During the current funding period, we demonstrated that Rab25 is a driver of the 1q22 amplicon in breast cancer contributing to tumor aggressiveness and a worsened outcome. Further Rab25: 1) DNA, RNA and protein levels are coordinately elevated in breast cancers, 2) DNA, RNA and protein levels as well as a Rab25 transcriptome correlate with patient outcomes, particularly in hormone receptor (HR) positive tumors, 3) levels are high in HR positive and HER2 positive tumors and low in basal/triple negative tumors, 4) is upregulated during cellular stress, 5) increases cell growth, colony formation, motility and invasion of breast cancer cells particularly under stress conditions, 6) inhibits stress-induced apoptosis and autophagy, and 7) increases growth of xenografts. Our operating hypothesis is that increased levels of Rab25 contribute to aggressiveness of breast cancer a n d worsened patient outcome by enabling breast cancer cells to survive hypoxia, nutrient and anoikis stresses present during cancer development and metastases through coordinate regulation of the P13K/AKT, LKB1/AMPK, and p27 pathways that mediate the decision to enter autophagy and/or apoptosis under nutrient stress conditions. We will test the hypothesis through the following aims:
AIM 1. Determine the underlying mechanisms by which Rab25 contributes to breast cancer aggressiveness We will test the hypothesis that Rab25: 1) alters receptor and nutrient transporter internalization and recycling to the membrane, 2) improves bioenergetics, 3) alters the interplay between AKT and AMPK mediated regulation of p27, 4) alters expression or function of critical components of the apoptosis and autophagy cascades and 5) is sufficient to increase metastasis in breast cancer xenografts.
AIM 2. Determine the role of Rab25 in initiation and progression of breast cancer using animal models. We will determine whether regulatable mammary specific expression of Rab25 is sufficient to alter breast development, regression and apoptosis post lactation or tumor development. Given the demonstration by Dr. Muller in this PPG that AKT plays a critical role in polyoma virus middle T (PyVmT) and erbB2 transgenic models and our preliminary data that Rab25 activates the P13K/AKT pathway, we will determine whether Rab25 alters the frequency or latency of breast cancer and metastases in tumor-prone mice expressing wild type PyVmT or activated erbB2 as well as PyVmT unable to link to the PISK pathway.
AIM 3. Determine the role of Rab25 in breast cancer prognosis and outcomes Our preliminary data indicate that Rab25 DNA, RNA and protein levels as well as a Rab25 transcriptome correlate with patient outcomes, particularly in HR positive tumors. We will assess an independent large series of high quality breast cancer samples to determine whether a coordinate analysis of Rab25 DNA, RNA and protein levels or the Rab25 transcriptome will provide a robust method to predict patient outcomes and response to therapy.
We demonstrated Rab25 is a driver of the most common amplicon (1 q22) in breast cancer. Rab25 DNA, RNA and protein levels correlate wilh patient outcome, particularly in HR positive tumors indicating that Rab25 regulates the aggressiveness of breast cancer. Expression of Rab25 increases proliferation, survival, motility and invasion of breast cancer cell lines. The proposed studies will determine the mechanisms by which Rab25 increases tumor aggressiveness and determine whether Rab25 predicts response to therapy. Together, these will lead to the development of drugs targeting Rab25 and its mechanism of action (see letter from GSK) as well as implementation of Rab25 as a biomarker improving patient outcomes.
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