Identification of p130Cas/ErbB2-dependent invasive signatures in transformed mammary epithelial cells

Abstract

Understanding transcriptional changes during cancer progression is of crucial importance to develop new and more efficacious diagnostic and therapeutic approaches. It is well known that erbB2 is overexpressed in about 25% of human invasive breast cancers. We have previously demonstrated that p130Cas overexpression synergizes with erbB2 in mammary cell transformation and promotes erbB2-dependent invasion in 3-dimensional (3D) cultures of human mammary epithelial cells. Here, by comparing coding and non-coding gene expression profiles, we define the invasive signatures associated with concomitant p130Cas overexpression and erbB2 activation in 3D cultures of mammary epithelial cells. Specifically, we have found that genes involved in amino acids synthesis (CBS, PHGDH), cell motility, migration (ItPKa, PrDM1), and angiogenesis (Hey1) are upregulated, while genes involved in inflammatory response (Saa1, S100a7) are downregulated. In parallel, we have shown that the expression of specific mirNas is altered. among these, mir-200b, mir-222, mir-221, mir-r210, and mir-424 are upregulated, while mir-27a, mir-27b, and mir-23b are downregulated. overall, this study presents, for the first time, the gene expression changes underlying the invasive behavior following p130Cas overexpression in an erbB2 transformed mammary cell model.

Metastatic Heterogeneity of Breast Cancer Cells Is Associated with Expression of a Heterogeneous TGFβ-Activating miR424–503 Gene Cluster

“…Our current finding that Smad7 and Smurf2 protein levels are simultaneously and directly suppressed by overexpressed miR424-503 cluster in metastatic breast cancer cells without alterations in their mRNA levels, therefore, represents a novel posttranscriptional model for a coordinated regulation of these 2 factors. Although miRNAs have been reported to target Smad7 (36,37), and miR424 or miR503 overexpression has been separately found to be associated with poor prognosis in breast cancer (38,39), our results provides the first demonstration for miRNA Importantly, this newly identified mode of action is clinically relevant, as shown by our human specimens' data. Thus, a coordinated miRNA modulation of both Smad7 and Smurf2 appears to be an importantly new layer of TGFb signaling in breast cancer metastasis.…”

Inositol-1,4,5-trisphosphate 3-kinase-A (ITPKA) is frequently over-expressed and functions as an oncogene in several tumor types

“…Consistent with this result, 21 years later Pincini et al (2013) [50] showed that ITPKA belongs to the invasive signature of p130Cas/ErbB2 transformed MCF10A.B2 breast cancer cells. In addition to ErbB2, also the v-scr oncogene seems to be sufficient to induce expression of ITPKA.…”

Dysregulation of Blimp1 transcriptional repressor unleashes p130Cas/ErbB2 breast cancer invasion

“…It was therefore decided that we evaluate the possible interactions of miR-23b in this context, as it has previously been demonstrated to be downmodulated in invasive acini 4 , and that Blimp1 was predicted to be one of its putative targets (TargetScan v. 6.2).…”