Targeting of mutant-p53 and MYC as a novel strategy to inhibit oncogenic SPAG5 activity in triple negative breast cancer - Research Article

Sep 21, 2026

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Breast cancer treatment benefits from biomarker-driven targeting in luminal and HER-2 enriched tumors, yet triple negative breast cancer (TNBC) remains difficult due to heterogeneity and limited prognostic markers. The study focuses on sperm associated Antigen 5 (SPAG5), a mitotic spindle component frequently overexpressed in advanced breast cancer, including TNBC. It analyzes how mutant p53 and MYC cooperate, alongside YAP-driven transcriptional regulation, to control SPAG5 expression and assess impacts on TNBC cell behavior and therapy sensitivity.

LanguageEnglish

CategoryResearch & Report

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Pages15

Reading Time38 min

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Introduction

Materials and Methods

Cell lines and culture conditions

Cell Death and Disease context

[www.nature.com/cddis](www.nature.com/cddis) ARTICLE OPEN Targeting of mutant-p53 and MYC as a novel strategy to inhibit oncogenic SPAG5 activity in triple negative breast cancer Valeria Canu 1, Sebastiano Vaccarella 1, Andrea Sacconi2, Claudio Pulito 1, Frauke Goeman 3, Matteo Pallocca2,4, Daniela Rutigliano 1, Sima Lev 5, Sabrina Strano3 ✉ and Giovanni Blandino 1 ✉ © The Author(s) 2024 INTRODUCTION Breast cancer (BC) is the most frequent cancer among women worldwide. Current histopathological classiﬁcation and targeted treatment signiﬁcantly improved prognosis of luminal and HER-2 enriched tumors, whereas triple negative breast cancer (TNBC), routinely classiﬁed as a group of highly heterogenous disease, still lacks of speciﬁc prognostic and therapeutic biomarkers [1] . Beyond transcriptomic classiﬁcation of TNBC into Basal-like 1/2, mesenchymal, luminal and androgen receptor positive subtype, further stratiﬁcation is critical to dissect their genetical landscape and plan effective anticancer therapy [2–4] . Sperm associated Antigen 5 (SPAG5) is an essential component of mitotic spindle, needed for chromosome alignment and sister chromatids segregation during anaphase [5–7] . Frequently overexpressed in advanced BC [8], including TNBC, SPAG5 is considered to be an efﬁcient prognostic factor [9, 10] . Ampliﬁcation of SPAG5 gene is associated with BC growth, positive lymph node status, anthracycline vulnerability, poor prognosis, and TP53 mutations [11] . TP53 is the most common mutated gene across cancers, including BC. TP53 gene, encode for a transcription factor involved in cell cycle regulation, apoptosis, DNA repair, and metabolic processes [12] . In BC, TP53 mutations account for about 30% but their frequency markedly increases to ~80% in TNBC [6] . Major alterations in the TP53 gene are missense mutations, which are frequently located in the DNA binding domain (R175, R248, R249, R273, R282), and result in gain of oncogenic activity [13] . In cancer cells, the oncogenic function of mutant p53 proteins (mut-p53) can be enhanced through interaction with other transcription factors or coactivator, including the Hippo pathway transducer YAP [14, 15] . Previously, we showed that SPAG5 depletion strongly impaired proliferation and migration of TNBC cell lines, and identiﬁed SPAG5 as a direct transcriptional target of YAP/TAZ/ TEAD [16] . Here, we analyzed the expression levels of SPAG5, YAP and p53 transcripts in METABRIC dataset, and found that the expression levels of YAP and SPAG5 increased along with p53 mutations in more aggressive BC histotypes. This, was associated with elevated level of TP53 mutant-dependent MYC signature. MYC depletion, or inhibition by small-molecule inhibitors, reduced SPAG5 expression, clonogenicity, and sensitized TNBC cells lines to cisplatin, 5-ﬂuorouracil and paclitaxel. We further found that SPAG5 is a direct target of MYC, and collectively showed that mut-p53, YAP and MYC coordinately function to regulate SPAG5 expression. Our data, introduce mut-p53-MYC-SPAG5 expression as bona ﬁde predictors of patient’s outcome, and reliable biomarkers for effective anticancer therapies. MATERIALS AND METHODS Cell lines and culture conditions All cell lines were obtained from ATCC. Human cell line MDA-MB-231 was maintained in Dulbecco’s Modiﬁed Eagle Medium (DMEM) (Invitrogen- 1Translational Oncology Research Unit, Department of Research, Diagnosis and Innovative Technologies, IRCCS Regina Elena National Cancer Institute, Rome, Italy. 2Biostatistics, Bioinformatics and Clinical Trial Center, IRCCS Regina Elena National Cancer Institute, Rome, Italy. 3Department of Research, Diagnosis and Innovative Technologies, UOSD SAFU, Translational Research Area, IRCCS Regina Elena National Cancer Institute, Rome, Italy. 4Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy. 5Department of Molecular Cell Biology, Weizmann Institute of Science, Reho

FAQs

Why is SPAG5 relevant in triple negative breast cancer?

SPAG5 is a mitotic spindle component involved in chromosome alignment and segregation, and it is frequently overexpressed in advanced breast cancer, including TNBC, where it is associated with prognosis and clinical features.

How do mutant p53 and MYC relate to SPAG5 regulation?

The study reports that mutant p53 and MYC signatures align with increased SPAG5 expression, and that SPAG5 is a direct target of MYC, with coordinated regulation involving mut-p53, YAP, and MYC.

What did inhibiting MYC or depleting MYC affect in TNBC cells?

MYC depletion or small-molecule inhibition reduced SPAG5 expression and clonogenicity, and sensitized TNBC cell lines to cisplatin, 5-fluorouracil, and paclitaxel.

Sep 21, 2026

Uploaded by Ezra