From Mice To Humans: Identification Of Commonly Deregulated Genes In Mammary Cancer Via Comparative SAGE Studies
Abstract
Genetically engineered mouse mammary cancer models have been used over the years as systems to study human breast cancer. However, much controversy exists on the utility of such models as valid equivalents to the human cancer condition. To perform an interspecies gene expression comparative study in breast cancer we used a mouse model that most closely resembles human breast carcinogenesis. This system relies on the transplant of p53 null mammary epithelial cells into the cleared mammary fat pads of syngeneic hosts. Serial analysis of gene expression (SAGE) was used to obtain gene expression profiles of normal and tumor samples from this mouse mammary cancer model (>300,000 mouse mammary-specific tags). The resulting mouse data were compared with 25 of our human breast cancer SAGE libraries (>2.5 million breast-specific tags). We observed significant similarities in the deregulation of specific genes and gene families when comparing mouse with human breast cancer SAGE data. A total of 72 transcripts were identified as commonly deregulated in both species. We observed a systematic and significant down-regulation in all tumors from both species of various cytokines, including CXCL1 (GRO1), LIF, interleukin 6, and CCL2. All of the mouse and most human mammary tumors also displayed decreased expression of genes known to inhibit cell proliferation, including NFKBIA (IKB alpha), GADD45B, and CDKN1A (p21); transcription related genes such as CEBP, JUN, JUNB, and ELF1; and apoptosis-related transcripts such as IER3 and GADD34/PPP1R15A. Examples of overexpressed transcripts in tumors from both species include proliferation-related genes such as CCND1, CKS1B, and STMN1 (oncoprotein 18); and genes related to other functions such as SEPW1, SDFR1, DNCI2, and SP110. Importantly, abnormal expression of several of these genes has not been associated previously with breast cancer. The consistency of these observations was validated in independent mouse and human mammary cancer sets.
This is the first interspecies comparison of mammary cancer gene expression profiles. The comparative analysis of mouse and human SAGE mammary cancer data validates this p53 null mouse tumor model as a useful system closely resembling human breast cancer development and progression. More importantly, these studies are allowing us to identify relevant biomarkers of potential use in human studies while leading to a better understanding of specific mechanisms of human breast carcinogenesis.
Contact: maaldaz-at-mdanderson.org
Supplementary information:
Supplementary Table I: Differentially Expressed genes in P53 null Mouse Mammary Tumors Compared to Normal Mouse Mammary Epithelium (p < 0.05) (Raw data. 92 KB Excel file, zipped.)
Supplementary Table II: Commonly Deregulated Genes in Mouse and Human Mammary Tumors (Raw data. 32 KB Excel file, zipped.)
Table 1: Commonly Deregulated Genes in Mouse and Human Mammary Tumors (Genes categorized according to function. 24 KB Word file, zipped.)
Figure 2: Heat Map of Commonly Deregulated Genes in Mouse and Human Breast Tumors (click to see full size image in a new window, low resolution image is below.)
