Regulated splicing of the α6 integrin cytoplasmic domain determines the fate of breast cancer stem cells.
Although the α6β1 integrin has been implicated in the function of breast and other cancer stem cells (CSCs), little is known about its regulation and relationship to mechanisms involved in the genesis of CSCs. We report that a CD44(high)/CD24(low) population, enriched for CSCs, is comprised of distinct epithelial and mesenchymal populations that differ in expression of the two α6 cytoplasmic domain splice variants: α6A and α6B. α6Bβ1 expression defines the mesenchymal population and is necessary for CSC function, a function that cannot be executed by α6A integrins. The generation of α6Bβ1 is tightly controlled and occurs as a consequence of an autocrine vascular endothelial growth factor (VEGF) signaling that culminates in the transcriptional repression of a key RNA-splicing factor. These data alter our understanding of how α6β1 contributes to breast cancer, and they resolve ambiguities regarding the use of total α6 (CD49f) expression as a biomarker for CSCs.
Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Hira Lal
HL
Goel
Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Tatiana
T
Gritsko
Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Bryan
B
Pursell
Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Cheng
C
Chang
The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Leonard D
LD
Shultz
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Dale L
DL
Greiner
Department of Bioscience and Nutrition, Center for Biosciences, Karolinska Institute, Novum, 14183 Huddinge, Sweden.
Jens Henrik
JH
Norum
Department of Bioscience and Nutrition, Center for Biosciences, Karolinska Institute, Novum, 14183 Huddinge, Sweden.
Rune
R
Toftgard
Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Leslie M
LM
Shaw
Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: arthur.mercurio@umassmed.edu.
Arthur M
AM
Mercurio
D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D051927:CD24 Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D039503:Integrin alpha6 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D012326:RNA Splicing / Q000502:physiology*; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C069077:BMI1 protein, human; D051927:CD24 Antigen; C539364:ESRP1 protein, human; D018960:Hyaluronan Receptors; D039503:Integrin alpha6; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D042461:Vascular Endothelial Growth Factor A; D063150:Polycomb Repressive Complex 1