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    Lipocortin/Annexin I as a Unique Target of Mechanism-Based Chemoprevention of Breast Cancer

    Scientific Abstract:
    Lipocortins, also termed as annexins, are a family of the proteins that bind to phospholipids in a calcium dependent manner, and are proposed to function in signal transduction of various growth factors, thus regulating cell proliferation and differentiation of a variety of cells. Available evidence suggests that lipocortin I is involved in an early stage of human breast cancer development, since it is absent in normal breast tissues, while its level parallels malignancy of breast cancer. However, biochemical and molecular mechanisms of functions of lipocortin I in breast cancer development remain poorly understood. Our laboratory has recently discovered that the nuclear lipocortin I-calcyclin heterotetramer catalyzes a helicase activity towards damaged DNA and stimulates the translesion DNA synthesis bypassing the damaged site by error-prone DNA polymerases such as Pol beta, thereby increasing mutations. Since gene alterations by mutagenesis are important in the etiology of breast cancer as evident from the findings that defects of the DNA repair systems such as BRCA 1 and p53 are closely associated with risks and/or prognosis of breast cancer, we hypothesize that lipocortin I is involved in an early stage of initiation and/or malignant transformation of breast cancer by increasing gene mutations. Since isoflavonoids that are epidemiologically reported to reduce the risks of breast cancer and/or that increase the latency of breast cancer in animal models are found to inhibit lipocortin I helicase activity, we will establish in the present proposal that lipocortin I is a unique target of mechanism-based chemoprevention for breast cancer. Our Specific Aims are (a) to investigate whether transformation of the human breast epithelial cell line, MCF 10F, by carcinogens parallels levels of lipocortin I in MCF 10F breast epithelial cells as manipulated by the transfection with siRNA and cDNA plasmids of lipocortin I, and (b) whether potencies of isoflavonoids in inhibition of lipocortin I helicase activity parallel those in prevention of the chemical induced transformation in the MCF 10F cell line. This proposed research will provide novel information that mutagenesis via lipocortin I is an important step in an early stage of breast cancer development, and that lipocortin I is a unique target of mechanism-based chemoprevention against breast cancer. Furthermore, the methods developed in this proposal will provide a tool towards quick screening of various compounds for clinical chemoprevention of breast cancer, and will provide information concerning modes of their action. Therefore, this proposed research will open a new avenue to develop new potent derivatives for chemoprevention of breast cancer.

    Lay Abstract:
    While conventional treatments with anti-cancer drugs and surgical operations have recently improved the survival of patients with breast cancer, they do not influence the incidence of breast cancer. Therefore, prevention of breast cancer among populations of risks by using simple compounds such as diets and anti-hormone agents is an urgent and important issue. However, most of compounds tested for such preventive purposes are based on their inhibitory on various models of tumor development, and mode of their action remains poorly understood. Since the inhibition of cancer initiation is the most effective target for cancer prevention, we looked for biological markers in an early stage of breast cancer development. The protein called as lipocortin or annexin I has been reported to be absent in normal breast tissues, but its cellular level parallels degree of malignancy of breast cancer. Therefore, this protein is thought to be involved in an early stage of breast cancer development. Our laboratory has recently found that this protein apparently increases mutations of various genes, thus not only initiating cancer but also enhancing malignancy of cancer. Isoflavonoids, compounds that are present in vegetables and soy products, inhibit functions of this protein, thereby inhibiting gene mutations. These compounds are reported to reduce incidence of breast cancer among women with risks, and to delay breast cancer formation in animal models. Therefore, we hypothesize that lipocortin/annexin I plays an important biological role in an early stage of breast cancer development, and that this protein serves as a unique target of prevention of breast cancer. To test this hypothesis, we plan (a) to investigate whether appearance of cancer phenotypes in cultured human breast cells, a model system for breast cancer, parallels level of lipocortin I as manipulated by the molecular biology techniques, and (b) to screen isoflavonoids for clinical prevention of breast cancer by comparing inhibition of lipocortin/annexin I functions with inhibition of cancer phenotypes in the cultured model of breast cancer. Our proposed research will establish that gene mutation mediated through lipocortin/annexin I is an important step in an early stage of breast cancer development, and that this protein is a unique target for prevention of breast cancer. Furthermore, the methods developed in this proposal will provide a tool towards quick screening of various compounds for clinical prevention of breast cancer and information concerning modes of their action. Therefore, it will open up a novel avenue for quick development of new and more potent drugs for breast cancer prevention.