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    Research Grants Awarded

    Role Of The Fn14/Nf-Kb Signaling Pathway In Her2-Positive Breast Cancer

    Grant Mechanism:
    Investigator Initiated Research

    Scientific Abstract:
    Breast cancer is the most common malignant disease in Western women; indeed, ~40,000 women in the USA are predicted to die from this disease in 2007. Surgery, chemotherapy, radiation therapy, and targeted therapy are the predominant treatment modalities for breast cancer patients. Primary breast tumor cells frequently travel through the blood to distant organs (in particular bone, liver and lung) and this metastatic spread is responsible for the majority of breast cancer deaths. Effective tumor cell metastasis requires the sequential completion of a complex, multistep process, which includes invasion through the tumor stroma, intravasation through the endothelium, survival in the circulatory system and extravasation into a distant site. Our laboratory is studying the role of the tumor necrosis factor (TNF) superfamily member TNF-like weak inducer of apoptosis (TWEAK) and its cell surface receptor fibroblast growth factor-inducible 14 (Fn14) in tumor cell metastasis. Recent studies performed in collaboration with Dr. Heather Cunliffe?s group at the Translational Genomics Research Institute in Phoenix have indicated that Fn14 is highly expressed in human epidermal growth factor receptor-2 (HER2)-positive/estrogen receptor (ER)-negative breast tumors and that Fn14 expression levels can modulate breast cancer cell invasiveness in vitro. The HER2 gene is overexpressed in ~25% of invasive breast tumors and HER2 overexpression is associated with increased metastatic potential and poor patient survival. Trastuzumab (Herceptin), a humanized monoclonal antibody directed against the HER2 extracellular domain, has proven efficacy for treatment of HER2+ breast cancer patients, but not all patients respond to this therapy and many of the patients who do respond develop resistance within one year of treatment initiation. Therefore, both de novo and acquired resistance to trastuzumab is a major clinical concern. We hypothesize that Fn14 overexpression in HER2+ breast tumor cells in vivo contributes to the aggressive nature of HER2+ metastatic breast cancer. Specifically, we propose that elevated Fn14 expression in these cells will promote TWEAK-independent Fn14 signal transduction; and in particular, activation of the nuclear factor (NF)-kB pathway. We predict that constitutive Fn14/NF-kB signaling in HER2+/Fn14+ breast tumor cells will both increase cellular invasive capacity and promote trastuzumab resistance. Three Specific Aims have been formulated to test our overall hypothesis. They are: (1) To determine whether Fn14 overexpression in HER2+ breast cancer cells stimulates cellular invasiveness and/or resistance to trastuzumab, and if this is the case, whether NF-kB activation is critical for these cellular effects, (2) To determine whether Fn14-overexpressing HER2+ breast cancer cells have enhanced metastatic activity and/or trastuzumab resistance in vivo, and (3) To determine whether anti-Fn14 antibodies can inhibit Fn14 signaling in HER2+/Fn14+ breast cancer cells. The proposed studies should provide important novel information on the role of the Fn14 cell surface receptor in tumor invasion/drug resistance and will provide insight into whether this protein is a potential therapeutic target for human breast cancer.

    Lay Abstract:
    Breast cancer is the leading cause of cancer-related deaths in women worldwide; indeed, ~40,000 women in the USA are predicted to die from this disease in 2007. Surgery, chemotherapy, radiation therapy, and the relatively new molecule-based therapy referred to as targeted therapy (e.g., the use of tamoxifen or aromatase inhibitors for patients with tumors that express the estrogen receptor), are the predominant treatment modalities for breast cancer patients. Primary breast tumor cells frequently invade the tumor stroma and then travel through the blood or lymphatic vessels to distant organs (in particular, bone, liver and lung). This metastatic spread is responsible for the majority of breast cancer deaths. Our laboratory is studying the role of a secreted protein named tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its cell surface receptor fibroblast growth factor-inducible 14 (Fn14) in breast tumor cell invasion and metastasis. In our most recent studies, we have found that Fn14 may be a novel regulator of breast cancer cell motility. Also, we have discovered that Fn14 is highly expressed in a particular breast tumor subtype, specifically, in tumors that overexpress a cell surface protein named human epidermal growth factor receptor 2 (HER2). It is known that HER2 overexpression in breast tumors is associated with reduced disease-free and overall survival. Trastuzumab (Herceptin), a protein-based drug administered to HER2+ breast cancer patients, has beneficial effects but not all patients respond to this therapy and many of the patients who do respond develop resistance within one year of treatment initiation. We hypothesize that Fn14 overexpression in HER2+ breast tumor cells may both stimulate tumor cell invasiveness and promote Herceptin resistance. We will test this novel hypothesis by generating HER2+ breast cancer cell lines expressing either basal or elevated levels of the Fn14 receptor and analyzing their properties in both cell culture assays and in mice. This study should advance our understanding of breast cancer biology and could ultimately lead to a reduction in breast cancer mortality. For example, if our hypothesis is experimentally confirmed, then therapeutic agents targeting the Fn14 receptor, either used alone or in combination with other agents, could prove beneficial for treatment of those breast cancer patients with HER2 overexpression (which represent ~25% of all diagnosed breast cancer patients). Indeed, new therapeutics targeting this molecule may be particularly valuable for the many patients with HER2+ tumors that do not respond at all or who eventually develop resistance to HER2-targeted drugs. In summary, the proposed research may have high impact with respect to our basic understanding of tumor cell invasion/drug resistance and it could also indicate whether Fn14 targeting could be a novel therapeutic strategy for increasing breast cancer patient survival.