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

Abstract

SUMMARYCDH1 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.

Network-based approaches elucidate differences within APOBEC and clock-like signatures in breast cancer

“…Cadherins are important in the maintenance of cell adhesion and polarity, and alterations of these functions can contribute to tumorigenesis. CDH1 germline mutations have been associated with hereditary lobular breast cancer [61] and hereditary diffuse gastric cancer [62,63], while a recent study linked mutations in CDH1 and PIK3CA to the immune-related invasive lobular carcinoma of the breast [64]. In breast cancer, mutations in CDH1-PIK3CA module are mutually exclusive with mutations in TP53 and are strongly enriched in Luminal A subtype [65].…”

YAP/TAZ: Drivers of Tumor Growth, Metastasis, and Resistance to Therapy

“…[ 169 ] Recent evidence suggests that PI3K‐Akt signaling also inhibits the Hippo pathway to promote YAP/TAZ activation to drive cell proliferation and malignancy. [ 99,115,170‐178 ] Importantly, further work is necessary to identify the molecular mechanism by which PI3K‐Akt signaling inhibits the Hippo pathway. In addition, while PI3K‐Akt signaling appears necessary to promote YAP/TAZ activation, it is apparently not sufficient, as cells also require mechanical stimulation or other additional inputs to activate YAP/TAZ.…”

“…There is some evidence that YAP/TAZ may confer resistance of cancer cells to immunotherapy, through upregulation of PD‐L1 expression, [ 82 ] or through regulation of macrophages/myeloid derived suppressor cell (MDSC) cell infiltrates. [ 86,100,177,178,286 ] Thus, targeting YAP/TAZ may be an ideal “adjuvant” for combination with immunotherapy.…”

Progress and applications of mass cytometry in sketching immune landscapes

“…With relative high cellular throughput and high dimensions, CyTOF is an ideal and potent technique that reveals intratumor heterogeneity in a variety of tumors, including breast, [70][71][72][73] lung, [74][75][76][77] oropharyngeal, 78 brain, [79][80][81][82][83] colon, 7,11,84,85 ovarian, 86,87 kidney, 88,89 gastric cancer, 90,91 leukemia and lymphoma, 19,[92][93][94][95] and melanoma. 96,97 A summary of single-cell CyTOF studies on primary tumors of various human cancers is presented in Table 3.…”