Gene Expression and Microarrays
Gene
Homologs and alignments
Phylogeny
Motifs and domains
Ontology
Gene expression and
microarrays
Gene Expression Omnibus (GEO)
GEO provides a search database for microarray data, searchable by gene name, organism, or disease, among many other criteria [1,3]. Search under "datasets" resulted in only two entries that provided a heatmap, but the experiments were looking at the expression of other genes in cells deficient in BRCA1. Therefore, I was unable to compare BRCA1 expression to other proteins using clustering and GO term analysis, and I chose to use a different approach.
By using detailed search criteria for gene profiles, I looked at two types of experiments. In both cases I searched for experiments done in human cells and had BRCA1 as the annotated gene. In one group I looked at non-breast cancers for change in BRCA1 expression compared to normal. In the other group, I limited search criteria to breast samples.
Non-breast cancers
Colon cancer cell line (HCT116) GDS2755
The following data was achieved by expressing microRNA miR-34a in cell lines [2]. This microRNA was found to decrease in many human cancers, and the authors proposed that this microRNA may affect the transcription of genes who's activation depends on p53. The data on BRCA1 shows that expression of miR-34a in HCT116, a colon cancer cell line, increases the expression of BRCA1 (Figure 1).
From GEO, 2009. DataSet record GDS2755. Retrieved from www.ncbi.nlm.nih.gov/sites/GDSbrowser?acc=GDS2418.
Figure 1. Expression of BRCA1 in colon cancer cell line HCT116. Note that the expression and percentile rank of the cells overexpressing miR-34a are greater than control samples, though no statistical analysis is included.
Vulvar intraepithelial neoplasia (VIN) lesions GDS2418
This specific study looked at expression of genes in VIN lesions, which are associated with HPV infections, as well as naturally [5]. The expression of BRCA1 increases in VIN lesions compared to normal control tissues (Figure 2).
From GEO, 2009. DataSet record GDS2418. Retrieved from http://www.ncbi.nlm.nih.gov/sites/GDSbrowser?acc=GDS2418.
Figure 2. Expression of BRCA1 in VIN lesions. Note that the expression and percentile rank of these samples were greater than control samples, though no statistical analysis is included.
Pulmonary adenocarcinoma GDS1650
Pulmonary adenocarcinomas are largely caused by carcinogen exposure, and this study looks at gene expression in pulmonary adenocarcinomas [6]. They found that in a large number of tumor samples BRCA1 decreased compared to normal paired tissue (Figure 3).
From GEO, 2009. DataSet record GDS1650. Retrieved from http://www.ncbi.nlm.nih.gov/sites/GDSbrowser?acc=GDS1650.
Figure 3. Expression of BRCA1 in pulmonary adenocarcinomas. Note that the majority of tumors had lower expression of BRCA1 than their normal counterparts.
Breast cancers
Breast cancer cell line (MCF-7) GDS2744
In this study, the authors treated breast cancer cell line MCF-7 with dioxin, a known carcinogen [4]. BRCA1 gene expression appears to decrease slightly, though due to variation in the samples, this is not as clear (Figure 4).
From GEO, 2009. DataSet record GDS1650. Retrieved from http://www.ncbi.nlm.nih.gov/sites/GDSbrowser?acc=GDS2744.
Figure 4. Expression of BRCA1 in breast cancer cell line MCF-7 treated with dioxin. Note that dioxin treatment decreases the expression of BRCA1 in some samples, though the percentile rank does not change as much.
Analysis
First I would just like to note that searching for BRCA1 in GEO returned so many results that the four examples I am describing here cannot completely summarize the expression of BRCA1 in cancers. Indeed, many of the microarrays showed no obvious difference in expression of BRCA1, which is expected, as there are hundreds of other ways to thwart the cell cycle and progress to cancer. I selected these four examples using strict search criteria and a visual sorting of more obvious changes in expression.
Biologically, both a decrease and an increase in BRCA1 expression in cancer can be explained. An increase in expression of this tumor suppressor gene would presumably result whenever DNA damage occurs in the cell, and since cancer is marked by extreme genetic aberrations, I would expect BRCA1 levels to rise to try to reverse this. In other cancers BRCA1 expression decreases. In these cases, mutation of a tumor suppressor gene may be a pivotal event in progression to cancer.
These explanations are further corroborated by the methods used in the microarrays I described above. The two cases in which the expression decreased were tissues that were exposed to carcinogens, both naturally (pulmonary adenocarcinoma), and experimentally (breast cancer cell line). On the other hand, tumors and cell lines that are not exposed to such mutagens are attemting to halt the cell cycle with a wild-type BRCA1. Do note, however, that from these studies, we do not know if mutations in BRCA1 are truely present.
Since the main focus of these studies was not mainly on BRCA1, I propose more specific expression analysis of this gene in a variety of tissue types under somewhat similar conditions. Because the experiments I selected vary in experimental system and manipulation, the expression levels between conditions cannot be compared as effectively.
[1] Barrett, T., Troup, D.B, Wilhite, S.E., Ledoux, P., Rudnev, D., Evangelista, C., Kim, I.F., Soboleva, A.,
Tomashevsky, M., and Edgar, R. (2007). NCBI GEO: mining tens of millions of expression profiles--database
and tools update. Nucleic Acids Research, 35(Database issue):D760-D765. doi:10.1093/nar/gkl887.
[2] Chang, T.C., Wentzel, E.A., Kent, O.A., Ramchandran, K., Mellendore, M., Lee, K.H., Feldmann, G., Yamakuchi,
M., Ferlito, M., Lowenstein, C.J., Arking, D.E., Beer, M.A., Maitra, A., and Mendell, J.T. (2007). Transactivation of
miR-34a by p53 broadly influences gene expression and promotes apoptosis. Molecular Cell, 26(5):745-752.
[3] Edgar, R., Domrachev, M., and Lash, A.E. (2002). Gene Expression Omnibus: NCBI gene expression and
hybridization array data repository. Nucleic Acids Research, 30(1):207-210. doi:10.1093/nar/30.1.207.
[4] Hsu, E.L., Yoon, D., Choi, H.H., Wang, F., Taylor, R.T., Chen, N., Zhang, R., Hankinson, O. (2007). A proposed
mechanism for the protective effect of dioxin against breast cancer. Toxicol Sci,
98(2):436-44. doi:10.1093/toxsci/kfm125.
[5] Santegoets, L.A., Seters, M., Helmerhorst, T.J., Heijmans-Antonissen, C. Hanifi-Moghaddam, P., Ewing, P.C., van
Ijcken, W.F., van der Spek, P.J., van der Meijden, W.I., and Blok, L.J. (2007). HPV related VIN: highly proliferative
and diminished responsiveness to extracellular signals. Int J Cancer, 121(4):759-66. doi:10.1002/ijc.22769.
[6] Stearman, R.S., Dwyer-Nield, L., Zerbe, L., Blaine, S.A., Chan, Z., Bunn, P.A.Jr., Johnson, G.L., Hirsch, F.R.,
Merrick, D.T., Franklin, W.A., Baron, A.E., Keith, R.L., Nemenoff, R.A., Malkinson, A.M., Geraci, M.W. (2005).
Analysis of orthologous gene expression between human pulmonary adenocarcinoma and a carcinogen-
induced murine model. Am J Pathol, 167(6):1763-75.
Site created by Jessica D. Kueck
Genetics 677 Assignment, Spring 2009
University of Wisconsin-Madison
