The TFAP2C/AP-2? transcription factor regulates the expression of a number of key genes that control oncogenesis and progression in breast cancer. Amplification of the TFAP2C gene locus is common in cancer and overexpression of TFAP2C is associated with a worse clinical outcome. TFAP2C regulates the expression of estrogen receptor-alpha (ERa)-associated genes including the RET proto-oncogene encoding a receptor tyrosine kinase (RTK), which is expressed more commonly in ERa-positive luminal breast cancers. Our recent findings identified RET as a novel therapeutic target in breast cancer. Ligand-activated RET regulates cell growth through the activation of multiple signaling pathways including the MAP kinase/ERK and PI3 kinase/Akt pathways. Knockdown of RET expression or treatment with tyrosine kinase inhibitors (TKI) with anti-RET activity such as sunitinib or vandetanib induces apoptosis of breast cancer cells. Whereas anti-estrogens block proliferation (measured by S-phase or Ki-67), anti-RET therapy induces apoptosis (measured by cleaved caspase 3 (CC3) or TUNEL), with combination therapy resulting in greater response than either alone. Furthermore, blocking RET activity can increase sensitivity to anti-estrogens and has the potential to induce hormone response in hormone unresponsive breast cancers. The response of primary breast cancers to TKI is dependent upon RET expression, indicating that RET may be used as a marker to predict therapeutic response to TKI therapy. The expression of EGFR is also regulated by TFAP2C and recent evidence suggests that in some breast cancers TKIs with activity against both RET and EGFR, such as vandetanib, may offer greater clinical effectiveness. We hypothesize that RET is a novel therapeutic target for breast cancer therapy; we further hypothesize that EGFR may cooperate with RET and co-targeting these RTKs may be effective in breast cancer. We propose to further the development of RET and potentially EGFR as therapeutic targets in breast cancer. Mechanisms regulating the expression of RET will be elucidated by examining the role of epigenetic chromatin modifications, co-factor interaction and post-translational modification of TFAP2C as potential mechanisms controlling RET expression in breast cancer. We will examine the cooperative effects of RET and EGFR mediating responsiveness to vandetanib in a panel of primary breast cancer isolates and establish a correlation between expression of RET and/or EGFR and vandetanib response as determined by ERK activation. To establish further clinical relevance, we propose an IRB-approved clinical trial utilizing a two- week preoperative therapy window with vandetanib to establish a correlation between RET expression and response to vandetanib as determined by changes in the surrogate molecular markers, Ki-67, CC3 and TUNEL. The overall impact of the studies will create a new paradigm in breast cancer directed therapy by establishing RET as a therapeutic target in breast cancer.

Public Health Relevance

Although hormonal therapy is effective in treating patients with ER?-positive breast cancer, approximately one- third of patients with ER?-positive tumors do not respond or develop hormone resistance. We have identified the RET proto-oncogene as a potential novel molecular target for breast cancer based on the finding that blocking RET (potentially in cooperation with EGFR) induces hormone response in hormone-resistant breast cancer. This proposal will elucidate mechanisms regulating the expression of RET, will determine the cooperative effect of EGFR and will provide important results from a randomized clinical trial that will evaluate the effectiveness of anti-RET treatment in the clinical setting.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Song, Min-Kyung H
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University of Iowa
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Iowa City
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Liu, Q; Kulak, M V; Borcherding, N et al. (2018) A novel HER2 gene body enhancer contributes to HER2 expression. Oncogene 37:687-694
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De Andrade, James P; Park, Jung M; Gu, Vivian W et al. (2016) EGFR Is Regulated by TFAP2C in Luminal Breast Cancer and Is a Target for Vandetanib. Mol Cancer Ther 15:503-11
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