Evidence for phenotypic plasticity in aggressive triple-negative breast cancer: human biology is recapitulated by a novel model system.
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.
Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, USA.
Nicholas C
NC
D'Amato
Julie H
JH
Ostrander
Michelle L
ML
Bowie
Christopher
C
Sistrunk
Alexander
A
Borowsky
Robert D
RD
Cardiff
Katie
K
Bell
Lawrence J T
LJ
Young
Karl
K
Simin
Robin E
RE
Bachelder
Jeff
J
Delrow
Alyssa
A
Dawson
Lisa D
LD
Yee
Krzysztof
K
Mrózek
Timothy M
TM
Clay
Takuya
T
Osada
Victoria L
VL
Seewaldt
D000328:Adult; D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D003582:Cytogenetics; D058750:Epithelial-Mesenchymal Transition; D005091:Exons; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007621:Karyotyping; D051379:Mice; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010641:Phenotype; D011379:Prognosis
D016895:Culture Media, Serum-Free