Adult, Animals, Antineoplastic Agents, Hormonal, Biomarkers, Breast Neoplasms, Cell Communication, Cell Line, Tumor, Cluster Analysis, Combined Modality Therapy, Computational Biology, Disease Models, Animal, Drug Resistance, Neoplasm, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Regulatory Networks, Humans, Immunohistochemistry, Liver Neoplasms, Mice, Middle Aged, Neoplasm Grading, Neoplasm Metastasis, Transcriptome, Treatment Outcome, Xenograft Model Antitumor Assays
Science Foundation Ireland (08-IN1- B1853 and 12/1A/1294). Health Research Board of Ireland (HRB/POR/ 2012/101). Breast Cancer Campaign (2013MaySP022). Irish Cancer Society Collaborative Cancer Research Centre grant, CCRC13GAL.
PURPOSE: Disease recurrence is a common problem in breast cancer and yet the mechanisms enabling tumor cells to evade therapy and colonize distant organs remain unclear. We sought to characterize global expression changes occurring with metastatic disease progression in the endocrine-resistant setting.
EXPERIMENTAL DESIGN: Here, for the first time, RNAsequencing has been performed on matched primary, nodal, and liver metastatic tumors from tamoxifen-treated patients following disease progression. Expression of genes commonly elevated in the metastases of sequenced patients was subsequently examined in an extended matched patient cohort with metastatic disease from multiple sites. The impact of tamoxifen treatment on endocrine-resistant tumors in vivo was investigated in a xenograft model.
RESULTS: The extent of patient heterogeneity at the gene level was striking. Less than 3% of the genes differentially expressed between sequential tumors were common to all patients. Larger divergence was observed between primary and liver tumors than between primary and nodal tumors, reflecting both the latency to disease progression and the genetic impact of intervening therapy. Furthermore, an endocrine-resistant in vivo mouse model demonstrated that tamoxifen treatment has the potential to drive disease progression and establish distant metastatic disease. Common functional pathways altered during metastatic, endocrine-resistant progression included extracellular matrix receptor interactions and focal adhesions.
CONCLUSIONS: This novel global analysis highlights the influence of primary tumor biology in determining the transcriptomic profile of metastatic tumors, as well as the need for adaptations in cell-cell communications to facilitate successful tumor cell colonization of distant host organs.
Medicine and Health Sciences | Surgery
McBryan J, Fagan A, McCartan D, Bane FT, Varešlija D, Cocchiglia S, Byrne C, Bolger J, McIlroy M, Hudson L, Tibbitts P, Gaora PÓ, Hill AD, Young LS. Transcriptomic Profiling of Sequential Tumors from Breast Cancer Patients Provides a Global View of Metastatic Expression Changes Following Endocrine Therapy. Clinical Cancer Research. 2015;21(23):5371-9
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