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

doi:10.1016/j.celrep.2018.09.056

Cdh1 and Pik3ca Mutations Cooperate to Induce Immune-Related Invasive Lobular Carcinoma of the Breast

Cell Rep. 2018 Oct 16;25(3):702-714.e6. doi: 10.1016/j.celrep.2018.09.056.

Authors

Yeji An¹, Jessica R Adams², Daniel P Hollern³, Anthony Zhao⁴, Stephen G Chang⁴, Miki S Gams⁴, Philip E D Chung⁵, Xiaping He³, Rhea Jangra², Juhi S Shah², Joanna Yang², Lauren A Beck², Nandini Raghuram¹, Katelyn J Kozma¹, Amanda J Loch², Wei Wang², Cheng Fan³, Susan J Done⁶, Eldad Zacksenhaus⁵, Cynthia J Guidos⁴, Charles M Perou⁷, Sean E Egan⁸

Affiliations

¹ 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.
² Program in Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G-0A4, Canada.
³ Lineberger Comprehensive Cancer Center, Departments of Genetics and Pathology, University of North Carolina, Chapel Hill, NC 27599, USA.
⁴ 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.
⁵ 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.
⁶ 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.
⁷ Lineberger Comprehensive Cancer Center, Departments of Genetics and Pathology, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: cperou@med.unc.edu.
⁸ 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. Electronic address: segan@sickkids.ca.

Abstract

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.

Keywords: Cdh1; Hif1a; Pik3ca; Rac1; Yap; immune checkpoint; immune infiltration; lobular breast cancer; tumor-associated macrophages; tumor-infiltrative lymphocytes.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / metabolism
Animals
Cadherins / physiology*
Carcinoma, Lobular / immunology
Carcinoma, Lobular / metabolism
Carcinoma, Lobular / pathology*
Cell Cycle Proteins / metabolism
Class I Phosphatidylinositol 3-Kinases
Female
Gene Expression Regulation, Neoplastic*
Mammary Neoplasms, Animal / immunology
Mammary Neoplasms, Animal / metabolism
Mammary Neoplasms, Animal / pathology*
Mice
Mice, Knockout
Mutation*
Myeloid Cells / immunology
Myeloid Cells / metabolism
Myeloid Cells / pathology
Neoplasm Invasiveness
Phosphatidylinositol 3-Kinases / physiology*
T-Lymphocytes / immunology
T-Lymphocytes / metabolism
T-Lymphocytes / pathology
Transcriptome
YAP-Signaling Proteins
rac GTP-Binding Proteins / metabolism

Substances

Adaptor Proteins, Signal Transducing
Cadherins
Cdh1 protein, mouse
Cell Cycle Proteins
YAP-Signaling Proteins
Yap1 protein, mouse
Class I Phosphatidylinositol 3-Kinases
Pik3ca protein, mouse
rac GTP-Binding Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding