Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, CA, 95064, USA.
Cell Cycle and Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, St Andrews Place, Melbourne, VIC, 3002, Australia.
Sci Rep. 2019 May 8;9(1):7079. doi: 10.1038/s41598-019-43444-8.
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 Vang1CKO glands display normal branching while Vangl2 and Vangl2 tissue exhibit several phenotypes. In MMTV-Cre;Vangl2 glands, cell turnover is reduced and lumens are narrowed. A Vangl2 missense mutation in the Vangl2 tissue leads to mammary anlage sprouting defects and deficient outgrowth with transplantation of anlage or secondary tissue fragments. In successful Vangl2 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;Vangl2 and Vangl2 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.
VANGL 家族的平面细胞极性蛋白与乳腺癌有关，但其在乳腺生物学中的功能尚不清楚。在这里，我们利用一系列 Vang1 和 Vangl2 小鼠等位基因来研究 VANGL 家族成员在乳腺中的必要性。我们发现 Vang1CKO 腺体显示出正常的分支，而 Vangl2 和 Vangl2 组织则表现出多种表型。在 MMTV-Cre;Vangl2 腺体中，细胞更替减少，腔变窄。Vangl2 组织中的 Vangl2 错义突变导致乳腺原基发芽缺陷，并导致原基或次级组织片段移植后的生长不足。在成功的 Vangl2 生长中，观察到三种形态表型：膨胀的导管、多余的终芽和异位腺泡。在乳腺囊肿的基底或腔层中选择性缺失 Vangl2 会观察到层特异性缺陷。基底隔室的缺失抑制了囊肿的形成，但在腔隔室中则产生相反的效果。MMTV-Cre;Vangl2 和 Vangl2 组织上的候选基因分析显示 Bmi1 表达显著减少，Vangl2 敲低囊肿中过表达 Bmi1 可挽救缺陷。我们的结果表明 VANGL2 是正常乳腺发育所必需的，并表明基底与腔乳腺隔室的功能要求不同。
