Differentially Expressed Genes Regulating the Progression of Ductal Carcinoma in Situ to Invasive Breast Cancer
Menée sur des échantillons tumoraux prélevés sur des patientes atteintes d'un cancer du sein (53 carcinomes canalaires in situ et 52 cancers invasifs) et à l'aide de xénogreffes, cette étude identifie des profils d'expression de gènes spécifiques des carcinomes in situ et invasif
Molecular mechanisms mediating the progression of ductal carcinoma in situ (DCIS) to invasive breast cancer (IBC) remain largely unknown. We used gene expression profiling of human DCIS (n=53) and IBC (n=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 IBC. The degree of overlap of the genes with nine similar studies in the literature was 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 was able to correctly categorize 96%, 93%, and 85% of samples in this study and two similar independent studies, respectively. To study the progression of DCIS to IBC in vivo, we introduced human DCIS cell lines engineered to express specific genes into a "mammary intraductal DCIS" (MIND) xenograft model. Progression of xenografts to IBC 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 human DCIS and IBC, which include novel genes regulating tumor progression. Targeting some of these genes may improve the detection, diagnosis, and therapy of DCIS.
Cancer Research 2012