Mesenchymal/stromal gene expression signature relates to basal-like breast cancers, identifies bone metastasis and predicts resistance to therapies

• Published in: PloS one Vol. 5; no. 11; p. e14131
• Main Authors: Marchini, Cristina, Montani, Maura, Konstantinidou, Georgia, Orrù, Rita, Mannucci, Silvia, Ramadori, Giorgio, Gabrielli, Federico, Baruzzi, Anna, Berton, Giorgio, Merigo, Flavia, Fin, Stefania, Iezzi, Manuela, Bisaro, Brigitte, Sbarbati, Andrea, Zerani, Massimo, Galiè, Mirco, Amici, Augusto
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 30.11.2010; Public Library of Science (PLoS)
• Subjects: Analysis; Animals; Biology; Blotting, Western; Bone cancer; Bone Neoplasms - drug therapy; Bone Neoplasms - genetics; Bone Neoplasms - secondary; Bone tumors; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer; Cancer genetics; Cancer metastasis; Cancer therapies; Carcinoma; Cell Line, Tumor; Chemotherapy; Cluster Analysis; Computer applications; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; Diagnostic systems; DNA microarrays; Drug Resistance, Neoplasm - genetics; Epithelial Cells - metabolism; Female; Gene expression; Gene Expression Profiling; Genetics and Genomics/Gene Expression; Genetics and Genomics/Medical Genetics; Genomes; Genotype & phenotype; Histology; Humans; Immunization; Kinases; Laboratories; Mesenchymal stem cells; Mesenchymal Stromal Cells - metabolism; Mesenchyme; Mesoderm - metabolism; Mesoderm - pathology; Metastases; Metastasis; Mice; Morphology; Mutation; Neoadjuvant Therapy - methods; Oligonucleotide Array Sequence Analysis; Oncology/Breast Cancer; Phosphorylation; Reverse Transcriptase Polymerase Chain Reaction; Sarcoma; Signal Transduction; Signatures; Stem cells; Stroma; Stromal Cells - metabolism; Stromal Cells - pathology; Therapy; Tumor cells; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0014131

Mounting clinical and experimental evidence suggests that the shift of carcinomas towards a mesenchymal phenotype is a common paradigm for both resistance to therapy and tumor recurrence. However, the mesenchymalization of carcinomas has not yet entered clinical practice as a crucial diagnostic paradigm. By integrating in silico and in vitro studies with our epithelial and mesenchymal tumor models, we compare herein crucial molecular pathways of previously described carcinoma-derived mesenchymal tumor cells (A17) with that of both carcinomas and other mesenchymal phenotypes, such as mesenchymal stem cells (MSCs), breast stroma, and various types of sarcomas. We identified three mesenchymal/stromal-signatures which A17 cells shares with MSCs and breast stroma. By using a recently developed computational approach with publicly available microarray data, we show that these signatures: 1) significantly relates to basal-like breast cancer subtypes; 2) significantly relates to bone metastasis; 3) are up-regulated after hormonal treatment; 4) predict resistance to neoadjuvant therapies. Our results demonstrate that mesenchymalization is an intrinsic property of the most aggressive tumors and it relates to therapy resistance as well as bone metastasis.