A study coordinated by Sapienza University and published in the Nature group's journal Cell Death & Differentiation identified new molecular pathways involved in the onset and progression of triple-negative breast cancer, one of the most aggressive forms of breast cancer. This disease tends to progress very rapidly and can recur after some time, despite drug therapies.

The problem in treating this type of neoplasm is the almost total absence of molecules that can normally be used as targets for specific therapies, such as oestrogen and progesterone receptors and the HER2 receptor.

The study conducted by Sabrina Zema (Umberto Veronesi Foundation fellow) as part of the Sapienza research group coordinated by Diana Bellavia, with the support of the Pasteur Institute Italy – Cenci Bolognetti Foundation, opens up unprecedented prospects for the identification of new molecular targets in triple-negative breast cancer.

In particular, researchers focused their attention on the Mastermind-like1 (MAML1) protein, whose expression levels are often very high in this type of tumour.

In addition to its already known role in the transcription of genes involved in cell transformation, research identified a non-canonical role for MAML1 as a “molecular switch”, capable of orchestrating the activation of the main oncogenic signalling pathways that determine tumour cell transformation and enable them to acquire the malignant characteristics typical of triple-negative tumours.

Specifically, it was found that MAML1 is able to inhibit the Itch enzyme, which normally keeps many potentially oncogenic proteins under control. Therefore, its reduction may contribute to tumour development.

Thanks to more sensitive and precise experimental techniques and an integrated approach combining new experiments with data from the literature, it was possible to analyse in detail the interaction between MAML1 and Itch and understand its biological consequences. This allowed MAML1 to be assigned a completely new role in the regulation of proteins involved in tumour processes.

In light of this evidence, MAML1 emerges as a potential molecular target of therapeutic relevance in triple-negative breast cancer, opening up prospects for the development of innovative treatment strategies aimed at modulating tumour signalling networks.

‘Understanding these mechanisms,’ says Professor Diana Bellavia, ‘is essential for developing more targeted and effective therapies in the future and can have a real impact on health, demonstrating how important it is to invest in basic research. The study stems from experimental activities conducted in Sapienza laboratories, which prove Sapienza’s ability to produce original and internationally competitive knowledge.’

References: Sabrina Zema et al., MAML1 drives Notch and Hedgehog oncogenic pathways by inhibiting Itch activity in triple-negative breast cancer

DOI: https://www.nature.com/articles/s41418-025-01613-5

Further Information:

Diana Bellavia - Department of Molecular Medicine

diana.bellavia@uniroma1.it