Molecular Analysis of DCIS Progression in a Mouse Model
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Breast cancer development is a multi-step process, starting from a benign stage, through histologically and molecularly distinct intermediate proliferative stage of hyperplastic epithelium, and leading to invasive cancer and metastasis. The analysis of breast lesions indicates that early lesions are molecularly different from normal epithelium. DCIS (ductal carcinoma in situ) is a type of pre-malignant lesion in human breast tissue that has a high rate of transformation to invasive cancer. Our knowledge of this transformation process is still incomplete, especially at the molecular level, despite an increasing number of genes being associated with breast cancer. Understanding the molecular mechanism will lead to identification of biomarkers for early breast lesions and their prognosis, as well as molecular targets for preventive therapy.
 
 
 
 
 
 
 
 The overall goal of this project is to study a well-characterized mouse model of breast cancer development by correlating the biology and molecular profiles of hyperplasia and tumor tissues. Our aim is to identify possible key regulators of this malignant transformation. The research will be based on a novel mouse model of DCIS. In this model, premalignant mouse mammary tissue has been maintained for many generations by serial transplantation into new host animals. These tissues, called hyperplastic outgrowths (HPO), were originally derived from hyperplastic epithelium of young, genetically engineered animals that expressed the polyomavirus middle T antigen in mammary glands (MMTV-PyVmT). They are histologically indistinguishable from human DCIS and will transform into malignant tumors, if allowed to grow. We will use normal, premalignant (HPO), and tumor tissues from the same mouse mammary fat pads (i.e., breasts) to study the gene expression differences. Since the mammary fat pads have been processed for histology after the sample extraction, the molecular differences can be correlated with the morphology and histology of each tissue. We also plan to develop cell lines from the tumor and HPO tissues. The purpose of these cell lines is to experimentally test the role of any suspected genes in breast cancer progression. For example, we will be able to employ the newly developed technique of “RNAi” inhibition to selectively block individual genes, and determine the effects on proliferation, migration, and invasion. Moreover, we will be able to treat these cells with chemical inhibitors for certain genes to block their function and assess the effects on tumor development before testing them on the animal model.
 
 
 
 
 
 
 
 Initial studies have shown that HPO tissues in our model are similar to human DCIS in their histology, biology, and molecular alterations. Development and thorough characterization of this model and cell culture lines will be beneficial because they can be used as tools to design treatment and preventive therapy for breast cancer.