TY - JOUR
T1 - Evidence for Phenotypic Plasticity in Aggressive Triple-Negative Breast Cancer
T2 - Human Biology Is Recapitulated by a Novel Model System
AU - Ostrander, Julie H
AU - D'Amato, Nicholas C.
AU - Bowie, Michelle L.
AU - Sistrunk, Christopher
AU - Borowsky, Alexander
AU - Cardiff, Robert D.
AU - Bell, Katie
AU - Young, Lawrence J.T.
AU - Simin, Karl
AU - Bachelder, Robin E.
AU - Delrow, Jeff
AU - Dawson, Alyssa
AU - Yee, Lisa D.
AU - Mrózek, Krzysztof
AU - Clay, Timothy M.
AU - Osada, Takuya
AU - Seewaldt, Victoria L.
PY - 2012/9/25
Y1 - 2012/9/25
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0045684
DO - 10.1371/journal.pone.0045684
M3 - Article
C2 - 23049838
AN - SCOPUS:84866656942
SN - 1932-6203
VL - 7
JO - PloS one
JF - PloS one
IS - 9
M1 - e45684
ER -