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Evidence for phenotypic plasticity in aggressive triple-negative breast cancer: human biology is recapitulated by a novel model system.

ABSTRACT: Breast cancers with a basal-like gene signature are primarily triple-negative, frequently metastatic, and carry a poor prognosis. Basal-like breast cancers are enriched for markers of breast cancer stem cells as well as markers of epithelial-mesenchymal transition (EMT). While EMT is generally thought to be important in the process of metastasis, in vivo evidence of EMT in human disease remains rare. Here we report a novel model of human triple-negative breast cancer, the DKAT cell line, which was isolated from an aggressive, treatment-resistant triple-negative breast cancer that demonstrated morphological and biochemical evidence suggestive of phenotypic plasticity in the patient. The DKAT cell line displays a basal-like phenotype in vitro when cultured in serum-free media, and undergoes phenotypic changes consistent with EMT/MET in response to serum-containing media, a unique property among the breast cancer cell lines we tested. This EMT is marked by increased expression of the transcription factor Zeb1, and Zeb1 is required for the enhanced migratory ability of DKAT cells in the mesenchymal state. DKAT cells also express progenitor-cell markers, and single DKAT cells are able to generate tumorspheres containing both epithelial and mesenchymal cell types. In vivo, as few as ten DKAT cells are capable of forming xenograft tumors which display a range of epithelial and mesenchymal phenotypes. The DKAT model provides a novel model to study the molecular mechanisms regulating phenotypic plasticity and the aggressive biology of triple-negative breast cancers.

SUBMITTER: D'Amato NC

PROVIDER: S-EPMC3458110 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Evidence for phenotypic plasticity in aggressive triple-negative breast cancer: human biology is recapitulated by a novel model system.

D'Amato Nicholas C NC Ostrander Julie H JH Bowie Michelle L ML Sistrunk Christopher C Borowsky Alexander A Cardiff Robert D RD Bell Katie K Young Lawrence J T LJ Simin Karl K Bachelder Robin E RE Delrow Jeff J Dawson Alyssa A Yee Lisa D LD Mrózek Krzysztof K Clay Timothy M TM Osada Takuya T Seewaldt Victoria L VL

PloS one 20120925 9

Breast cancers with a basal-like gene signature are primarily triple-negative, frequently metastatic, and carry a poor prognosis. Basal-like breast cancers are enriched for markers of breast cancer stem cells as well as markers of epithelial-mesenchymal transition (EMT). While EMT is generally thought to be important in the process of metastasis, in vivo evidence of EMT in human disease remains rare. Here we report a novel model of human triple-negative breast cancer, the DKAT cell line, which w ...[more]

PMID: 23049838

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Project description:: Triple-negative breast cancer (TNBC) accounts for 15% of all breast cancers and is associated with poor long-term outcomes compared with other breast cancer subtypes. Because of the lack of approved targeted therapy, at present chemotherapy remains the mainstay of treatment for early and advanced disease. TNBC is enriched for germline BRCA mutation, providing a foundation for the use of this as a biomarker to identify patients suitable for treatment with DNA-damaging agents. Inherited and acquired defects in homologous recombination DNA repair, a phenotype termed "BRCAness," may be present in a large proportion of TNBC cases, making it an attractive selection and response biomarker for DNA-damaging therapy. Triple-negative breast cancer is a diverse entity for which additional subclassifications are needed. Increasing understanding of biologic heterogeneity of TNBC has provided insight into identifying potentially effective systemic therapies, including cytotoxic and targeted agents. Numerous experimental approaches are under way, and several encouraging drug classes, such as immune checkpoint inhibitors, poly(ADP-ribose) polymerase inhibitors, platinum agents, phosphatidylinositol-3-kinase pathway inhibitors, and androgen receptor inhibitors, are being investigated in TNBC. Molecular biomarker-based patient selection in early-phase trials has the potential to accelerate development of effective therapies for this aggressive breast cancer subtype. TNBC is a complex disease, and it is likely that several different targeted approaches will be needed to make meaningful strides in improving the outcomes.Triple-negative breast cancer (TNBC) is an aggressive subtype that is associated with poor outcomes. This article reviews clinical features and discusses the molecular diversity of this unique subtype. Current treatment paradigms, the role of germline testing, and platinum agents in TNBC are reviewed. Results and observations from pertinent clinical trials with potential implications for patient management are summarized. This article also discusses the clinical development and ongoing clinical trials of novel promising therapeutic agents in TNBC.

Dataset Information

Evidence for phenotypic plasticity in aggressive triple-negative breast cancer: human biology is recapitulated by a novel model system.

Publications

Evidence for phenotypic plasticity in aggressive triple-negative breast cancer: human biology is recapitulated by a novel model system.

Similar Datasets

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