Biology Reference
In-Depth Information
14.4 Identifying Proteins that Collaborate with BRCA1
in the Regulation of the Centrosome
Many genomes have been sequenced and now that large-scale microarray databases and
protein-protein interaction databases are publicly available online, informatics methods
can be used to identify genes/proteins that interact with a protein of interest. Using such a
bioinformatics approach and making use of publicly available microarray data, proteins
were identified that might collaborate with BRCA1, BRCA2, ATM, and CHK2 (Pujana
et al.
2007
). Among the 164 genes identified, HMMR stood out as a gene that is highly
correlated with BRCA1. Depletion of HMMR resulted in centrosome amplification, a
phenotype seen upon BRCA1 depletion. Interestingly, depleting both genes suppressed
the phenotype. In addition, SNPs linked to HMMR were associated with an increased
prevalence of breast cancer in certain populations (Pujana et al.
2007
). Finding a gene
whose expression is correlated with BRCA1 and that functions in a BRCA1 controlled
pathway such as centrosome regulation adds confidence to such bioinformatic
approaches. Therefore, using bioinformatics to find other genes that collaborate with
BRCA1 in the regulation of centrosomes will be of great importance in the future
knowing the importance of centrosome regulation in breast tumorigenesis.
14.5 Concluding Remarks
Regulation of the duplication and the function of the centrosome are critical for the
adequate transmission of genetic material to daughter cells. Defects in the
mechanisms that control centrosome number and/or function result in centrosome
abnormalities that will promote genetic instability and ultimately tumorigenesis.
The centrosome is regulated by many oncogenes and tumor suppressors. Dis-
rupting the function of these genes will cause centrosome abnormalities that will
contribute to the development and progression of breast cancer. BRCA1 E3
ubiquitin ligase activity is essential for the regulation of centrosome number in
mammary cells. Loss of BRCA1, as seen in many breast tumors, will result in
supernumerary centrosomes. AURKA is overexpressed in 62 % of human breast
cancer (Miyoshi et al.
2001
). Since AURKA inhibits BRCA1 enzymatic activity,
such an overexpression will also result in the same phenotype seen upon loss of
BRCA1: centrosome amplification. Since BRCA1 is a major player in breast
cancer, screening BRCA1 mutants using functional assays such as the centrosome
assay will definitely be of great importance in the genetic counseling process for
individuals with family history of breast cancer. In addition, finding genes that
collaborate with BRCA1 in the control of centrosome number will also be essential
in finding new players that might contribute to the pathogenesis of the disease.
Acknowledgments This work was supported by funding from the NIH/NCI (R01 CA141090
and R01 CA111480) to J.D.P.
