Breast cancer remains the leading cause of death from malignant tumours among women worldwide. In the era of precision medicine, which aims to tailor treatment to each individual patient, identifying robust biomarkers represents a major challenge for guiding therapeutic decisions and supporting the development of targeted therapies. This review focuses on ATIP3, a protein with anticancer properties encoded by the candidate tumour suppressor gene MTUS1, whose expression levels are markedly reduced in breast cancer.
The MTUS1 gene, located at chromosomal position 8p22 — a region frequently lost in many solid tumours — gives rise through alternative splicing to several isoforms, including ATIP1 and ATIP3. ATIP3, the predominant isoform in peripheral tissues, is a microtubule-associated protein that regulates microtubule dynamics. It notably interacts with the protein EB1 and contributes to maintaining the integrity of the mitotic spindle. The authors recall that the decreased expression of MTUS1 in cancers appears to result from mechanisms of gene expression dysregulation, in particular epigenetic ones (promoter methylation, regulation by microRNAs and long non-coding RNAs), rather than from genomic alterations.
Clinically, analyses of patient cohorts have established that a low level of ATIP3 is significantly associated with an unfavourable prognosis and reduced five-year survival, including in metastatic forms. The prognostic value is strengthened when ATIP3 expression is combined with that of its partner EB1, which is overexpressed in aggressive tumours: across five independent cohorts, the combination of both markers proved more informative than either taken alone. ATIP3 also emerges as a predictive biomarker of response to taxane-based chemotherapies (paclitaxel, docetaxel), which benefit only a small fraction (15 to 20%) of primary tumours. Counterintuitively, it is ATIP3 deficiency that sensitises tumour cells to low doses of taxanes: it promotes the accumulation of paclitaxel along interphase microtubules and induces, during mitosis, centrosome amplification and the formation of multipolar spindles, sources of aneuploidy. Beyond a certain threshold, these abnormalities cause massive cell death.
Thus, aneuploidy, a marker of aggressive tumours, also constitutes a therapeutically exploitable Achilles' heel. The authors envisage strategies aimed at restoring physiological levels of MTUS1 — epigenetic drugs, antagomirs — or at targeting the molecular complexes involving ATIP3. With approximately 170,000 new cases of ATIP3-deficient triple-negative tumours worldwide each year, such a targeted approach would represent a significant advance in addressing a major public health problem, with other ATIP3-deficient solid tumours potentially also benefiting from it.