University of Wisconsin–Madison

Cancer Genetic & Epigenetic Mechanisms (GEM)

The Genetic and Epigenetic Mechanisms (GEM) pursues basic and translational research to discover novel cancer genetic and epigenetic mechanisms, to translate mechanistic insights derived principally from mouse models and primary human cancer samples to human cancer, and to leverage the mechanistic insights to advance cancer diagnosis and treatment. GEM investigators develop new technologies to better detect variants, deploy mechanistic studies to discover the functional consequences of variants and engage in translational efforts to exploit these variants for better prevention, early detection and therapy.

SELECT RECENT ACCOMPLISHMENTS

  • Precision Medicine Paradigm to Increase Chemotherapeutic Efficacy in Breast Cancer

    Through analyzing mitotic mechanisms, the Weaver/Burkard team published a landmark paper that led to a paradigm shift in understanding the mechanism underlying efficacy of the chemotherapeutic agent paclitaxel. Whereas paclitaxel is one of the most commonly used drugs to treat primary and metastatic breast cancer, only 41-58% of patients’ benefit. There is no way to predict responsiveness prior to therapy. Non-responsive patients can be subjected to serious side effects, including life-threatening leukopenia and peripheral neuropathy that greatly diminish quality of life and consequent delay in receiving efficacious therapies. A biomarker to identify responsive patients would improve outcomes for many of the 1.7 million patients worldwide that are diagnosed with breast cancer each year.

  • Multi-parametric Breast Cancer Diagnosis

    Using novel machine learning, Page and Burnside are collaborating to improve the identification of patients that require biopsy by using mammography features (variables), electronic health records (EHR), and genetic markers (SNPs) to personalize breast cancer risk prediction and reduce over-diagnosis. The machine learning methods developed show potential to more accurately select women who need interventional procedures, thus sparing those who do not.

     

     

  • Protein Arginine Methyltransferase Function in Breast Cancer

    CARM1-mediated BAF155 methylation promotes breast cancer cell proliferation

    CARM1 encodes a protein arginine methyltransferase that plays a central role in estrogenreceptor (ER)-mediated transcription and breast cancer cell proliferation. These actions involve methylation of histone H3 and the BAF155 subunit of the SWI/SNF chromatin remodeling complex. Xu’s group discovered a reader complex PAF1c that recognizes H3 di-methylated at R17 and demonstrated that the PAF1c subunit Ctr9 is a key player in ER regulons. This study provided rationale for targeting Ctr9 to overcome endocrine resistance in ER-positive breast cancers. Identifying CARM1 substrates will inform cancer mechanisms from diverse perspectives, including understanding drug resistance and establishing how chromatin remodeling controls progression.