A Precisely Regulated Gene Expression Cassette Potently Modulates Metastasis and Survival in Multiple Solid Cancers

Abstract

Successful tumor development and progression involves the complex interplay of both pro- and anti-oncogenic signaling pathways. Genetic components balancing these opposing activities are likely to require tight regulation, because even subtle alterations in their expression may disrupt this balance with major consequences for various cancer-associated phenotypes. Here, we describe a cassette of cancer-specific genes exhibiting precise transcriptional control in solid tumors. Mining a database of tumor gene expression profiles from six different tissues, we identified 48 genes exhibiting highly restricted levels of gene expression variation in tumors (n = 270) compared to nonmalignant tissues (n = 71). Comprising genes linked to multiple cancer-related pathways, the restricted expression of this “Poised Gene Cassette” (PGC) was robustly validated across 11 independent cohorts of ∼1,300 samples from multiple cancer types. In three separate experimental models, subtle alterations in PGC expression were consistently associated with significant differences in metastatic and invasive potential. We functionally confirmed this association in siRNA knockdown experiments of five PGC genes (p53CSV, MAP3K11, MTCH2, CPSF6, and SKIP), which either directly enhanced the invasive capacities or inhibited the proliferation of AGS cancer cells. In primary tumors, similar subtle alterations in PGC expression were also repeatedly associated with clinical outcome in multiple cohorts. Taken collectively, these findings support the existence of a common set of precisely controlled genes in solid tumors. Since inducing small activity changes in these genes may prove sufficient to potently influence various tumor phenotypes such as metastasis, targeting such precisely regulated genes may represent a promising avenue for novel anti-cancer therapies.

The BRG1 ATPase of chromatin remodeling complexes is involved in modulation of mesenchymal stem cell senescence through RB–P53 pathways

“…Several genes show tightly regulated expression, in which even subtle alterations may disrupt the normal functioning of cells (Kholodenko, 2000;Yu et al, 2008). One explanation for why certain genes require precise control is their potential to regulate, or be involved in balancing, disparate downstream pathways possessing mutually opposing activities (Yu et al, 2008).…”

“…One explanation for why certain genes require precise control is their potential to regulate, or be involved in balancing, disparate downstream pathways possessing mutually opposing activities (Yu et al, 2008). This may be the case with BRG1, which can modulate gene expression in either a positive or a negative manner (Trotter and Archer, 2008).…”

Data driven derivation of cutoffs from a pool of 3,030 Affymetrix arrays to stratify distinct clinical types of breast cancer

“…We included 238 of our own samples (datasets Frankfurt, Frankfurt-2, and Frankfurt-3) which have been described previously (Ahr et al 2002 [9], [10], Rody et al 2008 [11], Ruckhäberle et al 2008 [12], and Rody et al 2007 [13], respectively) as well as 2792 samples from 22 different publicly available datasets (Table 1): Rotterdam [14][15][16], Mainz [17], Trans-BIG [18], Oxford-Untreated [19], London [20], London-2 [21], Oxford-Tamoxifen, Veridex-Tam [22], Stockholm [23], Uppsala [24,25], San Francisco [26], New York [27], MDA133 [28], EORTC [29], Edinburgh [30], ExpO [31], Signapore [32], Genentech [33], Boston [34], Berlin [35], Paris [36], and Tampa [37]. For comparability, only the ProbeSets from the Affymetrix HG-U133A microarray were used from seven datasets where HG-U133?…”

Loss of the Notch effector RBPJ promotes tumorigenesis

“…1 D). and adjacent normal breast tissue (n = 13; Yu et al, 2008). (C) Analysis of RBPJ expression and RBPJ genomic copy loss (n = 277) versus no loss (neutral, n = 551) in invasive breast cancers (TCGA data).…”