Pathology

Biography

Biography: Xi Wang

Abstract

Breast cancer is a heterogenous group of diseases. Molecular sub-classification has divided it into 5 different subtypes (luminal A and B, Her2, basal like and triple-negative non-basal). Although this stratification has impacted on breast cancer treatments and outcomes, patient response to targeted therapy or chemotherapy remains highly unpredictable. Dissection of the normal epithelium is fundamental to understanding breast cancer heterogeneity. Terminal ductal lobular unit (TDLU) is the primary site where the breast carcinogenesis initiates. It consists of two types of cells: Luminal epithelium and myoepithelium. Even inside the luminal epithelium, different cell types are present. For instance, only approximately 10-20% of luminal cells express ER, while majority of the luminal cells are ER negative. We studied the expression of AR and ER in normal breast luminal cells and found that their distribution pattern is the same as what was revealed in invasive breast carcinomas indicating that ER/AR positive luminal cells may serve as the “cell of origin” of ER/AR positive tumors. These different types of luminal cells could subject to different genetic mutations which could further confound the inter-tumor heterogeneity. We found that Tocopherol-Associated Protein (TAP), a vitamin E binding protein was co-expressed with ER in normal/benign breast luminal cells but was down regulated in 46% of ER positive breast carcinomas. This down regulation was associated with poorer clinical outcome in ER positive breast cancer patients. Our study on p53 alteration in breasts of BRCA carriers and non-carriers revealed that p53 positive normal/benign cells were ER negative luminal cells. We hypothesis that these cells could serve as the “p53 signature” to predict future risk for a high grade breast carcinoma.