Abstract

The VANGL family of planar cell polarity proteins is implicated in breast cancer however its function in mammary gland biology is unknown. Here, we utilized a panel of Vang1 and Vangl2 mouse alleles to examine the requirement of VANGL family members in the murine mammary gland. We show that Vang1CKOΔ/Δ glands display normal branching while Vangl2flox/flox and Vangl2Lp/Lp tissue exhibit several phenotypes. In MMTV-Cre;Vangl2flox/flox glands, cell turnover is reduced and lumens are narrowed. A Vangl2 missense mutation in the Vangl2Lp/Lp tissue leads to mammary anlage sprouting defects and deficient outgrowth with transplantation of anlage or secondary tissue fragments. In successful Vangl2Lp/Lp outgrowths, three morphological phenotypes are observed: distended ducts, supernumerary end buds, and ectopic acini. Layer specific defects are observed with loss of Vangl2 selectively in either basal or luminal layers of mammary cysts. Loss in the basal compartment inhibits cyst formation, but has the opposite effect in the luminal compartment. Candidate gene analysis on MMTV-Cre;Vangl2flox/flox and Vangl2Lp/Lp tissue reveals a significant reduction in Bmi1 expression, with overexpression of Bmi1 rescuing defects in Vangl2 knockdown cysts. Our results demonstrate that VANGL2 is necessary for normal mammary gland development and indicate differential functional requirements in basal versus luminal mammary compartments.

Details

Title
VANGL2 regulates luminal epithelial organization and cell turnover in the mammary gland
Author
Smith, Prestina 1 ; Godde Nathan 2 ; Rubio Stefany 1 ; Melawit, Tekeste 1 ; Vladar, Eszter K 3   VIAFID ORCID Logo  ; Axelrod, Jeffrey D 4   VIAFID ORCID Logo  ; Henderson, Deborah J 5 ; Milgrom-Hoffman, Michal 6 ; Humbert, Patrick O 7   VIAFID ORCID Logo  ; Hinck, Lindsay 1 

1  University of California, Department of Molecular, Cell and Developmental Biology, Santa Cruz, USA (GRID:grid.205975.c) (ISNI:0000 0001 0740 6917) 
2  Cell Cycle and Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, St Andrews Place, Melbourne, Australia (GRID:grid.1055.1) (ISNI:0000000403978434); University of Melbourne, Sir Peter MacCallum Department of Oncology, Parkville, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X); Commonwealth Scientific and Industrial Research Organisation (CSIRO), Australian Animal Health Laboratory, Victoria, Australia (GRID:grid.1016.6) 
3  Stanford University School of Medicine, Department of Pathology, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956); University of Colorado Denver School of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine and Department of Cell and Developmental Biology, Aurora, USA (GRID:grid.430503.1) (ISNI:0000 0001 0703 675X) 
4  Stanford University School of Medicine, Department of Pathology, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956) 
5  Newcastle University, Cardiovascular Research Centre, Institute of Genetic Medicine, Newcastle upon Tyne, UK (GRID:grid.1006.7) (ISNI:0000 0001 0462 7212) 
6  La Trobe University, Department of Biochemistry & Genetics, La Trobe Institute for Molecular Science, Melbourne, Australia (GRID:grid.1018.8) (ISNI:0000 0001 2342 0938) 
7  Cell Cycle and Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, St Andrews Place, Melbourne, Australia (GRID:grid.1055.1) (ISNI:0000000403978434); University of Melbourne, Sir Peter MacCallum Department of Oncology, Parkville, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X); La Trobe University, Department of Biochemistry & Genetics, La Trobe Institute for Molecular Science, Melbourne, Australia (GRID:grid.1018.8) (ISNI:0000 0001 2342 0938); University of Melbourne, Department of Biochemistry & Genetics, Parkville, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X); University of Melbourne, Department of Clinical Pathology, Parkville, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X) 
Publication year
2019
Publication date
2019
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41598-019-43444-8
ProQuest document ID
2221826303
Copyright
© The Author(s) 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.