MAML1 drives Notch and Hedgehog oncogenic pathways by inhibiting Itch activity in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous breast cancer subtype with poor patient outcomes. TNBC heterogeneity arises from multiple dysregulated pathways, including Notch and Hedgehog, which contribute to tumor initiation, progression, and drug resistance. Identifying common molecular regulators of TNBC aggressiveness is crucial for developing effective therapeutic strategies. Here, we demonstrate that the transcriptional coactivator MAML1 drives TNBC aggressiveness by regulating Notch1 and Gli1 stability through the E3 ubiquitin ligase Itch, functioning as an Itch-negative regulator. Mechanistically, MAML1 interacts with Itch via its PPQY motif and promotes K63-linked self-ubiquitylation of Itch, deregulating its expression/activity. Using a Maml1-deficient mouse model, we reveal an inverse correlation between MAML1 and Itch levels, where the loss of MAML1 stabilizes Itch and suppresses Notch1 and Gli1 activity. Conversely, MAML1 upregulation enhances Notch1 and Gli1 expression, driving accelerated TNBC tumor growth and faster multiorgan metastasis in vivo. Accordingly, we show that MAML1 is overexpressed in a cohort of TNBC patients, and the combined overexpression of MAML1/Notch1 and MAML1/Gli1 correlates with poor clinical outcomes by in silico analysis. Our findings establish a dual role for MAML1 as a transcriptional coactivator and a post-translational regulator of Itch, thereby amplifying Notch and Hedgehog oncogenic signaling. This study uncovers MAML1 as a key driver of TNBC progression and a potential therapeutic target for fighting TNBC aggressiveness and heterogeneity.

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Journal
Cell Death and Differentiation
Published
2025-11-21
DOI
https://doi.org/10.1038/s41418-025-01613-5
Primary Topic
Hedgehog Signaling Pathway Studies
Type
article
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article

MAML1 drives Notch and Hedgehog oncogenic pathways by inhibiting Itch activity in triple-negative breast cancer

Laura Di Magno, F. Di Fazio, Antongiulio Faggiano, Claudio Talora et al.
Cell Death and Differentiation
Hedgehog Signaling Pathway Studies
article

MAML1 drives Notch and Hedgehog oncogenic pathways by inhibiting Itch activity in triple-negative breast cancer

Laura Di Magno, F. Di Fazio, Antongiulio Faggiano, Claudio Talora, Samantha Cialfi, Alice Turdo, Diana Bellavia, Rocco Palermo, Carmine Nicoletti, Bruna Cerbelli, Giovanna Peruzzi, Biagio Palmisano, Sabrina Zema, Maria Pelullo, Maria Valeria Giuli, Lucia Di Marcotullio, Isabella Screpanti, Matilde Todaro, Gianluca Canettieri, Giulia d’Amati, Saula Checquolo, Martina Leopizzi, Daniel D’Andrea, Sara Di Savino
article en

Abstract

Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous breast cancer subtype with poor patient outcomes. TNBC heterogeneity arises from multiple dysregulated pathways, including Notch and Hedgehog, which contribute to tumor initiation, progression, and drug resistance. Identifying common molecular regulators of TNBC aggressiveness is crucial for developing effective therapeutic strategies. Here, we demonstrate that the transcriptional coactivator MAML1 drives TNBC aggressiveness by regulating Notch1 and Gli1 stability through the E3 ubiquitin ligase Itch, functioning as an Itch-negative regulator. Mechanistically, MAML1 interacts with Itch via its PPQY motif and promotes K63-linked self-ubiquitylation of Itch, deregulating its expression/activity. Using a Maml1-deficient mouse model, we reveal an inverse correlation between MAML1 and Itch levels, where the loss of MAML1 stabilizes Itch and suppresses Notch1 and Gli1 activity. Conversely, MAML1 upregulation enhances Notch1 and Gli1 expression, driving accelerated TNBC tumor growth and faster multiorgan metastasis in vivo. Accordingly, we show that MAML1 is overexpressed in a cohort of TNBC patients, and the combined overexpression of MAML1/Notch1 and MAML1/Gli1 correlates with poor clinical outcomes by in silico analysis. Our findings establish a dual role for MAML1 as a transcriptional coactivator and a post-translational regulator of Itch, thereby amplifying Notch and Hedgehog oncogenic signaling. This study uncovers MAML1 as a key driver of TNBC progression and a potential therapeutic target for fighting TNBC aggressiveness and heterogeneity.

Cell Death and Differentiation
Italian Institute of Technology (IT), University of Bristol (GB), Center for Nano Science and Technology (IT), Azienda Ospedaliera Universitaria Policlinico "Paolo Giaccone" di Palermo (IT), Institute for Complex Systems (IT), Istituto Pasteur (IT), National Research Council (IT), Interventi Geo Ambientali (Italy) (IT), Sapienza University of Rome (IT), University of Palermo (IT)
Openalex Percentile: Top 68%
Hedgehog Signaling Pathway Studies
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