Molecular Characterization of Breast Duct Epithelium at Risk for Breast Cancer

Division Of Clinical Sciences - Nci

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Abstract

This project is designed to define the cytologic, ductal architectural, and molecular characteristics of breast ducts and ductal epithelial cells of women at normal risk and at high risk for breast cancer, including Caucasian, Hispanic and African American women. This information is needed to define the early changes in the carcinogenic pathway for breast cancer, to develop an improved classification and molecular signature of preneoplastic breast tissue for risk assessment, to identify new targets and to facilitate selection and monitoring of women for breast cancer prevention, and to define the molecular basis for disparities in the development and presentation of breast cancer. This project includes the following clinical and laboratory study: Protocol 02-C-0077, Characterization of High-Risk Breast Duct Epithelium by Cytology, Breast Duct Endoscopy, and Gene Expression Profile (DN Danforth, PI). This protocol examines by ductal lavage and ductal endoscopy the breast ducts and ductal epithelium of women at normal risk and at high risk for breast cancer. The studies conducted under protocol 02-C-0077 have provided important clarification of the clinical and prognostic role of cytologic atypia in women at risk for breast cancer. Chronic inflammation has long been recognized as an important factor promoting the development of cancer, as well as promoting expression of immune checkpoint proteins which can inhibit lymphocytes and immunosurveillance. Our studies have further defined the presence of intraductal cytologic atypia. In normal risk subjects cytologic atypia was present in 25.7%, but was not associated with altered gene expression by microarray profiling, or with abnormalities on ductal endoscopy or on breast MRI, or on follow-up, providing the important observation that cytologic ductal atypia in normal risk subjects does not appear to be of clinical significance. In high-risk subjects atypia was present in 22.9%, and follow-up MRI revealed a ductal carcinoma in 13.7% of patients, indicating the importance of ductal evaluation in high-risk subjects. These findings have recently been reported [Danforth, DN., et al. Characteristics of breast ducts in normal risk and high-risk women and their relationship to ductal cytologic atypia. Cancer Prev Res, 2020;13:1027-36]. An important secondary objective of the study is to determine the presence of mammary stem cells in the ductal microenvironment. Mammary stem cells (MSC) are considered the progenitors of all ductal cell types. Importantly, mammary stem cells may also be transformed into cancer stem cells (CSC), the origin of breast cancer. Identification of MSCs or CSCs in the breast ductal cellular compartment could have important implications for understanding early breast carcinogenesis. Recent evidence has also indicated the presence of a microbiome in breast tissue. We recently performed a pilot study in which 8 frozen ductal samples were analyzed by 16s rRNA sequencing through the CCR Microbiome Core Facility. We identified microbia in all samples with the following relative distribution according to phylum: Bacteroidetes Firmacutes Protobacteria Actinobacteria. This confirmed the feasibility of studying the microbiome in our normal risk and high-risk breast ductal samples. Further characterization of the microbiome in our ductal samples will clarify the relation of the intraductal microbiome to breast cancer risk and as a potential cause of chronic intraductal inflammation which we have observed in the high-risk ducts. Work on this project was completed in FY23.