Paracrine WNT5A Signaling Inhibits Expansion of Tumor-Initiating Cells.
Cancer Res
; 75(10): 1972-82, 2015 May 15.
Article
em En
| MEDLINE
| ID: mdl-25769722
ABSTRACT
It is not well understood how paracrine communication between basal and luminal cell populations in the mammary gland affects tumorigenesis. During ErbB2-induced mammary tumorigenesis, enriched mammary stem cells that represent a subpopulation of basal cells exhibit enhanced tumorigenic capacity compared with the corresponding luminal progenitors. Transcript profiling of tumors derived from basal and luminal tumor-initiating cells (TIC) revealed preferential loss of the noncanonical Wnt ligand WNT5A in basal TIC-derived tumors. Heterozygous loss of WNT5A was correlated with shorter survival of breast cancer patients. In a mouse model of ErbB2-induced breast cancer, Wnt5a heterozygosity promoted tumor multiplicity and pulmonary metastasis. As a TGFß substrate, luminal cell-produced WNT5A induced a feed-forward loop to activate SMAD2 in a RYK and TGFßR1-dependent manner to limit the expansion of basal TIC in a paracrine fashion, a potential explanation for the suppressive effect of WNT5A in mammary tumorigenesis. Our results identify the WNT5A/RYK module as a spatial regulator of the TGFß-SMAD signaling pathway in the context of mammary gland development and carcinogenesis, offering a new perspective on tumor suppression provided by basal-luminal cross-talk in normal mammary tissue.
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Base de dados:
MEDLINE
Assunto principal:
Células-Tronco Neoplásicas
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Neoplasias da Mama
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Proteínas Proto-Oncogênicas
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Proliferação de Células
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Proteínas Wnt
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Neoplasias Pulmonares
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article