title: Paracrine WNT5A Signaling Inhibits Expansion of Tumor-Initiating Cells.
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.
authors.affiliation: 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.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Borcherding
authors.affiliation: 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.
authors.forename: David
authors.initials: D
authors.lastname: Kusner
authors.affiliation: Department of Pathology, University of Iowa, College of Medicine, Iowa City, Iowa. Immunology Program, University of Iowa, College of Medicine, Iowa City, Iowa.
authors.forename: Ryan
authors.initials: R
authors.lastname: Kolb
authors.affiliation: Department of Pathology, University of Iowa, College of Medicine, Iowa City, Iowa. College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, P.R. China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xie
authors.affiliation: Department of Pathology, University of Iowa, College of Medicine, Iowa City, Iowa.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Fang
authors.initials: F
authors.lastname: Yuan
authors.affiliation: Medical Science Training Program, University of Iowa, College of Medicine, Iowa City, Iowa.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Velez
authors.affiliation: Department of Pathology, University of Iowa, College of Medicine, Iowa City, Iowa.
authors.forename: Ryan
authors.initials: R
authors.lastname: Askeland
authors.affiliation: 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.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Weigel
authors.affiliation: 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.
authors.forename: Weizhou
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D049109:Cell Proliferation; D005260:Female; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D008810:Mice, Inbred C57BL; D014411:Neoplastic Stem Cells / Q000502:physiology*; D019899:Paracrine Communication; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051899:Smad2 Protein / Q000378:metabolism; D059467:Transcriptome; D016212:Transforming Growth Factor beta / Q000502:physiology; D051153:Wnt Proteins / Q000502:physiology*; D000071818:Wnt-5a Protein
chemical_list: D011518:Proto-Oncogene Proteins; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein