Primary breast tumor-derived cellular models: Characterization of tumorigenic, metastatic, and cancer-associated fibroblasts in dissociated tumor (DT) cultures

Katherine Drews-Elger, Joeli A. Brinkman, Philip Miller, Sanket H. Shah, J. Chuck Harrell, Thiago G. Da Silva, Zheng Ao, Amy Schlater, Diana J. Azzam, Kathleen Diehl, Dafydd Thomas, Joyce M. Slingerland, Charles M. Perou, Marc E. Lippman, Dorraya El-Ashry

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24 Scopus citations

Abstract

Our goal was to establish primary cultures from dissociation of breast tumors in order to provide cellular models that may better recapitulate breast cancer pathogenesis and the metastatic process. Here, we report the characterization of six cellular models derived from the dissociation of primary breast tumor specimens, referred to as "dissociated tumor (DT) cells." In vitro, DT cells were characterized by proliferation assays, colony formation assays, protein, and gene expression profiling, including PAM50 predictor analysis. In vivo, tumorigenic and metastatic potential of DT cultures was assessed in NOD/SCID and NSG mice. These cellular models differ from recently developed patient-derived xenograft models in that they can be used for both in vitro and in vivo studies. PAM50 predictor analysis showed DT cultures similar to their paired primary tumor and as belonging to the basal and Her2-enriched subtypes. In vivo, three DT cultures are tumorigenic in NOD/SCID and NSG mice, and one of these is metastatic to lymph nodes and lung after orthotopic inoculation into the mammary fat pad, without excision of the primary tumor. Three DT cultures comprised of cancer-associated fibroblasts (CAFs) were isolated from luminal A, Her2-enriched, and basal primary tumors. Among the DT cells are those that are tumorigenic and metastatic in immunosuppressed mice, offering novel cellular models of ER-negative breast cancer subtypes. A group of CAFs provide tumor subtype-specific components of the tumor microenvironment (TME). Altogether, these DT cultures provide closer-to-primary cellular models for the study of breast cancer pathogenesis, metastasis, and TME.

Original languageEnglish (US)
Pages (from-to)503-517
Number of pages15
JournalBreast Cancer Research and Treatment
Volume144
Issue number3
DOIs
StatePublished - Apr 2014

Keywords

  • ER-negative breast cancer
  • Metastatic xenograft models
  • Primary cultures
  • Tumors

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    Drews-Elger, K., Brinkman, J. A., Miller, P., Shah, S. H., Harrell, J. C., Da Silva, T. G., Ao, Z., Schlater, A., Azzam, D. J., Diehl, K., Thomas, D., Slingerland, J. M., Perou, C. M., Lippman, M. E., & El-Ashry, D. (2014). Primary breast tumor-derived cellular models: Characterization of tumorigenic, metastatic, and cancer-associated fibroblasts in dissociated tumor (DT) cultures. Breast Cancer Research and Treatment, 144(3), 503-517. https://doi.org/10.1007/s10549-014-2887-9