Centrosome amplification: a suspect in breast cancer and racial disparities

  1. Ritu Aneja
  1. Department of Biology, Georgia State University, Atlanta, Georgia, USA
  1. Correspondence should be addressed to R Aneja; Email: raneja{at}gsu.edu
  1. Figure 1

    Centrosome amplification (A) and abnormally augmented centrosome volume (B) in malignant breast tissue.

  2. Figure 2

    Potential deleterious consequences of CA on chromosome stability based on the class of merotely. (A) Multi-merotely: Many microtubules are attached to the incorrect spindle pole, resulting in chromosome missegregation and aneuploid daughter cells. (B) Equi-merotely: Roughly an equivalent number of microtubules are attached to the two spindle poles, so chromosome lagging occurs due to opposite polar forces. In most cases, the chromosome segregates to the right cell as a micronucleus (1). Occasionally, however, the chromosome missegregates and either forms a micronucleus or rejoins nuclear chromosomes (2). Lagging chromosomes can become trapped in and damaged by the cleavage furrow. They are either removed from the cleavage site or the cleavage furrow regresses, resulting in polyploidization, which may itself be tumorigenic, along with consequent further CA (3).

  3. 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 pseudo-bipolar 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.

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