{
  "abstract": "Background Breast cancer associated gene 1 (BRCA1) mutant malignancy is an aggressive subtype of breast cancer caused by mutations in the BRCA1 gene. Disease was thought to be caused by an accumulation of genetic damage, but more recently we have evidence showing that there are other factors in the microenvironment such as the immune cells are involved in the initiation of this disease. Many breast tumor subtypes are categorized as cold tumors with low immune infiltration and poor response to immunotherapy. But BRCA1 deficient tumors have been shown to be associated with a more conspicuous immune cell infiltration than other breast cancer subtypes.Methods We use a genetically engineered mouse model that lacks BRCA1 and p53 genes for this study. Additionally, we analyzed BRCA1 mutant and tumor tissues from patients. Using a combination of single cell genomics and spatial proteomics we identify changes in the immune microenvironment of the BRCA1 mutant tissues. We also employ methods such as flow cytometry and immunofluorescence to quantify immune cell populations in the BRCA1 mutant tissues.Results Through my analysis of single cell sequencing data and by flow cytometry, there is a substantial increase in pro-inflammatory macrophages within the BRCA1 mutant tissues at the premalignant stage. There is a change in the macrophage phenotype, transitioning from tissue-resident to a more inflammatory type within the microenvironment. Using a powerful spatial proteomics technology, I have also found a substantial accumulation of immune cells in the mutant tissues prior to tumor formation particularly surrounding the epithelial structures. It appears that these immune cells are mostly F4/80+ macrophages. Using in-vitro mammary organoids co-cultured with the mammary gland macrophages from the BRCA1 mutant mice, I found that that there is increased growth and branching of the epithelium. We observe a similar pro-inflammatory microenvironment in human BRCA1 mutation carriers as well.Conclusions Our data suggests that there is a pro-inflammatory immune microenvironment in the premalignant tissues prior to tumor formation with accumulation of macrophages. Our in-situ analysis suggests that there could be potential interactions between tumor/epithelial cells and macrophages at the premalignant stage. If it is established that the macrophages play a critical role in the initiation of this disease, it would represent a significant paradigm shift in the field. Moreover, it would open the possibility of utilizing immunotherapies as a means of potential strategies for cancer prevention in individuals with BRCA1 mutations.",
  "authors": [
    {
      "affiliations": [
        "University of California, Irvine, Irvine, CA, USA"
      ],
      "name": "Angela Lincy Prem Antony Samy"
    },
    {
      "affiliations": [
        "University of California, Irvine, Irvine, CA, USA"
      ],
      "name": "Victoria Mai"
    },
    {
      "affiliations": [
        "University of California, Irvine, Irvine, CA, USA"
      ],
      "name": "Tatyana Lev"
    },
    {
      "affiliations": [
        "University of California, Irvine, Irvine, CA, USA"
      ],
      "name": "Maren Pein"
    },
    {
      "affiliations": [
        "University of California, Irvine, Irvine, CA, USA"
      ],
      "name": "Isam Adam"
    },
    {
      "affiliations": [
        "University of California, Irvine, Irvine, CA, USA"
      ],
      "name": "Erika Zagni"
    },
    {
      "affiliations": [
        "University of California, Irvine, Irvine, CA, USA"
      ],
      "name": "Sharmila Mallya"
    },
    {
      "affiliations": [
        "University of California, Irvine, Irvine, CA, USA"
      ],
      "name": "Hannah Savage"
    },
    {
      "affiliations": [
        "University of California, Irvine, Irvine, CA, USA"
      ],
      "name": "Devon A Lawson"
    }
  ],
  "title": "1207 Targeting the pro-inflammatory microenvironment to prevent cancer initiation in BRCA1 mutation carriers",
  "uid": "5fa3f4ff-474c-5d60-87d0-3bc0fee31a5f"
}