Aneuploidy, defined as an abnormal number of chromosomes, is one of the hallmarks of cancer cells. It frequently results from defective mitotic division, whether due to checkpoint abnormalities, improper attachment of chromosomes to spindle microtubules, or multipolar division. Its consequences, however, are the subject of a genuine paradox: while aneuploidy is associated with tumorigenesis and an unfavorable prognosis, it can also slow tumor growth and promote cell death. Previous work on the matter has led to the notion of a threshold: moderate aneuploidy confers an advantage on cancer cells and promotes tumorigenesis, whereas excessive aneuploidy becomes deleterious and triggers cell death.
This observation sheds light on the therapeutic challenge addressed in this review. In breast cancer, chemotherapy combines DNA-targeting agents (anthracyclines) and spindle poisons (taxanes), the latter impairing chromosome segregation by inducing multipolar spindles. Yet this treatment benefits only 10 to 20% of patients, hence the importance of identifying biomarkers predictive of response in order to spare resistant patients from unnecessary treatments and their adverse effects. In a recent study comparing transcriptional and clinical data from three independent cohorts treated in the neoadjuvant setting, the team identified the microtubule-associated protein ATIP3 — encoded by the tumor suppressor gene MTUS1 — as a novel predictive biomarker. A low level of ATIP3 in the tumor predicts, with good accuracy, increased sensitivity to chemotherapy. This protein, already known to stabilize the microtubule network and to be underexpressed in 47% of invasive breast carcinomas and 85% of triple-negative tumors, also has prognostic value.
Immunofluorescence and time-lapse microscopy experiments showed that ATIP3 depletion induces mitotic defects — centrosome amplification and multipolar spindles — associated with poor chromosome segregation and increased aneuploidy, without altering sensitivity to anthracyclines. The addition of low doses of taxanes exacerbates all of these abnormalities, further increasing the proportion of aneuploid cells and cell death. In other words, taxane treatment cooperates with ATIP3 loss to reach a deleterious level of chromosomal instability. Consistently, 65% of tumors with low ATIP3 expression are aneuploid, compared with 42% of tumors with high expression, and 60% of the former display high chromosomal instability, compared with 40% of the latter.
These results support the idea that the frequency of aneuploidy could determine the response to taxane-based chemotherapy, a hypothesis currently being evaluated in a clinical study. Since aneuploidy is very rare in normal cells, compounds capable of impairing chromosome segregation could exhibit high specificity for cancer cells with few side effects.