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    Awarded Grants
    Effects of Soy on Estrogen Insuficency-induced Tamoxifen-Nonresponsive Breast Cancer

    Scientific Abstract:
    Effects of soy products on estrogen insufficiency-induced tamoxifen-nonresponsive breast cancer Background: More than 60% of human breast cancers (BRCA) are estrogen receptor-positive (ER(+)), and these tumors are supposed to respond to antiestrogenic therapy with tamoxifen (TAM). However, nearly 40% of them do not respond to TAM despite the presence of ER in malignant tissues. These TAM-nonresponsive (TAM-NR) cancers contribute to a significant part of BRCA related death. Effective treatment regimens with fewer side effects are urgently needed. The mechanisms whereby ER(+) breast tumors do not respond to TAM remain largely unknown. We hypothesized that the long-term exposure of estrogen-dependent BRCA cells in an estrogen-insufficient environment is in part responsible for the development of the TAM-NR phenotype, and soybean contains bioactive components that inhibit the progression of TAM-NR breast tumor. To test this hypothesis, we have assessed the responsiveness to TAM of a MCF-7 sub cell line (MCF-7/TAM-NR), previously established in our lab after long-term culture in an estrogen-insufficient medium, against the parent MCF-7 cells. In vitro bioassays showed that MCF-7/TAM-NR cells had higher growth rates and reduced expressions of ER-alpha and BRCA1, and were less responsive to TAM, compared with the parent MCF-7 cells. Pilot animal studies indicated that, while the growth of the parent MCF-7 tumor was inhibited by soy phytoestrogen genistein and a soy phytochemical concentrate (SPC), the growth of MCF-7/TAM-NR tumor was not affected by genistein or TAM, but significantly inhibited by SPC. Objective/Hypothesis: The objectives of this proposal are: 1) to investigate the effect of soy phytochemicals on the progression of ER(+)/TAM-NR breast tumor; and 2) to determine the molecular markers that are responsible for the development of TAM-NR breast tumor and are potential targets in designing effective treatment regimens. Our hypothesis is that soybean contains bioactive phytochemical components that inhibit the growth of estrogen insufficiency-induced TAM-NR breast tumor by modulating biomarkers that are responsible for the development of TAM-NR breast tumor. Specific Aims: Specific aim 1is to determine the effect of soy phytochemicals on the growth of MCF-7/TAM-NR breast tumor and modulations of cellular and molecular markers in an orthotopic breast tumor model. Specific aim 2 is to identify by cDNA microarray technique biomarkers that may be responsible for the development of the ER(+)/TAM-NR phenotype of breast tumor. Specific aim 3 is to identify biomarkers that are sensitive to SPC treatment to elucidate mechanisms by which soy phytochemicals inhibit the growth of ER(+)/TAM-NR breast tumor in vivo. Study Design: MCF-7/TAM-NR cells will be implanted into mammary fat pad of immune deficient mice to develop an estrogen-dependent breast tumor model to evaluate the effect of SPC, genistein, and TAM on tumor growth. Cellular and molecular markers that are related to tumor growth and estrogen-pathways such as tumor proliferation index, apoptotic index and angiogenesis, and expressions of ER and BRCA1 will be determined. By using cDNA microarray assays, we will compare the expression patterns of genes in both the parent MCF-7 and MCF-7/TAM-NR tumors to determine which genes/pathways are modulated in the development of TAM-NR phenotype. Gene expression patterns will also be compared between the control and TAM- or SPC-treated MCF-7/TAM-NR tumors to determine which genes/pathways that are responsible for the development of TAM-NR tumors are modulated by SPC. Real time-PCR, Western blot and/or immunohistochemical staining will be used to determine the expressions of gene transcripts and proteins. Potential Outcomes and Benefits of the Research: Results derived from our proposed research will provide an effective regimen that can be translated into clinical practice for the treatment of ER(+)/TAM-NR BRCA. In vivo mechanistic studies will facilitate identification of tumor markers that are associated with the development of TAM-NR phenotype. These identified tumor markers will be expected to be used in characterizing ER(+) breast tumors that may not respond to TAM treatment, but may be sensitive to dietary/alternative treatment such as SPC supplementation.

    Lay Abstract:
    Effects of soy products on estrogen insufficiency-induced tamoxifen-nonresponsive breast cancer More than 60% of human breast cancers are dependent on female hormone called estrogens for growth. Tamoxifen is currently the first-line therapy for treatment of these hormone-dependent breast cancers. However, nearly 40% of them do not respond to tamoxifen treatment, and the reasons these tumors do not respond to tamoxifen remain largely unknown. These tamoxifen-nonresponsive cancers contribute to a significant part of breast cancer related death. Effective treatment regimens with fewer side effects are urgently needed. We have developed a cell model to mimic hormone-dependent and tamoxifen-nonresponsive breast cancer. We also conducted a pilot animal study and found that a novel soy product, a mixture of soy bioactive components, significantly inhibited the growth of tamoxifen-nonresponsive breast cancer. In this proposal, we plan to further evaluate the anti-tumor growth activity of this novel product. We will also measure a series of tumor markers by using advanced research techniques to find out which tumor markers are responsible for the development of these tamoxifen-nonresponsive breast tumors. These identified markers can help us to understand why these tumors do not respond to tamoxifen, to design drugs for effective cancer treatment, and more importantly to predict which breast tumors may not respond to tamoxifen treatment so that other effective treatments such as soy supplementation can be used.