Tumor Cell-Derived Periostin Regulates Cytokines That Maintain Breast Cancer Stem Cells.
Basal-like breast cancer (BLBC) is an aggressive subtype of breast cancer which is often enriched with cancer stem cells (CSC), but the underlying molecular basis for this connection remains elusive. We hypothesized that BLBC cells are able to establish a niche permissive to the maintenance of CSCs and found that tumor cell-derived periostin (POSTN), a component of the extracellular matrix, as well as a corresponding cognate receptor, integrin α(v)β(3), are highly expressed in a subset of BLBC cell lines as well as in CSC-enriched populations. Furthermore, we demonstrated that an intact periostin-integrin β3 signaling axis is required for the maintenance of breast CSCs. POSTN activates the ERK signaling pathway and regulates NF-κB-mediated transcription of key cytokines, namely IL6 and IL8, which in turn control downstream activation of STAT3. In summary, these findings suggest that BLBC cells have an innate ability to establish a microenvironmental niche supportive of CSCs.


CONCLUSIONS
The findings reported here indicate that POSTN produced by CSCs acts to reinforce the stem cell state through the activation of integrin receptors and the production of key cytokines.
Department of Medicine, Molecular Medicine Program, Section of Biomedical Genetics and Cancer Center, Boston University School of Medicine, Boston, Massachusetts.
Arthur W
AW
Lambert
Department of Medicine, Molecular Medicine Program, Section of Biomedical Genetics and Cancer Center, Boston University School of Medicine, Boston, Massachusetts. Department of Genetics and Genomics, Boston University School of Medicine, Boston, Massachusetts.
Chen Khuan
CK
Wong
Department of Medicine, Molecular Medicine Program, Section of Biomedical Genetics and Cancer Center, Boston University School of Medicine, Boston, Massachusetts.
Sait
S
Ozturk
Department of Medicine, Molecular Medicine Program, Section of Biomedical Genetics and Cancer Center, Boston University School of Medicine, Boston, Massachusetts. Department of Genetics and Genomics, Boston University School of Medicine, Boston, Massachusetts.
Panagiotis
P
Papageorgis
Department of Medicine, Molecular Medicine Program, Section of Biomedical Genetics and Cancer Center, Boston University School of Medicine, Boston, Massachusetts.
Rekha
R
Raghunathan
Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts.
Yuriy
Y
Alekseyev
Clinical and Translational Science Institute, Boston University, Boston, Massachusetts.
Adam C
AC
Gower
Department of Chemistry, Boston University, Boston, Massachusetts.
Björn M
BM
Reinhard
Department of Medicine, Molecular Medicine Program, Section of Biomedical Genetics and Cancer Center, Boston University School of Medicine, Boston, Massachusetts.
Hamid M
HM
Abdolmaleky
Department of Medicine, Molecular Medicine Program, Section of Biomedical Genetics and Cancer Center, Boston University School of Medicine, Boston, Massachusetts. Department of Genetics and Genomics, Boston University School of Medicine, Boston, Massachusetts. Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts. samthia@bu.edu.
Sam
S
Thiagalingam
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D039302:Integrin alphaVbeta3; D020935:MAP Kinase Signaling System; D051379:Mice; D014411:Neoplastic Stem Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis
D015815:Cell Adhesion Molecules; D016207:Cytokines; D039302:Integrin alphaVbeta3; C512835:POSTN protein, human