title: Triple negative breast cancer initiating cell subsets differ in functional and molecular characteristics and in γ-secretase inhibitor drug responses.
abstract: Increasing evidence suggests that stem-like cells mediate cancer therapy resistance and metastasis. Breast tumour-initiating stem cells (T-ISC) are known to be enriched in CD44(+) CD24(neg/low) cells. Here, we identify two T-ISC subsets within this population in triple negative breast cancer (TNBC) lines and dissociated primary breast cancer cultures: CD44(+) CD24(low+) subpopulation generates CD44(+) CD24(neg) progeny with reduced sphere formation and tumourigenicity. CD44(+) CD24(low+) populations contain subsets of ALDH1(+) and ESA(+) cells, yield more frequent spheres and/or T-ISC in limiting dilution assays, preferentially express metastatic gene signatures and show greater motility, invasion and, in the MDA-MB-231 model, metastatic potential. CD44(+) CD24(low+) but not CD44(+) CD24(neg) express activated Notch1 intracellular domain (N1-ICD) and Notch target genes. We show N1-ICD transactivates SOX2 to increase sphere formation, ALDH1+ and CD44(+) CD24(low+) cells. Gamma secretase inhibitors (GSI) reduced sphere formation and xenograft growth from CD44(+) CD24(low+) cells, but CD44(+) CD24(neg) were resistant. While GSI hold promise for targeting T-ISC, stem cell heterogeneity as observed herein, could limit GSI efficacy. These data suggest a breast T-ISC hierarchy in which distinct pathways drive developmentally related subpopulations with different anti-cancer drug responsiveness.
authors: Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA; Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA.
authors: Diana J
authors: DJ
authors: Azzam
authors: Dekuang
authors: D
authors: Zhao
authors: Jun
authors: J
authors: Sun
authors: Andy J
authors: AJ
authors: Minn
authors: Prathibha
authors: P
authors: Ranganathan
authors: Katherine
authors: K
authors: Drews-Elger
authors: Xiaoqing
authors: X
authors: Han
authors: Manuel
authors: M
authors: Picon-Ruiz
authors: Candace A
authors: CA
authors: Gilbert
authors: Seth A
authors: SA
authors: Wander
authors: Anthony J
authors: AJ
authors: Capobianco
authors: Dorraya
authors: D
authors: El-Ashry
authors: Joyce M
authors: JM
authors: Slingerland
mesh_terms: D000080924:Aldehyde Dehydrogenase 1 Family; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity; D051927:CD24 Antigen / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D050697:Retinal Dehydrogenase / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D051927:CD24 Antigen; D004791:Enzyme Inhibitors; D018960:Hyaluronan Receptors; D007527:Isoenzymes; D051880:Receptors, Notch; D055748:SOXB1 Transcription Factors; D000080924:Aldehyde Dehydrogenase 1 Family; C510223:ALDH1A1 protein, human; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase; D053829:Amyloid Precursor Protein Secretases
keywords: GSI; Notch1; Sox2; breast cancer stem cells; metastasis
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