Ashley Garrett Rivenbark, PhD
The major research interest of my lab is to elucidate epigenetic mechanisms in breast cancer (and other cancers) that can be exploited for development of new diagnostics and therapeutic treatments. Invasive breast cancer is a major health problem. Cancers that overexpress HER2 (ErbB2) and that are hormone receptor negative (ER-/PR-/HER2-) are both aggressive forms of breast cancer that have proven to be difficult to treat even with some targeted approaches. Improvement of long-term outcomes and survival of HER2+ and triple-negative breast cancer patients requires identification of new therapies and development of innovative therapeutic strategies. It is well recognized that breast carcinogenesis is associated with alterations in epigenetic mechanisms, including gene-specific DNA methylation. However, the epigenetic mechanisms that influence cancer development are largely uncharacterized and unexplored. Further, the utility and efficacy of epigenetic therapies as part of innovative treatment strategies for breast cancer have not been fully investigated. My research vision is to explore basic mechanisms, identify new molecular targets, develop novel technologies, and perform translational research to specifically approach epigenetic mechanisms of gene regulation in breast cancer. Select projects are described in detail below.
Epigenetic targeting of HER2 and HER3 by artificial transcription factors — Breast cancers that overexpress the HER2 gene represent approximately 15%-30% of all invasive cancers, encompassing HER2+ and luminal B subtypes, and are associated with aggressive clinical behavior. A subset of patients (~25%) with HER2+ breast cancer display an objective response to the targeted drug trastuzumab (Herceptin). However, a substantial fraction of patients with HER2+ breast cancer will not respond to trastuzumab and other forms of HER2-specific treatment (lapatinib). Significantly, HER3 plays an essential role in HER2-mediated transformation, cell growth, survival, and drug resistance. Currently, there are no clinically approved targeted therapies for HER3. In light of these data, there is a pressing need to discover new and novel therapeutic strategies that target this extremely aggressive form of breast cancer. Previous studies have determined the utility of artificial transcription factors (ATFs) consisting of 6-zinc finger proteins (ZFPs) coupled with repressor domains in regulating gene expression. DNA methylation plays a critical role in gene-specific repression by incorporating silencing marks that are inherited as the cell divides, producing stable gene silencing. This project will generate novel epigenetic ATFs that target the promoters of HER2 and HER3 governing gene repression by directing the deposition of silencing methylation marks. This work will provide insight into the silencing and treatment potential of HER2 and HER3 and importantly, for the first time lead to the generation of novel epigenetic remodeling ATFs that can be used as proof-of-principle to target other key genes that are overexpressed in breast tumorigenesis.
Epigenetic therapy — Triple-negative breast cancers do not express the estrogen or progesterone receptors (ER-/PR-) and do not display amplification/overexpression of HER2 (HER2-), rendering them refractory to treatment using targeted agents like tamoxifen (targeting ER) and trastuzumab (targeting HER2). These cancers encompass the basal-like and claudin-low molecular subtypes of breast cancer. These breast cancers contribute disproportionately to breast cancer morbidity and mortality (with very poor disease-free and overall survival), reflecting their aggressive clinical behavior, tendency to recur, and general resistance to cytotoxic chemotherapy. Hence, the best options for treatment are only marginal and can be quickly depleted as these patients are managed. With failure of chemotherapy and disease progression, most of these patients succumb to their disease within five years. It follows that improvement of the progression-free and long-term outcomes for patients with triple-negative breast cancer will require new and innovative treatment strategies. Only a limited number of genetic mutations have been associated with loss of ER expression in ER- breast cancers. Rather, DNA methylation-dependent epigenetic mechanisms of gene silencing account for loss of ER expression in most ER- breast cancers. Therefore, re-expression of ER could be accomplished through application of demethylating drug treatments. Previous studies have shown that the majority (~76%) of triple-negative breast cancers express a hypermethylation defect characterized by hyperactivity of DNA methyltransferase (DNMT) enzymes, specific overexpression of DNMT3b, and concurrent DNA methylation-dependent silencing of multiple genes, including ESR1 which encodes for ER. I am interested in employing triple-negative breast cancer model cell lines in vitro and cancer xenografts in vivo to examine the efficacy of demethylating treatment (using 5-aza-2’-deoxycytidine) (i) to effect re-expression of epigenetically silenced ESR1 in ER- breast cancers, enabling the therapeutic use of tamoxifen, and (ii) to effect the re-expression of molecular pathways that sensitize breast cancer cells to cytotoxic chemotherapy. These studies will advance our understanding of how targeting the cancer methylome using clinically available demethylating drugs can improve outcomes of triple-negative breast cancer, setting the stage for discovery of new demethylating drugs and treatment strategies.
View list of publications from PubMed