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
    Awarded Grants
    Epithelial Dependence on the Vasculature

    Scientific Abstract:
    Background: It has become evident that the interactions between the tumor and stroma have a significant impact on cancer progression, and are still poorly understood. The vasculature is an important part of the tumor stroma and studies have demonstrated the importance of the vasculature to breast cancer progression. These studies have primarily focused on two aspects: 1. the prognostic value of angiogenesis in early lesions, and 2. the impact of angiogenesis inhibitors on tumor progression. These are very important, however, we intend to investigate the relationship between the vascular stroma and mammary epithelium from a novel angle. We want to know whether the response of the stroma is rate-limiting for a subsequent epithelial response. Because the angiogenesis inhibitors have not yet been perfected for clinical use, it is unclear whether the parameters used in previously published animal models will hold up in humans. This is especially true because those published experiments relied on immuno-compromised mice and subcutaneous tumor implantation. Thus, to circumvent the uncertainty of which angiogenesis therapy will emerge clinically, our approach is generic in its approach to the vascular compartment yet, specific in its use of current anti-tumor therapies Objective: The approach we are taking is to determine the extent of dependence of the tumor epithelial response on a vascular response, as a proof-of-principle study to help determine the importance of using a therapy that targets the vasculature in breast cancer. Aims: 1. Evaluate the impact of endothelial cell Akt signaling on mammary gland involution 2. Evaluate the impact of endothelial cell Akt signaling on tumor response to anti-tumor therapies 3. Evaluate the impact of silencing endothelial cell Akt signaling on mammary gland involution 4. Evaluate the impact of silencing endothelial cell Akt signaling on tumor response to anti-tumor therapies Study Design: Specifically we will use a transgenic model to block vascular involution in normal involuting mammary glands and in mammary tumors treated with conventional modalities such as tamoxifen and taxol. To look at the same question from the other side, we will decrease survival signaling using a PTEN trangenic model (or RNAi model) and see if this accelerates mammary gland involution and a mammary tumor response to tamoxifen and taxol. Our transgenic mice have inducible endothelial cell expression of in the endothelium in a normal or spontaneous tumor promoting background (PyV mT). These mice will be evaluated for their responses to post-weaning mammary gland involution or to anti-tumor based therapies in the presence and absence of endothelial cell-Akt expression. Akt silencing will be either direct, using RNAi, or indirect, using PTEN expression. Potential Outcomes: If blocking vascular involution proves to be rate-limiting in a mammary epithelial response, we will conclude that using a anti-angiogenic therapy will be an important part of combination therapy for breast cancer. In addition these experiments will tell us how important the PI3Kinase signaling pathway is for vascular involution in the mammary gland and tumor.

    Lay Abstract:
    This application is designed to consider the impact of vascular involution on the success of anti-tumor therapies in breast cancer. The idea behind anti-angiogenesis therapies is that loss of the vasculature will have secondary effects on 'starving' the tumor. While some clinical success has been achieved using anti-angiogenic approaches, these have not been in breast cancer studies. The approach we are taking is to determine the extent of dependence of the tumor epithelial response on a vascular response, as a proof-of-principle study to help determine the importance of using a therapy that targets the vasculature in breast cancer. Specifically we will use a transgenic model to block vascular involution (endothelial cell death) in normal involuting mammary glands and in mammary tumors treated with conventional modalities such as tamoxifen and taxol. To look at the same question from the other side, we will decrease survival signaling using a PTEN trangenic model and see if this accelerates mammary gland involution and a mammary tumor response to tamoxifen and taxol. If blocking vascular involution proves to be rate-limiting in a mammary epithelial response, we will conclude that using a anti-angiogenic therapy will be an important part of combination therapy for breast cancer. In addition these experiments will tell us how important the PI3Kinase signaling pathway is for vascular involution in the mammary gland and tumor.