Abstract PR10: Mammary epithelial architecture modulates field cancerization

Abstract

Abstract The architecture of the human breast undergoes extensive remodelling throughout puberty, the menstrual cycle, pregnancy, and involution with a risk of accumulating genetic alterations and tissue changes. Cells with mutations in cancer driver genes are abundant in tissues of healthy individuals, but rarely develop into tumors. However, the underlying mechanisms that prevent tumor formation are largely unknown. We utilized tissue clearing and imaged 15 disease-free human breasts and cancer resections with subcellular resolution to unravel the 3D architecture of thousands of mammary ducts per individual. Surprisingly, our analysis revealed that disease-free breasts carry a high burden of microscopic tissue lesions indicating widespread abnormal cell behaviour. Distinct mammary trees from the same breast differed in the kind and frequency of lesions, which coevolved scattered along the ductal routes. Combining 3D imaging of FFPE archived breast cancer resections with spatial CNV-seq revealed that, in half the cases, disease-free ductal segments neighbouring early cancer lesions contain molecular alterations. To resolve the mechanisms that regulate mutation spread, we compared the clonal behavior of cells with oncogenic mutations and neutral mutations in the mouse mammary gland epithelium. From the analysis of the clonal dynamics, we find that local tissue remodeling during the estrous cycle leads to the elimination of the majority of mutant clones, while accelerating the expansion of surviving clones. Thus, oncogenic mutations can spread along entire ducts before signs of transformation become apparent. Our data provides understanding of the earliest stages of epithelial evolution preceding disease. Citation Format: Hendrik A Messal, Cindy Cleyp0ol, Catrin Lutz, Stefan Hutten, Esther Lips, Jos Jonkers, Jelle Wesseling, Ronald Bleys, Ben Simons, Colinda Scheele, Jacco van Rheenen. Mammary epithelial architecture modulates field cancerization [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr PR10.