In vitro models as a window to learn how to change outcomes in women at high risk of developing breast cancer

Breast cancer is a heterogeneous disease, with different subtypes likely arising from distinct precursor cells in the normal breast. What remains unknown is how we can target distinct precancerous cell types to prevent or intercept breast cancers in high-risk populations in a personalized manner. We previously combined detailed single-cell analyses of histologically normal breast tissues from patients with inherited mutations in BRCA1 and BRCA2 to identify aberrant cell types enriched in these cancer-prone tissues. This proposal seeks to develop models to identify new targets for breast cancer prevention in diverse high-risk states, and to help determine who would benefit from these interventions. This will be performed by combining advances in organoid culturing with single-cell RNA sequencing, mass cytometry, and multiplexed immunofluorescence studies. First, organoids will be generated from the breast tissue of patients at increased risk of developing breast cancer based on the presence of imaging-based markers, focusing on background parenchymal enhancement (BPE) on MRI as an indicator of global risk of developing invasive cancer. Tissue-based and organoid-based techniques will be used to determine the cell types enriched and pathways deregulated in this disease state. Second, the tissue environment of women with DCIS in the setting of BPE who demonstrate response and nonresponse to endocrine therapies (in Project 4) will be evaluated. Third, high-risk states including young women who developed triple-negative breast cancer before the age of 40 will be evaluated for potential cancer prevention targets and deregulated pathways at the tissue level, including by the development of T cell-organoid co-culture systems to model immune surveillance. Finally, candidate prevention/ intervention strategies will be assessed in patient-derived organoid models of high-risk tissues to identify potential compounds for a future adaptive platform trial for breast cancer prevention (Project 4 aim 4). The project lead, Dr. Rosenbluth, is a breast medical oncologist with a research background in cell and cancer biology and with expertise in 3D culture models of cancer prevention. An expert team has been assembled for this project including Dr. Laura Esserman, an internationally recognized expert in breast cancer research, Dr. Laura van 't Veer, world renowned molecular biologist and inventor of MammaPrint, and Dr. Funmi Olopade, a leader in clinical cancer genetics and breast cancer prevention, as well as additional collaborators and experts in aspects of breast cancer research and in adaptive platform trials.