Cdh1 and Pik3ca Mutations Cooperate to Induce Immune-Related Invasive Lobular Carcinoma of the Breast
Yeji An,
Jessica R. Adams,
Daniel P. Hollern,
Anthony Zhao,
Stephen G. Chang,
Miki S. Gams,
Philip E.D. Chung,
Xiaping He,
Rhea Jangra,
Juhi S. Shah,
Joanna Yang,
Lauren A. Beck,
Nandini Raghuram,
Katelyn J. Kozma,
Amanda J. Loch,
Wei Wang,
Cheng Fan,
Susan J. Done,
Eldad Zacksenhaus,
Cynthia J. Guidos,
Charles M. Perou,
Sean E. Egan
Affiliations
Yeji An
Program in Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G-0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
Jessica R. Adams
Program in Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G-0A4, Canada
Daniel P. Hollern
Lineberger Comprehensive Cancer Center, Departments of Genetics and Pathology, University of North Carolina, Chapel Hill, NC 27599, USA
Anthony Zhao
Program in Developmental and Stem Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G-0A4, Canada; Department of Immunology, University of Toronto, Toronto, ON, Canada
Stephen G. Chang
Program in Developmental and Stem Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G-0A4, Canada; Department of Immunology, University of Toronto, Toronto, ON, Canada
Miki S. Gams
Program in Developmental and Stem Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G-0A4, Canada; Department of Immunology, University of Toronto, Toronto, ON, Canada
Philip E.D. Chung
Division of Cell and Molecular Biology, Toronto General Research Institute, University Health Network, and Department of Medicine, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
Xiaping He
Lineberger Comprehensive Cancer Center, Departments of Genetics and Pathology, University of North Carolina, Chapel Hill, NC 27599, USA
Rhea Jangra
Program in Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G-0A4, Canada
Juhi S. Shah
Program in Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G-0A4, Canada
Joanna Yang
Program in Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G-0A4, Canada
Lauren A. Beck
Program in Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G-0A4, Canada
Nandini Raghuram
Program in Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G-0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
Katelyn J. Kozma
Program in Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G-0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
Amanda J. Loch
Program in Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G-0A4, Canada
Wei Wang
Program in Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G-0A4, Canada
Cheng Fan
Lineberger Comprehensive Cancer Center, Departments of Genetics and Pathology, University of North Carolina, Chapel Hill, NC 27599, USA
Susan J. Done
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; The Campbell Family Institute for Breast Cancer Research at the Princess Margaret Cancer Centre and The Laboratory Medicine Program, University Health Network, Toronto, ON, Canada
Eldad Zacksenhaus
Division of Cell and Molecular Biology, Toronto General Research Institute, University Health Network, and Department of Medicine, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
Cynthia J. Guidos
Program in Developmental and Stem Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G-0A4, Canada; Department of Immunology, University of Toronto, Toronto, ON, Canada
Charles M. Perou
Lineberger Comprehensive Cancer Center, Departments of Genetics and Pathology, University of North Carolina, Chapel Hill, NC 27599, USA; Corresponding author
Sean E. Egan
Program in Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G-0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Corresponding author
Summary: CDH1 and PIK3CA are the two most frequently mutated genes in invasive lobular carcinoma (ILC) of the breast. Transcription profiling has identified molecular subtypes for ILC, one of which, immune-related (IR), is associated with gene expression linked to lymphocyte and macrophage infiltration. Here, we report that deletion of Cdh1, together with activation of Pik3ca in mammary epithelium of genetically modified mice, leads to formation of IR-ILC-like tumors with immune cell infiltration, as well as gene expression linked to T-regulatory (Treg) cell signaling and activation of targetable immune checkpoint pathways. Interestingly, these tumors show enhanced Rac1- and Yap-dependent transcription and signaling, as well as sensitivity to PI3K, Rac1, and Yap inhibitors in culture. Finally, high-dimensional immunophenotyping in control mouse mammary gland and IR-ILC tumors by mass cytometry shows dramatic alterations in myeloid and lymphoid populations associated with immune suppression and exhaustion, highlighting the potential for therapeutic intervention via immune checkpoint regulators. : An et al. describe the development and characterization of a mouse model for invasive lobular carcinoma (ILC) of the breast based on the two most mutated genes in human ILC. This model is analogous to immune-related ILC, shows myeloid and T cell alterations consistent with immune suppression and exhaustion, and represents a platform for therapeutics. Keywords: lobular breast cancer, Cdh1, Pik3ca, immune infiltration, immune checkpoint, Rac1, Yap, Hif1a, tumor-associated macrophages, tumor-infiltrative lymphocytes
