Medical School
Twin Cities
Every year in the United States over 1 million breast biopsies are performed to determine if suspicious lesions found by breast imaging could be cancer. Of these, 10-20% result in a diagnosis of invasive breast cancer. While the other 80-90% of biopsies are negative for invasive cancer, findings of ductal carcinoma in situ (DCIS) and hyperplasia, increase a woman’s risk for developing invasive breast cancer. Since about 20-30% of women with low-grade DCIS will develop breast cancer, and there are currently no biomarkers available to determine which women will develop invasive disease, surgical removal (with or without radiation) is recommended for all cases of DCIS. Since many women with low-grade DCIS will never develop invasive breast cancer, the result is significant over treatment. Thus, there is a critical need to develop biomarkers that predict which women are at the highest risk for developing breast cancer.
The key to preventing the development of breast cancer is understanding the molecular mechanisms that drive the transition from a high-risk lesion to invasive cancer. Additionally, it is important to consider that breast cancer is not a single disease. Based on molecular pathology there are three major subtypes, luminal (ER/PR+), HER2+ (HER2 amplification), and basal or triple negative breast cancer (TNBC), and at least five subtypes based on gene expression profiling. To date, breast cancer prevention is limited to agents that specifically target the ER, and prevention of ER+ invasive breast cancer. Progress in breast cancer prevention is dependent novel biomarkers that predict progression to all types of invasive disease. It is also important to consider the role of the microenvironment in tumor initiation and progression. Understanding the epithelial cell/microenvironment interactions and disruption of the pro-tumorigenic signals between abnormal epithelial cells and inflammatory cells has the potential to prevent breast cancer initiation and progression to invasive disease.
This group's research is focused on understanding the role of proline, glutamic acid, and leucine rich protein 1 (PELP1) in breast cancer initiation. They have found that altered localization of PELP1 to the cytoplasm promotes breast cancer initiation in our cell culture models. Additionally, they have found that cytoplasmic PELP1 promotes expression in inflammatory cytokines and chemokines, which they hypothesize promotes epithelial/inflammatory cell crosstalk. The in vitro and in vivo approaches used in this project allow the group to specifically address the crosstalk between epithelial cells expressing PELP1-cyto and inflammatory cells, and how this contributes to breast cancer initiation. The group's goal is that the results of these studies will be translated to develop novel breast cancer prevention strategies that target PELP1 and/or inflammatory signaling pathways downstream of PELP1.
Additionally, the researchers hypothesize that PELP1/SRC-3 complexes act as oncogenic signaling nodes that recruit and amplify cytoplasmic signaling pathways. These pathways mediate chromatin remodeling and enable reprogramming of activated SR-regulated transcriptomes that are required for aberrant changes in cell fate, such as the expansion of BCSC populations. Thus, the researchers aim to determine how PELP1/SRC-3 complexes reprogram SR transcriptomes. Their data suggest that altered PELP1 signaling leads to global chromatin remodeling. This would enable p-SRC-3-mediated coactivation of SR-dependent transcription at gene sets that instruct BCSC expansion. They predict that p-SRC-3 species alter SR promoter selection. They will use established in vitro models and integrated state-of-the-art approaches (ATACseq, RNAseq, and ChIPseq) to determine the effects of PELP1/SRC-3 activation on global chromatin remodeling and ER/PR target gene expression. These studies will determine how PELP1/p-SRC-3 complexes alter chromatin and co-activate SRs at unique genes that specify BCSC activity.
The researchers are also performing in vivo studies to determine if an increase in cancer stem-like populations has an effect on tumor growth and metastasis. For these studies they assess tumor burden via image analysis of H&E stained slides.