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Cancer Res. 2015 May 15;75(10):1972-82. doi: 10.1158/0008-5472.CAN-14-2761. Epub 2015 Mar 13.

Paracrine WNT5A Signaling Inhibits Expansion of Tumor-Initiating Cells.

Author information

1
Department of Pathology, University of Iowa, College of Medicine, Iowa City, Iowa. Medical Science Training Program, University of Iowa, College of Medicine, Iowa City, Iowa.
2
Department of Pathology, University of Iowa, College of Medicine, Iowa City, Iowa. Molecular and Cellular Biology Program, University of Iowa, College of Medicine, Iowa City, Iowa.
3
Department of Pathology, University of Iowa, College of Medicine, Iowa City, Iowa. Immunology Program, University of Iowa, College of Medicine, Iowa City, Iowa.
4
Department of Pathology, University of Iowa, College of Medicine, Iowa City, Iowa. College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, P.R. China.
5
Department of Pathology, University of Iowa, College of Medicine, Iowa City, Iowa.
6
Department of Pathology, University of Iowa, College of Medicine, Iowa City, Iowa. Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China.
7
Medical Science Training Program, University of Iowa, College of Medicine, Iowa City, Iowa.
8
Department of Surgery, University of Iowa, College of Medicine, Iowa City, Iowa. Holden Comprehensive Cancer Center, University of Iowa, College of Medicine, Iowa City, Iowa.
9
Department of Pathology, University of Iowa, College of Medicine, Iowa City, Iowa. Medical Science Training Program, University of Iowa, College of Medicine, Iowa City, Iowa. Molecular and Cellular Biology Program, University of Iowa, College of Medicine, Iowa City, Iowa. Immunology Program, University of Iowa, College of Medicine, Iowa City, Iowa. Holden Comprehensive Cancer Center, University of Iowa, College of Medicine, Iowa City, Iowa. weizhou-zhang@uiowa.edu.

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 TGFβ substrate, luminal cell-produced WNT5A induced a feed-forward loop to activate SMAD2 in a RYK and TGFβR1-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 TGFβ-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.

PMID:
25769722
PMCID:
PMC4433621
DOI:
10.1158/0008-5472.CAN-14-2761
[Indexed for MEDLINE]
Free PMC Article

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