Epithelial p53 Status Modifies Stromal-Epithelial Interactions During Basal-Like Breast Carcinogenesis
| Autor: | Melissa A. Troester, Alina M Hamilton, Lin Yang, Jason R. Pirone, Amy L. Oldenburg, Ashley M. Fuller |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Stromal cell Cell Context (language use) Breast Neoplasms Biology medicine.disease_cause Article 03 medical and health sciences 0302 clinical medicine Stroma Downregulation and upregulation Cell Line Tumor medicine Humans Neoplasm Invasiveness Gene Gene Expression Profiling Epithelial Cells Fibroblasts Phenotype Coculture Techniques 030104 developmental biology medicine.anatomical_structure Cell Transformation Neoplastic Oncology 030220 oncology & carcinogenesis Gene Knockdown Techniques Cancer research Female Stromal Cells Tumor Suppressor Protein p53 Carcinogenesis |
| Zdroj: | J Mammary Gland Biol Neoplasia |
| ISSN: | 1573-7039 |
| Popis: | Basal-like breast cancers (BBC) exhibit subtype-specific phenotypic and transcriptional responses to stroma, but little research has addressed how stromal-epithelial interactions evolve during early BBC carcinogenesis. It is also unclear how common genetic defects, such as p53 mutations, modify these stromal-epithelial interactions. To address these knowledge gaps, we leveraged the MCF10 progression series of breast cell lines (MCF10A, MCF10AT1, and MCF10DCIS) to develop a longitudinal, tissue-contextualized model of p53-deficient, pre-malignant breast. Acinus asphericity, a morphogenetic correlate of cell invasive potential, was quantified with optical coherence tomography imaging, and gene expression microarrays were performed to identify transcriptional changes associated with p53 depletion and stromal context. Co-culture with stromal fibroblasts significantly increased the asphericity of acini derived from all three p53-deficient, but not p53-sufficient, cell lines, and was associated with the upregulation of 38 genes. When considered as a multigene score, these genes were upregulated in co-culture models of invasive BBC with increasing stromal content, as well as in basal-like relative to luminal breast cancers in two large human datasets. Taken together, stromal-epithelial interactions during early BBC carcinogenesis are dependent upon epithelial p53 status, and may play important roles in the acquisition of an invasive morphologic phenotype. |
| Databáze: | OpenAIRE |
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