Susan G Komen  
I've Been Diagnosed With Breast Cancer Someone I Know Was Diagnosed Share Your Story Join Us And Stay Informed Donate To End Breast Cancer
    Home > Research & Grants > Grants Program > Research Grants > Research Grants Awarded > Abstract

    Research Grants Awarded

    The Role of RANK and IKKalpha in Breast Cancer Tumorigenesis

    Study Section:
    Postdoctoral Fellowship

    Scientific Abstract:
    Background: Breast cancer is the primary cause of cancer-related deaths among non-smoking females. NF-kappaBs are major conduits through which cells response to extracellular stimuli. NF-kappaB activation depends on phosphorylation of I-kappaBs by IKK. Our lab showed that IKKalpha was required for the activation of NF-kappaB by RANK signaling during pregnancy and by Her2/neu during tumorigenesis. In a subset of breast cancers, NF-kappaB and IKK activities are elevated. These evidences indicate a role of IKKalpha in breast cancer. RANK signaling to NF-kappaB in mammary epithelial cells is uniquely dependent on IKKalpha other than IKKbeta which is critical in immunity. Thus, this study is important for the development of novel breast cancer therapeutics. Objective/Hypothesis: (1) IKKalpha is important for breast tumorigenesis and provides resistance to anti-cancer drugs; (2) RANK activates IKKalpha in breast cancer cells and contributes to breast tumorigenesis through IKKalpha-dependent NF-kappaB activation. Specific Aims : (1) Examine the role of RANK and IKKalpha in breast tumorigenesis; (2) Characterize RANK signaling pathway by which RANK activates IKKalpha in human mammary epithelial cells; (3) Investigate the role of RANK and IKKalpha in human breast cancer. Study Design : C ells from Her2/neu mouse mammary tumor s will be transduced with retroviruses encoding IKKalpha , IKK beta, their kinase inactive mutant s, RANK or RANK RNAi individually. Their effects on a ctivation of NF-kappaB, cell proliferation rate, sensitivity to apoptosis-inducing drug s and ability to form tumor s in mice will be analyzed and compared with those of a GFP - retrovirus. RANK deficient and proficient mice will be crossed with c-neu mice. The tumor development and activation of IKK alpha and NF-kappaB will be compared. In human mammary epithelial cells, the RANK and IKKalpha associated proteins will be characterized via tandem affinity purification and mass spectrometry. Activities of RANK, IKKalpha NF-kappaB and Her2/neu will be analyzed in established breast cancer cell lines and primary tumor samples. The correlation among these activities and pathological diagnosis will be analyzed statistically. Potential Outcomes and Benefits of the Research : T his study will not only advance our understanding of breast tumorigenesis but also establish the role of RANK and IKK alpha as a potential drug target and prognostic biomarker for breast cancer .

    Lay Abstract:
    Background: Breast cancer is the primary cause of cancer-related deaths among non-smoking females. NF-kappaBs are important signal transducers which control cellular response to outside signals. NF-kappaB activation depends on phosphorylation of I-kappaBs by IKK. Our lab showed that IKKalpha was required mammary gland development and tumorigenesis. In breast cancer cells, NF-kappaB and IKK activities are elevated. These evidences indicate a role of IKKalpha in breast cancers. RANK signaling to NF-kappaB in mammary epithelial cells is uniquely dependent on IKKalpha other than IKKbeta which is critical in immunity. Thus, this study is important for the development of novel breast cancer therapeutics. Objective/Hypothesis: (1) IKKalpha is important for breast tumorigenesis and provides resistance to anti-cancer drugs; (2) RANK activates IKKalpha in breast cancer cells and contributes to breast tumorigenesis through IKKalpha-dependent NF -kappaB activation. Specific Aims : (1) Examine the role of RANK and IKKalpha in breast tumorigenesis; (2) Characterize RANK signaling pathway by which RANK activates IKKalpha in human mammary epithelial cells; (3) Investigate the role of RANK and IKKalpha in human breast cancer. Study Design : Cells from MMTV-Her2/neu mouse mammary tumors will be infected with retroviruses producing IKKalpha, IKKbeta, their kinase inactive versions, RANK or RANK RNAi. Their effects on activation of NF-kappaB, cell proliferation rate, sensitivity to apoptosis-inducing drugs and ability to form tumors in mice will be analyzed and compared with those of a retrovirus producing a non-related protein. RANK deficient and proficient mice will be crossed with tumorigenic mice. The tumor development and activation of IKKalpha and NF-kappaB will be compared. In human mammary epithelial cells, the RANK and IKKalpha associated proteins will be characterized via tandem affinity purification and mass spectrometry protein identification. Activities of RANK, IKKalpha NF-kappaB and Her2/neu will be analyzed in breast cancer cell lines and primary tumor samples. The correlation among these activities and pathological diagnosis will be analyzed statistically. Potential Outcomes and Benefits of the Research : T his study will not only advance our understanding of breast tumorigenesis but also establish the role of RANK and IKK alpha as a potential drug target and prognostic biomarker for breast cancer .