Chfr in Tumorigenesis and Paclitaxel Sensitivity in Breast Cancer

Investigators: Junjie Chen, Ph.D., Yale University School of Medicine; Scott Kaufmann, M.D., Ph.D., and Edith Perez, M.D., Mayo Clinic Cancer Center

Paclitaxel (Taxol) and docetaxel (Taxotere) are widely used in the treatment of breast cancer. These drugs, called microtule-targeting drugs, act on dividing cells, that is, cells that are going from one cell to two daughter cells through the process called mitosis.

Unfortunately, not all patients receive benefit from Taxol or Taxotere. In fact only about 30 to 50 percent of patients respond when these agents are utilized in the first-line treatment of metastatic disease. Further investigation is required to understand why some breast cancers respond to these chemotherapy drugs and some do not, and to identify breast cancer characteristics that will predict which patients will get benefit from them.

Previous research noted a potential link between a particular protein, Chfr, that is involved in the control of the process of cell division, and taxane sensitivity. However, these earlier studies did not explain whether Chfr down-regulation (when gene function is slow or inactive) played a causative role in the formation of tumors.

Project #1 goals include:

1. Studying the stage at which cancer cell division is most sensitive to taxanes.
2. Examining whether possessing a down-regulated Chfr gene contributes to breast cancer development in mice.
3. Determining whether Chfr down-regulation increases cancer cells' sensitivity to paclitaxel.

In our basic science laboratories, we are studying the role of Chfr, a mitotic checkpoint protein. Importantly, Chfr appears to be involved in tumorigenesis, which is the development of cancers. From our studies, we have demonstrated that Chfr downregulation (that is, decreasing Chfr in cells) directly contributes to the development of tumors. Studies also indicate that low levels of Chfr lead to increased sensitivity to forces that act on the division of cells, including treatment with the anti-tumor drugs Taxol and Taxotere.

Because Chfr is frequently decreased in primary breast tumors and low Chfr in cells in the laboratory is associated with Taxol sensitivity, this raises the question whether breast cancer patients with cancers that have low Chfr would benefit significantly from Taxol-containing treatment programs. Thus, we are exploring whether Chfr expression can be used as a predictor of response to Taxol-based chemotherapy.

The research team has generated what's called a knockout model in mice. This research method involves using mice that lack the Chfr gene and that do not produce the Chfr protein. Mayo researchers chose to use this model because it best mimics the situation in tumors with significantly reduced levels of Chfr.

Using the knockout model, Mayo researchers have demonstrated that Chfr down-regulation leads to tumor production in mice. This connection suggests that frequent down-regulation of Chfr is likely to be a critical step during tumor formation in humans.

Using these observations, Mayo researchers will also explore Chfr and taxane sensitivity in human breast cancer cells. Within the duration of this project, they will examine whether breast tumors with undetectable or low levels of Chfr expression would respond better to Taxol treatment than tumors with normal Chfr expression. More directly, they will study whether Chfr downregulation (that is, Chfr lowering) correlates with improved clinical outcome following Taxol treatment in breast cancer patients, potentially impacting current treatment strategies.