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 CD44high/CD24low population, enriched for CSCs, is comprised of distinct...
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doaj-4e1a162adbeb445b9041895eb65122512020-11-24T21:34:06ZengElsevierCell Reports2211-12472014-05-017374776110.1016/j.celrep.2014.03.059Regulated Splicing of the α6 Integrin Cytoplasmic Domain Determines the Fate of Breast Cancer Stem CellsHira Lal Goel0Tatiana Gritsko1Bryan Pursell2Cheng Chang3Leonard D. Shultz4Dale L. Greiner5Jens Henrik Norum6Rune Toftgard7Leslie M. Shaw8Arthur M. Mercurio9Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USADepartment of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USADepartment of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USADepartment of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USAThe Jackson Laboratory, Bar Harbor, ME 04609, USAProgram in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USADepartment of Bioscience and Nutrition, Center for Biosciences, Karolinska Institute, Novum, 14183 Huddinge, SwedenDepartment of Bioscience and Nutrition, Center for Biosciences, Karolinska Institute, Novum, 14183 Huddinge, SwedenDepartment of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USADepartment of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USAAlthough 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 CD44high/CD24low 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.http://www.sciencedirect.com/science/article/pii/S2211124714002563 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Hira Lal Goel Tatiana Gritsko Bryan Pursell Cheng Chang Leonard D. Shultz Dale L. Greiner Jens Henrik Norum Rune Toftgard Leslie M. Shaw Arthur M. Mercurio |
spellingShingle |
Hira Lal Goel Tatiana Gritsko Bryan Pursell Cheng Chang Leonard D. Shultz Dale L. Greiner Jens Henrik Norum Rune Toftgard Leslie M. Shaw Arthur M. Mercurio Regulated Splicing of the α6 Integrin Cytoplasmic Domain Determines the Fate of Breast Cancer Stem Cells Cell Reports |
author_facet |
Hira Lal Goel Tatiana Gritsko Bryan Pursell Cheng Chang Leonard D. Shultz Dale L. Greiner Jens Henrik Norum Rune Toftgard Leslie M. Shaw Arthur M. Mercurio |
author_sort |
Hira Lal Goel |
title |
Regulated Splicing of the α6 Integrin Cytoplasmic Domain Determines the Fate of Breast Cancer Stem Cells |
title_short |
Regulated Splicing of the α6 Integrin Cytoplasmic Domain Determines the Fate of Breast Cancer Stem Cells |
title_full |
Regulated Splicing of the α6 Integrin Cytoplasmic Domain Determines the Fate of Breast Cancer Stem Cells |
title_fullStr |
Regulated Splicing of the α6 Integrin Cytoplasmic Domain Determines the Fate of Breast Cancer Stem Cells |
title_full_unstemmed |
Regulated Splicing of the α6 Integrin Cytoplasmic Domain Determines the Fate of Breast Cancer Stem Cells |
title_sort |
regulated splicing of the α6 integrin cytoplasmic domain determines the fate of breast cancer stem cells |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2014-05-01 |
description |
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 CD44high/CD24low 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. |
url |
http://www.sciencedirect.com/science/article/pii/S2211124714002563 |
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