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    LRBA: A Target for More Effective Breast Cancer Treatments

    Scientific Abstract:
    LRBA: A Target For More Effective Breast Cancer Treatments Tamoxifen (TAM) that blocks estrogen receptor (ER) activity is the most efficient treatment for ER-positive breast cancer (BC). Unfortunately, most patients will become resistant to TAM and thus incurable. Growth factor receptors (GFR) are often overexpressed in TAM-resistant metastatic BCs (TRMBC), and are linked to poor prognosis and resistance to therapies. The development of gefitinib and Herceptin GFR inhibitors represents a major breakthrough in TRMBC therapy. However, they cause responses only in a small fraction of patients and are not curative due to the development of resistance. This is because cancer often has multiple mutations and evolves with time and treatment. Therefore, the development of resistance to therapies that target a single mutation, i.e. ER, EGFR or HER2 is inevitable, and such therapies are less effective. On the contrary, targeting a gene that is a convergent node for multiple survival pathways would likely lead to a more effective therapy. LRBA could be one of such genes, because (1) repression of LRBA significantly inhibits cell growth of multiple types of cancer cell line, but not normal cells; (2) LRBA is overexpressed in multiple types of cancer including BC, and potentially interacts with multiple pathways, including those of EGFR, HER2, Notch, PKA, RAS, and MAPK. Overactivation of these pathways plays a pivotal role in malignant growth of TRMBCs. Repression of LRBA may thus impair multiple survival pathways and sensitize BC cells to apoptosis. We hypothesize that targeting LRBA is more efficient to inhibit various BCs. To test this, we will use adenovirus-mediated RNAi to repress LRBA in a wider variety of BC cell lines to determine whether repression of LRBA inhibits cell growth in these BC lines that may have different survival pathways (Aim 1). Aim 2 will determine whether repression of LRBA in combination with chemotherapeutics achieves a greater growth inhibition of BC cells. Aim 3 will explore LRBA inhibition therapy in mouse models of xenograft and autochthonous BC tumors. TRMBC is not curative, which cost tens of thousands of American women’s life each year, because of the development of resistance. Identifying genes that are critical convergent node for multiple survival pathways should be a top priority. This proposal would likely lead to developing more effective therapies that have no or less resistance and toxicity problems, ultimately result in a cure for this disease.

    Lay Abstract:
    LRBA: A Target For More Effective Breast Cancer Treatments Tamoxifen (TAM) is the most efficient treatment for ER-positive breast cancer (BC). Unfortunately, most patients will become resistant to TAM. Growth factor receptors (GFR) are often overexpressed in BCs and are linked to poor prognosis and resistance to therapies. The development of gefitinib and Herceptin GFR inhibitors represents a major breakthrough in BC therapy. Both drugs can induce clinical responses in a variety of metastatic cancers and have been used clinically. However, they cause responses only in a small fraction of patients and are not curative due to the development of resistance. This is because cancer often has multiple mutations and evolves with time and treatments. Therefore, the development of resistance to therapies that target a single mutation is inevitable, and such therapies are less effective. On the contrary, targeting a gene that is a convergent node for multiple pathways would likely lead to a more effective therapy. LRBA could be one of such genes, because repression of LRBA significantly inhibits cell growth of multiple types of human cancer cell line, but not normal cells. Furthermore, LRBA is over-expressed in multiple types of cancer including BCs and potentially interacts with multiple key pathways. Over-activation of these pathways plays a pivotal role in malignant growth of TAM-resistant metastatic BCs. Therefore, repression of LRBA may impair multiple survival pathways, thus efficiently kill TAM-resistant BC cells. To test this hypothesis, we will use RNAi, the most efficient way to inhibit a gene’s function, to knockdown LRBA and see if repression of LRBA inhibits cell growth in a wider variety of BC cell lines and in mouse models of xenograft and spontaneous BC tumors. Right now, there is no cure for TAM-resistant metastatic BCs, which cost tens of thousands of American women’s life each year, resulting from our inability to prevent the development of resistance to therapies. Therefore, identifying genes that are critical convergent site for multiple pathways should be a top priority. If supported by the proposed studies, our hypothesis will lead to more effective therapy strategies that may result in a cure for this disease.