Tumor and Stem Cell Biology Differentially ExpressedGenesRegulating theProgressionof Ductal Carcinoma In Situ to Invasive Breast Cancer

Molecular mechanisms mediating the progression of ductal carcinoma in situ (DCIS) to invasive breast cancer remain largely unknown. We used gene expression profiling of human DCIS (n 1⁄4 53) and invasive breast cancer (n 1⁄4 51) to discover uniquely expressed genes that may also regulate progression. There were 470 total differentially expressed genes ( 2-fold; P < 0.05). Elevated expression of genes involved in synthesis and organization of extracellular matrix was particularly prominent in the epithelium of invasive breast cancer. The degree of overlap of the geneswith nine similar studies in the literaturewas determined to help prioritize their potential importance, resulting in 74 showing overlap in 2 studies (average 3.6 studies/gene; range 2–8 studies). Using hierarchical clustering, the 74-gene profile correctly categorized 96% of samples in this study and 94% of samples from 3 similar independent studies. To study the progression of DCIS to invasive breast cancer in vivo, we introduced human DCIS cell lines engineered to express specific genes into a "mammary intraductal DCIS" xenograft model. Progression of xenografts to invasive breast cancer was dramatically increased by suppressing four genes that were usually elevated in clinical samples of DCIS, including a protease inhibitor (CSTA) and genes involved in cell adhesion and signaling (FAT1, DST, and TMEM45A), strongly suggesting that they normally function to suppress progression. In summary, we have identified unique gene expression profiles of humanDCIS and invasive breast cancer, which include novel genes regulating tumor progression. Targeting some of these genes may improve the detection, diagnosis, and therapy of DCIS. Cancer Res; 72(17); 1–13. 2012 AACR.