Abstract 3588: The spindle assembly checkpoint gene Bub1b is essential for the survival of some breast cancers
Authors: Koyuncu Dilara , Goka Erik T. , Miller Philip C. , Lippman Marc E. 
Published: July 2016

As normal breast epithelium evolves towards malignancy, cells accumulate genomic changes that give them a replicative advantage while at the same time increasing their genomic instability. Increased genomic instability results in accumulation of genomic aberrations that compromise the genomic integrity and, therefore, threaten cell viability, thus putting cancer cells under mitotic stress. As a consequence, cancer cells evolutionarily must adapt themselves to compete with the possible detrimental effects of genomic instability. Finding a balance between the instability that gives them a replicative advantage and the instability that could lead them to mitotic catastrophe is crucial. The mitotic stress caused by genomic instability may require overexpression of certain spindle assembly checkpoint (SAC) genes, which can prevent mitotic catastrophe that would occur if cancer cells undergo mitosis prematurely. Although the full mechanism of action of SAC is yet to be elucidated, Bub1b through its protein BubR1 is an important part of this checkpoint, and inhibits the onset of anaphase until all chromosomes are aligned correctly at the metaphase plate.

Our analysis of clinical datasets shows a significant increase in the expression of Bub1b in breast cancer as compared to normal epithelia. Furthermore, Bub1b overexpression correlates with decreased overall survival in patient samples. Our analyses also show a pattern of increasing Bub1b overexpression in more aggressive variants of breast cancer such as triple negative tumors and high-grade tumors, which also tend to be more resistant to current therapies. Expression analyses of breast cancer cell lines reveal that Bub1b overexpression is positively correlated with more aggressive behavior.

We postulated that the requirement for Bub1b expression might be a vulnerability of rapidly proliferating cancers; therefore, its inhibition will result in cell death through mitotic catastrophe. Using RNA interference with siRNAs, we reduced Bub1b levels in a variety of breast cancer cells. Our results showed significant decrease in cell viability and clonogenicity in soft agar upon Bub1b knockdown, especially in triple negative breast cancer cell lines. However, the viability of normal breast epithelium cells, MCF12A, was not affected.

Our data indicate that Bub1b is a critical player in breast cancer viability, and further investigation of the role of Bub1b in promoting successful proliferation of breast cancer cells with genomic instability could provide a new therapeutic strategy particularly in concert with standard genotoxic treatments such as alkylators, spindle poisons and radiation therapy.

Citation Format: Dilara Koyuncu, Erik T. Goka, Philip C. Miller, Marc E. Lippman. The spindle assembly checkpoint gene Bub1b is essential for the survival of some breast cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3588.