Estrogen receptor, p38 MAPKs and topo IIa in breast cancer

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DESCRIPTION (provided by applicant): Estrogen receptor (ER) mediates estrogen signaling to promote breast cancer growth and thereby serves as a target for hormone therapy in ER+ breast cancer. DNA topoisomerase II1 (topo II1), on the other hand, maintains proper DNA topology and acts as a therapeutic target for both ER+ and ER- breast cancer. Although levels of intrinsic topo II1 protein correlate with sensitivity to its inhibitors, this protein is frequently depleted by its toxins and information about how topo II1 is maintained during the therapeutic stress is missing. p38 MAPKs consist of 1, 2, 3, and 4 proteins that are major kinase cascades to determine cellular response to upstream signals through regulating gene expressions. We showed during the past funding period that ER inhibits stress-induced cell death via c-Jun binding and our recent work further showed that ER specifically suppresses topo II drug-induced growth inhibition by attenuating p38 stimulations of topo II1 expression. It is proposed here that p38 MAPK activations maintain topo II1 expression that is antagonized by ER signaling, leading to increased topo II-drug toxicity in ER- breast cancer. This hypothesis is based on our preliminary studies showing 1) topo II inhibitors, but not taxol, are more potent in inhibiting ER- breast cancer growth that couples with increased intrinsic p383 but not topo II1 protein expression; 2) there are also increased p381 phosphorylations linked to resistance of topo II1 proteins to topo drug-induced depletion in ER- over ER+ cells, indicating a topo II1 maintaining activity of both p381 and p383 that is antagonized by ER signaling; 3) p383 antagonizes ER through binding / phosphorylating ER at S118; 4) p381 and p383 trans- activate topo II1 in ER- but not ER+ breast cancer but 5) only p381 binds to topo II1 protein. These results together suggest that p38 MAPKs maintain topo II1 expression that is suppressed by ER signaling leading to a sustained topo II1 protein expression and increased topo II drug toxicity in ER- breast cancer. Experiments in this second funding period will demonstrate if 1) p381 and p383 cooperate to maintain topo II1 protein expression through their over-expression in ER+ and depletion in ER- breast cancer, 2) ER antagonizes p381/p383 stimulations of topo II1 expression by directly binding p383 proteins and indirectly attenuating p381 phosphorylation; and 3) p38 MAPK activities determine the growth-inhibitory efficacy of topo II drugs against human breast cancer in vitro and in mice. Topo II inhibitor-containing chemotherapy is known for its higher therapeutic activity against ER- breast cancer for several decades and mechanism involved for this selectivity however remains unknown. This proposal will test the hypothesis that p38 MAPK activation in breast cancer acts to maintain topo II1 protein expression during therapeutic stress that is antagonized by ER signaling leading to increased topo II drug activity in ER- breast cancer. These studies will reveal a novel function of p38 stress MAPKs in regulating topo II1 expression through cross-talking with ER signaling and results obtained will contribute significantly to breast cancer therapy.