Breast cancer remains one of the leading causes of death from malignant tumors among women worldwide. While hormone therapy and HER2-targeted therapies are standard treatments for certain subtypes, options remain limited for tumors that have become resistant or for triple-negative cancers, which express neither hormone receptors nor HER2. From this precision-medicine perspective, the identification of new prognostic and predictive biomarkers appears essential. The microtubule cytoskeleton, a long-standing target of anticancer chemotherapy—notably through taxanes, which stabilize microtubules—plays a central role in cell division, migration, and intracellular transport. Its organization is tightly regulated by a large set of microtubule-associated proteins, including kinesins and kinases. The authors had previously identified a panel of 17 microtubule-related (MT-Rel) genes differentially expressed in taxane-resistant tumors; the present study assesses their expression, prognostic value, and functional impact.
This work shows that 14 of these genes (KIF4A, ASPM, KIF20A, KIF14, TPX2, KIF18B, KIFC1, AURKB, KIF2C, GTSE1, KIF15, KIF11, RACGAP1, STMN1) are overexpressed in breast tumors compared with adjacent healthy tissue, and even more strongly in the triple-negative subtype. Six of them (KIF4A, ASPM, KIF20A, KIF14, TPX2, KIF18B) show overexpression greater than 10-fold, and four (KIF11, AURKB, TPX2, KIFC1) prove essential for cell survival. The overexpression of these 14 genes, as well as the underexpression of three other MT-Rel genes (MAST4, MAPT, MTUS1), is associated with an unfavorable prognosis, with reduced overall survival and relapse-free survival. The analysis suggests an overall imbalance favoring microtubule destabilization: the overexpressed genes encode proteins that destabilize or depolymerize microtubules, whereas the underexpressed genes encode stabilizers, the whole tending to increase microtubule dynamics in cancer cells.
A systems-biology approach, extended to the functional partners of the 17 genes, made it possible to reconstruct a network of 41 genes and 87 connections. This network is organized into three major subnetworks corresponding to stages of mitosis: spindle assembly, chromosome segregation, and cytokinesis. Defects in these processes, likely linked to altered microtubule dynamics, promote aneuploidy and chromosomal instability, recognized hallmarks of cancer and tumor aggressiveness. Three genes—AURKB, KIF4A, and RACGAP1—contribute simultaneously to all three subnetworks. The authors designate AURKB, TPX2, and KIF4A as priority targets, and highlight the value of the mitotic Aurora kinases and their substrates, for which specific inhibitors have already been the subject of clinical trials. In conclusion, targeting actionable MT-Rel proteins and their partners, alone or in combination with taxane-based chemotherapy, is presented as a therapeutic strategy worth exploring in breast cancer.