Abstract
Abstract Background: The mammary gland exhibits extensive proliferative and differentiation potential throughout development. Wnt signaling has been recognized as a crucial player in multiple stages of mammary gland development, including mammary placode specification, gland branching morphogenesis, stem cell maintenance, and alveolar development. In our laboratory, prior research has revealed the importance of the β-catenin-independent noncanonical Wnt receptor, Ror2, in branching morphogenesis, cell differentiation, and actin-cytoskeletal dynamics within the mammary epithelium. However, the specific roles of Ror2 in the myoepithelial and luminal cell compartments have yet to be fully elucidated. Methods and Results: In this study, we investigated the functional role of Ror2 in these two distinct cell populations by developing mouse models with lineage-specific deletion of Ror2 in myoepithelial versus luminal epithelial compartments. To achieve this, we generated two tamoxifen-inducible, p63- and Keratin 8-specific Ror2 knockout mouse models, which carried a ROSA26-mT/mG fluorescent reporter for mammary myoepithelial cells and luminal cells, respectively. We induced postnatal Ror2 deletion at week 4 or 6 and assessed the mammary glands 2 to 4 weeks after Ror2 deletion. Through whole-mount imaging of mammary glands, we observed a significant increase in branching morphogenesis when Ror2 was deleted in the myoepithelial compartment, which was further confirmed in 3D branching assays in vitro. RNA-sequencing analysis revealed novel transcriptional alterations encompassing altered morphogenesis, cell differentiation, and intermediate filament organization upon Ror2 loss. Additional gene expression validation and immunofluorescence demonstrated altered myoepithelial cell fate specification, leading to a shift to a luminal-like cell fate, along with altered cell-cell adhesion among epithelial populations and abnormal branching morphogenesis within the developing gland. Moreover, luminal-specific deletion of Ror2 resulted in increased proliferation and abnormal lumen formation, both in vivo and in vitro. Conclusion: Our findings from these tissue-specific knockout mouse models highlight the critical role of the noncanonical Wnt receptor, Ror2, in regulating mammary epithelial cell fate, branching morphogenesis, and proliferation. These results also provide intriguing insights into the coordination between canonical and noncanonical Wnt signaling in mammary gland development, with potential implications for understanding breast cancer tumorigenesis and heterogeneity (Supported by NIH CA016303-46 and CPRIT RP210027). Citation Format: Hongjiang Si, Jeffrey Rosen, Chad Creighton, Kevin Roarty. Wnt/Ror2 signaling regulates myoepithelial cell fate and luminal cell proliferation during mammary development [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B012.
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