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Cdh1 and Pik3ca mutations cooperate to induce Immune-Related Invasive Lobular Carcinoma of the Breast

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 homozygous deletion of Cdh1 together with mutational activation of Pik3ca in mammary epithelium of genetically modified mice leads to rapid formation of IR-ILC-like tumors with immune cell infiltration, as well as gene expression signatures linked to TRegulatory (Treg) cell signaling and immune checkpoint inhibitor pathway activation. Interestingly, these tumors show enhanced Oct4-, Hif1á-, YAP-, Shh-, Rac- and Notch-dependent transcription/signaling, features in common with human IR-ILC and therefore potential targets for therapy. Gene expression profiling reveals immune infiltration and similarities to a subtype of human Invasive Lobular carcinoma.

ORGANISM(S): Mus musculus

PROVIDER: GSE107432 | GEO | 2018/10/16

REPOSITORIES: GEO

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Project description:Invasive lobular carcinoma (ILC) of the breast accounts for 5-15% of breast cancers and is characterized by loss of E-cadherin and believed to arise via a linear histological progression. Genomic studies have identified a clonal relationship between ILC and concurrent lobular carcinoma in situ (LCIS) lesions, suggesting that LCIS may be a precursor lesion. It has been shown that an LCIS diagnosis confers a 15-20% risk of progression to ILC, over a lifetime. Currently no molecular test or markers can identify LCIS lesions likely to progress to ILC. Since microRNA (miRNA) expression changes have been detected in a number of other cancer types, we explored whether their dysregulation might be detected during progression from LCIS to ILC. Using the Illumina miRNA profiling platform, designed for simultaneous analysis of 470 mature miRNAs, we analyzed the profiles of archived normal breast epithelium, LCIS lesions found alone, LCIS lesions concurrent with ILC, and the concurrent ILCs, as a model of linear histological progression toward ILC. We identified two sets of differentially expressed miRNAs, the first set highly expressed in normal epithelium, including hsa-miR-224, -139, -10b, -450, 140 and -365 and the second set upregulated during lobular neoplasia, including hsa-miR-375, -203, -425-5p, -183, -565 and -182. Using quantitative RT-PCR, we validated a trend of increased expression for hsa-mir-375, hsa-mir-182, and hsa-mir-183 correlating with ILC progression. As we detected increased expression of hsa-miR-375 in LCIS lesions synchronous with ILC, we sought to determine whether hsa-mir-375 might induce phenotypes reminiscent of lobular neoplasia by expressing it in the MCF10A 3D culture model of mammary acinar morphogenesis. Increased expression of hsa-miR-375 resulted in loss of cellular organization and acquisition of a hyperplastic phenotype. These data suggest that dysregulated miRNA expression contributes to lobular neoplastic progression. 6 specimens were analyzed in duplicate. One frozen normal lobular epithelium and the matched FFPE (1 month old) normal lobular epithelium. One lobular carcinoma in situ (LCIS) found alone, one LCIS synchronous with an invasive lobular carcinoma (ILC), the synchronous ILC (from a different archived block), and one ILC found alone without presence of any other breast cancer.

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Cdh1 and Pik3ca mutations cooperate to induce Immune-Related Invasive Lobular Carcinoma of the Breast

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