Neomorphic ERα Mutations Drive Progression in Breast Cancer and Present a Challenge for New Drug Discovery.

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2018-02-12

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Abstract

In this issue of Cancer Cell, Jeselsohn et al. dissect the function of several of the most clinically important estrogen receptor alpha mutants associated with endocrine therapy resistance in breast cancer and demonstrate that they manifest disease-relevant neomorphic activities that likely contribute to tumor pathogenesis.

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10.1016/j.ccell.2018.01.014

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McDonnell, Donald P, John D Norris and Ching-Yi Chang (2018). Neomorphic ERα Mutations Drive Progression in Breast Cancer and Present a Challenge for New Drug Discovery. Cancer Cell, 33(2). pp. 153–155. 10.1016/j.ccell.2018.01.014 Retrieved from https://hdl.handle.net/10161/16118.

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Scholars@Duke

McDonnell

Donald Patrick McDonnell

Glaxo-Wellcome Distinguished Professor of Molecular Cancer Biology, in the School of Medicine

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The research in our group is focused on the development and application of mechanism based approaches to identify novel therapeutics for use in the treatment and prevention of hormonally responsive cancers. Specifically we are interested in the pharmaceutical exploitation of the estrogen and androgen receptors as therapeutic targets in breast and prostate cancers and in defining how these receptors influence the pathogenesis of these diseases. These efforts have led to the discovery of several drugs that are currently being evaluated in the clinic as cancer therapeutics, and to the identification of potential biomarkers and predictors of response that can help to target the use of these new drugs. Most recently we have explored approaches to treat triple negative breast cancer and have identified an important pathway that links obesity/dyslipidemia and cancer risk.

Norris

John David Norris

Associate Research Professor in Pharmacology & Cancer Biology

Molecular pharmacology of the nucler receptor class of transcription factors. Special interest in the mode of action of tissue specific ligands for the estrogen and androgen receptors.

Chang

Ching-yi Chang

Associate Research Professor of Pharmacology and Cancer Biology

The main focus of my research has been to define the roles of nuclear hormone receptors (NHRs) in the pathogenesis of disease, with a focus on hormone-related cancers. 

During earlier stages of my research career, definition of the structural and molecular determinants of NHR receptor biology and pharmacology was the main focus. Information obtained from these studies was used to guide the development of receptor modulators for therapeutic interventions and to gain insights into the pharmacology of estrogen and androgen receptor ligands. More recently, my research has shifted to define receptor-mediated signaling pathways relevant to the pathogenesis of breast and prostate cancers. One example of this is the definition of signaling pathways downstream of the orphan nuclear receptor, estrogen-related receptor alpha (ERRα) in breast cancer. Using gene expression signature defined in breast cancer cells we demonstrated that the activity of ERRα tracks with poor prognosis in all breast cancer subtypes. We confirmed a causal role for ERRα in breast cancer growth in both cellular and xenograft models of breast cancer. More recently, we further defined the role(s) of this receptor in tumor metabolism and validated its utility as a therapeutic target in triple negative breast cancer (TNBC). In addition to the cancer cell intrinsic effects of ERRα, this receptor is also expressed in T cells and in macrophages. We are currently evaluating the impact of modulating ERRα activity in these immune cells and how that influences tumor biology. 


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