Abstract P5-07-06: Exploring the involvement of TTK kinase in centrosome amplification and Her2+ breast cancer

Abstract

Abstract The centrosome is the cellular organelle responsible for accurate chromosome segregation. In normal cellular function, regulation of the centrosome duplication cycle in concert with the cell cycle is necessary for accurate passage of genetic information. However, when modulators of the cell and/or centrosome duplication cycles are deregulated, this process can result in centrosome amplification (CA, the acquisition of more than two centrosomes), leading to improper segregation of chromosomes and genomic instability. CA generates low-level aneuploidy (which is tolerated) and polyploidy (selected against when checkpoints are present). An integral goal in the field of centrosome biology is to characterize how alterations in modulators of CA influence disease development. In cancer, CA is associated with aggressive tumor types and metastasis and is likely to affect response to treatment. However, the full role of CA in tumorigenesis is poorly understood. Specifically in breast cancer, CA is observed in pre-cancerous lesions, which suggests CA in conjunction with genomic instability is an early contributor to tumorigenesis. In an effort to study mechanisms associated with CA, we are investigating the function of CA in in vitro and in vivo breast cancer models. Our lab and others have detected that TTK (MPS1) kinase, a proposed modulator of centrosome duplication, is overexpressed in Her2+ breast cancer cell lines at the mRNA and protein level compared to non-transformed mammary epithelial cells. We hypothesize that overexpression of TTK leads to CA and that inhibiting TTK expression in cancer cells will prevent active generation of CA and CIN (chromosome instability), leading to suppressed tumorigenic properties and further cancer evolution. Preliminary data shows that transient knockdown of TTK via siRNA attenuates the degree of CA in Her2+ breast cancer cells. Additional preliminary data shows that stable abrogation of TTK via shRNA can inhibit the proliferation of Her2+ breast cancer cells but does not alter expression of some members in the intrinsic apoptotic pathway. Ongoing studies will address the impact of altering TTK expression on CA, CIN, downstream centrosomal duplication signaling and tumorigenic properties of breast cancer cells. The results of these studies will address the mechanistic complexities, such as what centrosomal signaling pathways associated with TTK are underlying CA in breast cancer. We believe this work will help discern how deregulated centrosome regulatory molecules influence mammary tumorigenesis and/or responses to treatment. Citation Format: Jamie L King, Harold I Saavedra. Exploring the involvement of TTK kinase in centrosome amplification and Her2+ breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-07-06.