The microtubule-targeting drugs paclitaxel and docetaxel are widely used in the treatment of breast cancer. Unfortunately, single-agent trials indicate that only 30-50% of patients respond to these taxane-based therapies. The goals of this application are to study a recently described pathway affecting sensitivity to these agents and evaluate the impact of alterations in this pathway in human breast cancer. Intensive studies over the past 20 years have elucidated multiple mechanisms of resistance to taxanes. Recent interest has focused on the role of changes in mitotic checkpoints as determinants of taxane sensitivity. Chfr encodes a 72 kDa polypeptide involved in a novel mitotic checkpoint pathway. Chfr expression is frequently down-regulated in many human cancers. Additionally, Chfr downregulation is associated with enhanced taxane sensitivity. These data raise the possibility that Chfr downregulation not only contributes to tumorigenesis, but also conveys increased sensitivity of breast cancers to taxanebased therapies. We recently generated Chfr-deficient mice and directly demonstrated that Chfr is required for mitotic checkpoint control, maintenance of genomic stability and tumor suppression in mice. Based on these data, we hypothesize that Chfr acts as a tumor suppressor in human breast cancer. Further, we postulate that breast cancers with Chfr downregulation will be more likely to respond to taxane-containing therapy. To test these hypotheses, we propose to: 1) study the mechanism by which Chfr regulates the mitotic checkpoint;2) examine whether Chfr downregulation contributes to breast cancer development in mice;3) determine whether Chfr downregulation increases paclitaxel sensitivity in vitro and in mouse models;4) explore the relationship between Chfr expression and paclitaxel sensitivity in clinical breast cancer specimens. These studies rely on the Breast Biospecimens and Biostatistics Cores. In summary, studies outlined here will elucidate the precise molecular role of CHFR in the control of mitotic progression, evaluate its contribution to breast cancer development and assess its value as a predictive marker of taxane sensitivity in breast cancer patients.
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