Investigator: Laura Gonzalez, Ph.D
Collaborators: Lihua Zhou (DFCI), Joan Brugge (HMS)
We are interested in identifying and characterizing genes that regulate critical events involved in the progression of breast cancer and in understanding the development of resistance to anti-estrogen drug treatment. In previous work done in collaboration with the Brugge lab, we used high throughput screens to identify genes that contribute to various cancer phenotypes including cell migration and acinar morphogenesis (Proc Natl Acad Sci U S A. 2004 101:1257; J Proteome Res. 2006 5:599; Mol Cell Biol. 2005 25:5282). More recently, we have focused on identifying proteins that contribute to drug resistance in breast cancer. We have produced several matching drug sensitive and resistant breast cancer cultured cell lines that we can use to study the factors that lead to drug resistance. These cells provide a useful resource to study which genes are inappropriately regulated in the drug resistant state. This research led to identifying a signature, based solely on differences in the resistant and sensitive subcloned cell lines, that can predict overall patient survival in tamoxifen treated patients (Figure 1). We used our clone collection of more than 500 human kinases in high throughput unbiased screens to identify 29 kinases that confer drug resistance on sensitive MCF7 subclones in repeated screens. Several of these kinases were also found in the tamoxifen resistance signature. Detailed investigation has now shown that one of these kinases both confers resistance on tamoxifen sensitive cells when ectopically expressed and kills resistant cells when knocked down by shRNA. In conclusion, the results will lead to important new findings relating to genes that are involved in breast development and resistance to hormonal treatment in breast cancer. We hope that defining gene pathways that are responsible for drug resistance will lead to combined treatments that will more effectively treat resistant cancers.
Figure 1.
Gene Expression Profiling. A signature of estrogen responsive genes that respond differentially in the sensitive vs. resistant cells. We found a signature of 68 genes that predicted better survival of patients that matched the “sensitive” signature, so these patients would be more likely to respond to Tamoxifen and hence have a longer survival time and lower probability of relapse compared with patients whose patterns are closer to the resistant cells. Several of the kinases that conferred tamoxifen resistance on the cells are among the genes in this signature.
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