The natural history of breast cancer remains largely undefined. More than 50% of clinical specimens exhibit aneuploidy. Among these aneuploid cancers, nearly half have chromosome copy numbers approaching tetraploid. The high incidence of aneuploidy in advanced breast cancer is thought to be a byproduct of chromosome mis-segregation resulting from mutations in tumor suppressor genes regulating cell cycle checkpoints and corresponding to disease progression. However, recent large-scale sequencing projects have revealed that most tumors contain approximately 14–20 different mutant genes, suggesting heterogeneity exists throughout the genomes of cancer cells. This notion revives the concept that aneuploidy resulting from chromosome mis-segregation or other similar mechanisms may play an active role leading to transformation and disease progression.

A novel p21-activated kinase 6 (PAK6) was recently identified to be an androgen receptor (AR) and estrogen receptor (ER) interacting protein. An estrogen-stimulated PAK6 activation was observed in BT474 breast cancer cells. This activation is mediated by estrogen-stimulated activation of PKA. At the cellular level, active PAK6 promotes transformation to metastatic phenotypes in MCF7 breast cancer cells as evidenced by increases in cell motility, matrigel invasion, and soft agar growth. Further characterization of MCF7 cells expressing a constitutively active PAK6 mutant revealed an accumulation of cells with higher ploidy as compared to that of parental cells. Using a proteomic approach to determine the PAK6 downstream target, we identified that Cdt1, a DNA pre-replicative complex subunit, is overexpressed in response to PAK6 activation. In eukaryotes, the expression and stability of Cdt1 are strictly regulated to ensure only one round of DNA replication in each cell cycle. Deregulated overexpression of Cdt1 has previously been demonstrated to induce aneuploidy and malignant transformation due to re-initiation of DNA replication within the same S-phase. The identification of Cdt1 overexpression in response to PAK6 activation provides a plausible mechanism for the observed accumulation of higher ploidy cells in MCF7 cells expressing active PAK6. Taken together these findings suggest a direct link between hormonal signals, DNA replication, and maintenance of genomic integrity.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-06-01.