TKI-gefitinib in TNBC-resistant cells. Mechanistically, we demonstrate that Notch3 is able to regulate the activated EGFR membrane localization into lipid rafts microdomains, as Notch3 inhibition, such as rafts depletion, induces the EGFR internalization and its intracellular arrest, without involving receptor degradation. Interestingly, these events are associated with the EGFR tyrosine dephosphorylation at Y1173 residue (but not at Y1068) by the protein tyrosine phosphatase H1 (PTPH1), thus suggesting its possible involvement in the observed Notch3-dependent TNBC sensitivity response to gefitinib. Consistent with this notion, a nuclear localization defect of phospho-EGFR is observed after combined blockade of EGFR and Notch3, which results in a decreased TNBC cell survival. Notably, we observed a significant correlation between EGFR and NOTCH3 expression levels by in silico gene expression and immunohistochemical analysis of human TNBC primary samples. Our findings strongly suggest that combined therapies of TKI-gefitinib with Notch3-specific suppression may be exploited as a drug combination advantage in TNBC treatment.",

author = "Giulia Diluvio and {Del Gaudio}, Francesca and Giuli, {Maria Valeria} and Giulia Franciosa and Eugenia Giuliani and Rocco Palermo and Besharat, {Zein Mersini} and Pignataro, {Maria Gemma} and Alessandra Vacca and Giulia d'Amati and Marella Maroder and Claudio Talora and Carlo Capalbo and Diana Bellavia and Saula Checquolo",

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doi = "10.1038/s41389-018-0051-9",

language = "English",

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T1 - NOTCH3 inactivation increases triple negative breast cancer sensitivity to gefitinib by promoting EGFR tyrosine dephosphorylation and its intracellular arrest

AU - Diluvio, Giulia

AU - Del Gaudio, Francesca

AU - Giuli, Maria Valeria

AU - Franciosa, Giulia

AU - Giuliani, Eugenia

AU - Palermo, Rocco

AU - Besharat, Zein Mersini

AU - Pignataro, Maria Gemma

AU - Vacca, Alessandra

AU - d'Amati, Giulia

AU - Maroder, Marella

AU - Talora, Claudio

AU - Capalbo, Carlo

AU - Bellavia, Diana

AU - Checquolo, Saula

PY - 2018

Y1 - 2018

N2 - Notch dysregulation has been implicated in numerous tumors, including triple-negative breast cancer (TNBC), which is the breast cancer subtype with the worst clinical outcome. However, the importance of individual receptors in TNBC and their specific mechanism of action remain to be elucidated, even if recent findings suggested a specific role of activated-Notch3 in a subset of TNBCs. Epidermal growth factor receptor (EGFR) is overexpressed in TNBCs but the use of anti-EGFR agents (including tyrosine kinase inhibitors, TKIs) has not been approved for the treatment of these patients, as clinical trials have shown disappointing results. Resistance to EGFR blockers is commonly reported. Here we show that Notch3-specific inhibition increases TNBC sensitivity to the TKI-gefitinib in TNBC-resistant cells. Mechanistically, we demonstrate that Notch3 is able to regulate the activated EGFR membrane localization into lipid rafts microdomains, as Notch3 inhibition, such as rafts depletion, induces the EGFR internalization and its intracellular arrest, without involving receptor degradation. Interestingly, these events are associated with the EGFR tyrosine dephosphorylation at Y1173 residue (but not at Y1068) by the protein tyrosine phosphatase H1 (PTPH1), thus suggesting its possible involvement in the observed Notch3-dependent TNBC sensitivity response to gefitinib. Consistent with this notion, a nuclear localization defect of phospho-EGFR is observed after combined blockade of EGFR and Notch3, which results in a decreased TNBC cell survival. Notably, we observed a significant correlation between EGFR and NOTCH3 expression levels by in silico gene expression and immunohistochemical analysis of human TNBC primary samples. Our findings strongly suggest that combined therapies of TKI-gefitinib with Notch3-specific suppression may be exploited as a drug combination advantage in TNBC treatment.

AB - Notch dysregulation has been implicated in numerous tumors, including triple-negative breast cancer (TNBC), which is the breast cancer subtype with the worst clinical outcome. However, the importance of individual receptors in TNBC and their specific mechanism of action remain to be elucidated, even if recent findings suggested a specific role of activated-Notch3 in a subset of TNBCs. Epidermal growth factor receptor (EGFR) is overexpressed in TNBCs but the use of anti-EGFR agents (including tyrosine kinase inhibitors, TKIs) has not been approved for the treatment of these patients, as clinical trials have shown disappointing results. Resistance to EGFR blockers is commonly reported. Here we show that Notch3-specific inhibition increases TNBC sensitivity to the TKI-gefitinib in TNBC-resistant cells. Mechanistically, we demonstrate that Notch3 is able to regulate the activated EGFR membrane localization into lipid rafts microdomains, as Notch3 inhibition, such as rafts depletion, induces the EGFR internalization and its intracellular arrest, without involving receptor degradation. Interestingly, these events are associated with the EGFR tyrosine dephosphorylation at Y1173 residue (but not at Y1068) by the protein tyrosine phosphatase H1 (PTPH1), thus suggesting its possible involvement in the observed Notch3-dependent TNBC sensitivity response to gefitinib. Consistent with this notion, a nuclear localization defect of phospho-EGFR is observed after combined blockade of EGFR and Notch3, which results in a decreased TNBC cell survival. Notably, we observed a significant correlation between EGFR and NOTCH3 expression levels by in silico gene expression and immunohistochemical analysis of human TNBC primary samples. Our findings strongly suggest that combined therapies of TKI-gefitinib with Notch3-specific suppression may be exploited as a drug combination advantage in TNBC treatment.

U2 - 10.1038/s41389-018-0051-9

DO - 10.1038/s41389-018-0051-9

M3 - Journal article

C2 - 29795369

SN - 0893-9675

VL - 7

SP - 1

EP - 15

JO - Critical Reviews in Oncogenesis

JF - Critical Reviews in Oncogenesis

M1 - 42

ER -

NOTCH3 inactivation increases triple negative breast cancer sensitivity to gefitinib by promoting EGFR tyrosine dephosphorylation and its intracellular arrest

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