Abstract
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.
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Availability of Data and Materials
The datasets generated during the current study are available in the NCBI Gene Expression Omnibus (GSE162553). Other materials generated during this study are available from the corresponding author upon reasonable request.
Code Availability
The code utilized in this study is available from the corresponding author upon reasonable request.
Abbreviations
- ADH:
-
Atypical ductal hyperplasia
- BBC:
-
Basal-like breast cancer
- DCIS:
-
Ductal carcinoma in situ
- ER:
-
Estrogen receptor
- FDR:
-
False discovery rate
- FEA:
-
Flat epithelial atypia
- OCT:
-
Optical coherence tomography
- PR:
-
Progesterone receptor
- RMF:
-
Reduction mammoplasty fibroblast
- TCGA:
-
The Cancer Genome Atlas
- *:
-
Protein truncation
- LOH:
-
Loss of heterozygosity
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Acknowledgements
We would like to acknowledge Katherine Hoadley, PhD, for assistance with TCGA data. We would also like to thank Yan Shi, PhD, of the UNC High-Throughput Sequencing Facility (HTSF) for assistance with Tape Station and microarray assays. The HTSF is supported in part by the UNC Lineberger Comprehensive Cancer Center and the University Cancer Research Fund.
Funding
This work was supported by P30 ES010126, U01 CA179715, and U01 ES019472 to MAT, and by R21 CA179204 and NSF CBET 1803830 to ALO. AMF received additional support from the UNC Royster Society of Fellows. AMH was supported by the UNC Program in Translational Medicine (T32 GM122741).
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Conceptualization: Ashley M. Fuller, Melissa A. Troester; Methodology: Ashley M. Fuller, Lin Yang, Jason R. Pirone, Amy L. Oldenburg, Alina M. Hamilton; Formal analysis and investigation: Ashley M. Fuller; Writing—original draft preparation: Ashley M. Fuller; Writing—review and editing: Ashley M. Fuller, Lin Yang, Alina M. Hamilton, Jason R. Pirone, Amy L. Oldenburg, Melissa A. Troester; Funding acquisition: Ashley M. Fuller, Amy L. Oldenburg, Melissa A. Troester; Resources: Amy L. Oldenburg, Melissa A. Troester; Supervision: Melissa A. Troester.
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Fuller, A.M., Yang, L., Hamilton, A.M. et al. Epithelial p53 Status Modifies Stromal-Epithelial Interactions During Basal-Like Breast Carcinogenesis. J Mammary Gland Biol Neoplasia 26, 89–99 (2021). https://doi.org/10.1007/s10911-020-09477-w
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DOI: https://doi.org/10.1007/s10911-020-09477-w