Breast cancer remains one of the leading causes of death from malignant tumors in women. Invasion of cancer cells into the axillary lymph nodes is a frequent complication associated with a poor prognosis. To reduce tumor growth and lymph node dissemination prior to surgery, clinicians often resort to neoadjuvant chemotherapy based on taxanes, such as paclitaxel and docetaxel. These molecules target microtubules: initially regarded as "mitotic poisons" that block the spindle and chromosome segregation, they also prove capable, at very low concentrations, of reducing cell migration and motility without affecting growth. The major problem remains that only a small proportion of patients—on the order of 15 to 20%—genuinely benefit from chemotherapy, hence the need for biomarkers predictive of treatment resistance.
In this context, the team focused on the ATIP3 protein, the main product of the tumor suppressor gene MTUS1 and a microtubule stabilizer. Previous work had established that a low level of ATIP3 in breast tumors is associated with greater sensitivity to taxanes, through a mechanism involving centrosome amplification and the formation of multipolar spindles leading to cell death. The present study aimed to determine whether ATIP3 deficiency also influences the non-mitotic effects of paclitaxel, particularly on cell migration and lymph node metastasis.
The authors analyzed ATIP3 expression in a cohort of 133 breast cancer patients, classified according to lymph node involvement after neoadjuvant chemotherapy. Low ATIP3 levels were found to be associated with reduced axillary lymph node metastasis. At the functional level, approaches based on ATIP3 silencing by RNA interference, wound-healing assays, cell polarity assays, and microtubule imaging (confocal microscopy, TIRF videomicroscopy, EB1 comet tracking) showed that ATIP3 depletion increases migration, front-rear polarity, and the dynamics of microtubule "plus" ends. Paradoxically, this depletion nevertheless sensitizes cells to the inhibitory effects of paclitaxel on these same processes. In parallel, ATIP3 silencing increases the incorporation of a fluorescent Taxol derivative (Flutax-1) along the microtubule network.
These observations support a model in which alterations in microtubule plus-end dynamics, in ATIP3-deficient cells, promote the intracellular accumulation of paclitaxel. This phenomenon would account for the increased sensitivity of breast tumors to chemotherapy, reinforcing the value of ATIP3 as a predictive biomarker of treatment response.