Molecular classification of breast cancer remains a major challenge for better stratifying patients and guiding therapeutic decisions. In this context, this work focused on two microtubule-associated proteins: EB1, encoded by the MAPRE1 gene and involved in binding to microtubule plus-ends, and ATIP3, encoded by the MTUS1 gene, which acts as a negative regulator of EB1. The hypothesis explored was that the combined analysis of the expression of these two biomarkers, rather than each considered in isolation, could improve disease diagnosis and prognosis.
To establish the diagnostic value of MAPRE1, the authors exploited splicing array analyses performed on 45 benign and 120 malignant breast tumors. The prognostic component relied on transcriptomic analyses (Affymetrix U133 array) conducted on an exploratory cohort of 150 invasive breast cancers, then confirmed in two independent series of 130 and 155 samples, with the molecular data systematically compared against the patients' clinical parameters. Finally, a tissue microarray derived from an independent cohort of 212 invasive tumors was subjected to immunostaining using antibodies directed against EB1 and ATIP3, in order to validate the observations at the protein level.
The results confirm that MAPRE1 constitutes both a diagnostic and prognostic marker of breast cancer. High MAPRE1 expression is associated with tumor malignancy, high histological grade, and unfavorable clinical outcome. Most importantly, the combined analysis reveals that a signature combining a high level of MAPRE1 and a low level of MTUS1 is significantly linked to tumor aggressiveness and to reduced patient survival. Multivariate analysis illustrates the robustness of this combination: in the transcriptomic cohort, the "cluster 3" profile (high MAPRE1 / low MTUS1) was associated with an increased risk compared with the other groups (hazard ratio of 3.5; p = 0.015), whereas MAPRE1 expression alone lost its significance in multivariate analysis. Immunohistochemical studies confirmed these trends: the high EB1 / low ATIP3 protein profile was correlated with higher mortality.
This work thus underscores the value of studying the combinatorial expression of the EB1 and ATIP3 genes and proteins rather than considering each biomarker separately. The authors identify a population of particularly aggressive breast tumors, characterized by a high EB1 / low ATIP3 profile, which could be taken into account in the development of new molecular therapies.