Abstract PD6-9: Molecular signatures of DCIS to invasive progression for basal-like breast cancers: An integrated mouse model and human tumor study
Authors: Aatish Thennavan, Xiaping He, Charles M Perou
Journal: Cancer Research (2020)

Abstract Invasive ductal cancers (IDC) have a variety of precursor lesions and molecular subtypes. Ductal Carcinoma in Situ (DCIS) is considered an important precursor stage immediately preceding IDC and has increased in its incidence in recent times. 20-40% of DCIS form IDC however, currently we lack robust molecular signatures to predict progression prone DCIS. Performing next generation sequencing in breast cancer DCIS precursors is likely to help elucidate their progression potential. Sequencing the progression path of IDC lesions in a mouse model, and in human samples of the same molecular subtype, should help to understand the drivers of transformation. We utilized the C3-TAG genetically engineered mouse model that forms DCIS like precursor lesions, and human breast DCIS-IDC pairs for genomic analyses. Through single cell RNA-sequencing, and bulk mRNA-seq, we identified disease stage specific, and cell population specific, signatures at three stages of breast cancer tumor progression in the C3-TAG mouse model. Through integrated analysis we subset cancer cells in the DCIS and tumor stage in C3-TAG and identify genes and gene signatures relevant in the IDC stage including HIF-1-alpha pathway (Fos proto-oncogene, lactate dehydrogenase A); glycolysis pathway (phosphoglycerate mutase 1, pyruvate kinase M1/2, aldolase, fructose-bisphosphate A, enolase 1); Metastasis associated protein (MTA3) complex (tubulin alpha 1c, tubulin alpha 4a) and endocrine resistance (cyclin dependent kinase inhibitor 2A, KRAS proto-oncogene, GTPase, heparin binding EGF like growth factor, cyclin D1). We also identified microenvironment signatures and detected gene changes in the immune, endothelial and fibroblast cells as DCIS transitions to IDC, including a sharp decline of CD8 T cell genes (CD274, C-C motif chemokine ligand 5, SLAM family member 7) from DCIS to IDC, highlighting an immune dysregulation as part of the transition from DCIS to IDC. Simultaneously, we retrieved a public microarray dataset of human DCIS/IDC pairs and performed Ribo-zero RNA-sequencing of 5 human basal-like DCIS/IDC and 5 Luminal A DCIS/IDC pairs. Utilizing gene set enrichment analysis, we show that our C3-TAG DCIS stage tumor cell signature was significantly enriched in the human basal-like DCIS, but not in Luminal A DCIS. These results highlight that the C3-TAG DCIS may recapitulate the biology of basal-like DCIS and that progression in basal-like may be different than in Luminal/ER+ cancers. Further interrogation of these DCIS and IDC stage specific signatures may lead to identification of a clinical marker of progression and/or a therapeutic target of early intervention. Citation Format: Aatish Thennavan, Xiaping He, Charles M Perou. Molecular signatures of DCIS to invasive progression for basal-like breast cancers: An integrated mouse model and human tumor study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD6-9.