Breast cancer remains the most common malignancy in women worldwide and, despite the therapeutic advances of the past decade, it still represents a major public health challenge. The clinical management of this heterogeneous disease relies on well-established clinicopathological features and on molecular biomarkers, including estrogen and progesterone receptors as well as the HER2 oncogene. Classification into molecular subtypes (luminal, HER2-positive, triple-negative) guides treatment decisions, yet tumors belonging to the same subtype retain considerable variability in prognosis and treatment response. In the context of precision medicine, the identification of novel prognostic biomarkers is therefore needed to distinguish patients with an unfavorable clinical course who might benefit from personalized therapies.
This review focuses on the microtubule cytoskeleton, whose assembly and dynamics are regulated by a large family of microtubule-associated proteins. Some of these proteins exert an oncogenic effect, while others act as tumor suppressors in breast cancer. The authors survey current knowledge on microtubule-associated tumor suppressors (collectively referred to by the acronym MATS) and assess their potential value as prognostic biomarkers. Several of these proteins—notably APC, ATIP3, BRCA1, CYLD, FHIT, LZTS1, merlin/NF2, NAV3, RASSF1A and VHL—share a localization within the microtubule network, the centrosome or the mitotic spindle, and generally contribute to microtubule stabilization. Their expression is frequently reduced in primary breast tumors, in proportions that vary depending on the protein considered, and results from inactivation mechanisms such as loss of heterozygosity, promoter hypermethylation, targeting by microRNAs, or post-translational degradation.
One of the major contributions of this review concerns the value of a combinatorial approach. The authors present recent work showing that the joint assessment of the expression of ATIP3, a tumor suppressor, and EB1, a protein with an oncogenic effect, improves prognostic prediction compared with the use of either biomarker alone. By classifying tumors according to the four possible combinations of low or high expression of these two markers, it emerges that tumors characterized by high EB1 and low ATIP3 expression have a more unfavorable prognosis than all other groups (p < 0.05). These observations are discussed in light of the growing complexity of the protein networks formed by microtubule-associated proteins, which coordinate the dynamics and functions of these structures. The authors conclude that further studies are needed to evaluate the prognostic value of the combined expression of different microtubule-associated tumor suppressors and their interaction partners in breast cancer.