Kessenbrock Kai, Smith Prestina, Steenbeek Sander Christiaan, Pervolarakis Nicholas, Kumar Raj, Minami Yasuhiro, Goga Andrei, Hinck Lindsay, Werb Zena
Department of Biological Chemistry, University of California, Irvine, CA 92697.
Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, CA 95064.
Proc Natl Acad Sci U S A. 2017 Mar 21;114(12):3121-3126. doi: 10.1073/pnas.1701464114. Epub 2017 Mar 7.
The mammary gland consists of an adipose tissue that, in a process called branching morphogenesis, is invaded by a ductal epithelial network comprising basal and luminal epithelial cells. Stem and progenitor cells drive mammary growth, and their proliferation is regulated by multiple extracellular cues. One of the key regulatory pathways for these cells is the β-catenin-dependent, canonical wingless-type MMTV integration site family (WNT) signaling pathway; however, the role of noncanonical WNT signaling within the mammary stem/progenitor system remains elusive. Here, we focused on the noncanonical WNT receptors receptor tyrosine kinase-like orphan receptor 2 (ROR2) and receptor-like tyrosine kinase (RYK) and their activation by WNT5A, one of the hallmark noncanonical WNT ligands, during mammary epithelial growth and branching morphogenesis. We found that WNT5A inhibits mammary branching morphogenesis in vitro and in vivo through the receptor tyrosine kinase ROR2. Unexpectedly, WNT5A was able to enhance mammary epithelial growth, which is in contrast to its next closest relative WNT5B, which potently inhibits mammary stem/progenitor proliferation. We found that RYK, but not ROR2, is necessary for WNT5A-mediated promotion of mammary growth. These findings provide important insight into the biology of noncanonical WNT signaling in adult stem/progenitor cell regulation and development. Future research will determine how these interactions go awry in diseases such as breast cancer.
乳腺由脂肪组织构成，在一个称为分支形态发生的过程中，脂肪组织会被一个由基底上皮细胞和管腔上皮细胞组成的导管上皮网络侵入。干细胞和祖细胞驱动乳腺生长，它们的增殖受多种细胞外信号的调节。这些细胞的关键调控途径之一是β-连环蛋白依赖性的经典无翅型MMTV整合位点家族（WNT）信号通路；然而，非经典WNT信号在乳腺干细胞/祖细胞系统中的作用仍不清楚。在这里，我们聚焦于非经典WNT受体受体酪氨酸激酶样孤儿受体2（ROR2）和受体样酪氨酸激酶（RYK），以及在乳腺上皮生长和分支形态发生过程中它们被典型的非经典WNT配体之一WNT5A激活的情况。我们发现，WNT5A在体外和体内通过受体酪氨酸激酶ROR2抑制乳腺分支形态发生。出乎意料的是，WNT5A能够促进乳腺上皮生长，这与其关系最为密切的WNT5B相反，WNT5B能有效抑制乳腺干细胞/祖细胞的增殖。我们发现，RYK而非ROR2是WNT5A介导的促进乳腺生长所必需的。这些发现为非经典WNT信号在成体干细胞/祖细胞调控和发育中的生物学特性提供了重要见解。未来的研究将确定这些相互作用在乳腺癌等疾病中是如何出现异常的。
