title: Gene expression profiling of cancer progression reveals intrinsic regulation of transforming growth factor-beta signaling in ErbB2/Neu-induced tumors from transgenic mice.
abstract: Upregulation of HER2/ErbB2/Neu occurs in 15-30% of human breast cancers and correlates with poor prognosis. Identification of ErbB2/Neu transcriptional targets should facilitate development of novel therapeutic approaches. Development of breast cancer is a multistep process; thus, to identify the transcriptomes associated with different stages of progression of tumorigenesis, we compared expression profiles of mammary tumors and preneoplastic mammary tissue from MMTV-Neu transgenic mice to expression profiles of wild-type mammary glands using Affymetrix microarrays. We identified 324 candidate genes that were unique to ErbB2/Neu-induced tumors relative to normal mammary gland tissue from wild-type controls. Expression of a subset of these genes (82) was also changed in the preneoplastic mammary glands compared to wild-type controls, indicating that they may play a pivotal role during early events of ErbB2/Neu-initiated mammary tumorigenesis. Further analysis of the microarray data revealed that expression of several known transforming growth factor (TGF)-beta target genes was altered, suggesting that the TGF-beta signaling cascade is downregulated in ErbB2/Neu-induced tumors. Western blot analysis for TGF-beta-Receptor-I/ALK5 and immunohistochemistry for TGF-beta-Receptor-I/ALK5 and phosphorylated/activated Smad2 confirmed that the Smad-dependent TGF-beta signaling cascade was inactive in these tumors. Although absent in most of the tumor, phosphorylated Smad2 was present in the periphery of tumors. Interestingly, presence of phosphorylated/activated Smad2 correlated with expression of Activin-Receptor-IB/ALK4, suggesting that although Smad-dependent TGF-beta signaling is absent in ErbB2/Neu-induced tumors, Activin signaling may be active at the leading edge of these tumors. Cumulatively, these data indicate that the TGF-beta pathway is intrinsically suppressed in ErbB2/Neu tumors via a mechanism involving loss of TGF-beta-Receptor-I/ALK5.
authors.affiliation: Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Landis
authors.forename: Darcie D
authors.initials: DD
authors.lastname: Seachrist
authors.forename: Marjorie E
authors.initials: ME
authors.lastname: Montañez-Wiscovich
authors.forename: David
authors.initials: D
authors.lastname: Danielpour
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Keri
mesh_terms: D029404:Activin Receptors / Q000378:metabolism; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D011230:Precancerous Conditions / Q000235:genetics* / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology*; D015398:Signal Transduction; D051899:Smad2 Protein; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D029404:Activin Receptors; D004268:DNA-Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D051899:Smad2 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; C497783:Smad2 protein, mouse