Figure 3.

How centrosome amplification (CA) may fuel tumor evolution and generate intratumor heterogeneity in breast cancer. (A) A carcinogenic insult induces CA and also the ability to tolerate its deleterious effects (e.g., TP53 mutation), or (B) a carcinogenic insult induces the ability to tolerate the deleterious effects of CA (e.g., compromised checkpoints, enhanced proliferative potential) followed by (C) a separate insult that induces CA. (D) The cell clusters amplified centrosomes and the cell divides in a pseudobipolar fashion for many divisions. (E) CA does not induce aneuploidy yet (so progeny remain diploid or near-diploid, depending on other phenotypes that may have been acquired during tumor evolution that impact ploidy). (F) Whatever drove CA in the first place persists in the cell, and centrosomes undergo further amplification. (G) In a subsequent mitosis, centrosome clustering eventually results in chromosome missegregation. (H) Some cells may achieve a karyotype that is compatible with survival (orange and yellow cells), whereas others may not (gray apoptotic cells) especially if aneuploidy is too severe. (I) The karyotype of some cells may confer enhanced tumorigenic potential, which results in clonal expansion and population of the tumor. (J) Eventually, subclones may acquire superior karyotypes and also expand (red cells), resulting in a potentially heterogenous tumor population.