In the United States, 211,000 women are diagnosed each year with breast cancer. Of the 42,000 breast cancer patients who overexpress the HER2 growth factor receptor, <35% are responsive to treatment with the HER2-disabling antibody, called trastuzumab (Herceptin). Despite those statistics, women diagnosed with breast cancer are now tested to determine how much of this important growth factor receptor is present in their tumor because patients whose treatment includes trastuzumab are three-times more likely to survive for at least 5 years and are two-times more likely to survive without a cancer recurrence. Unfortunately, even among the group whose cancers originally respond to trastuzumab, 25% of the metastatic breast cancer patients acquire resistance to trastuzumab within the first year of treatment. Follow-on "salvage" therapies have prolonged life for this group but have not been curative. Thus, it is critically important to understand the mechanisms of trastuzumab resistance and develop therapies that reverse or prevent it. Here, we report that molecular analysis of a cancer cell line that was induced to acquire trastuzumab resistance showed a dramatic increase in the amount of the cleaved form of the MUC1 protein, called MUC1*. We recently reported that MUC1* functions as a growth factor receptor on cancer cells and on embryonic stem cells. Here, we show that treating trastuzumab-resistant cancer cells with a combination of MUC1* antagonists and trastuzumab, reverses the drug resistance. Further, HER2-positive cancer cells that are intrinsically resistant to trastuzumab became trastuzumab-sensitive when treated with MUC1* antagonists and trastuzumab. Additionally, we found that tumor cells that had acquired Herceptin resistance had also acquired resistance to standard chemotherapy agents like Taxol, Doxorubicin, and Cyclophosphamide. Acquired resistance to these standard chemotherapy drugs was also reversed by combined treatment with the original drug plus a MUC1* inhibitor.
Gold nanoparticles hold great promise for studying protein-protein interactions because of their intrinsic optical properties. Pink when in a homogeneous suspension, the solution turns blue-gray when particles are drawn close together, for example, when immobilized proteins specifically interact with each other. However, the nanoparticle stability, size, and method of protein attachment contribute to the unreliable outcome of current assays. To overcome these hurdles, we developed novel and reliable methods first to synthesize homogenous particles of optimal diameter and second to apply a heterologous NTA-Ni-SAM coating for controlled orientation and optimal presentation of histidine-tagged proteins. Both methods were proven to greatly enhance assay sensitivity and specificity by increasing the signal and minimizing the nonspecific binding. Our assay reproducibly detected known protein-protein interactions and unambiguously identified small molecules that inhibited them. We believe our gold nanoparticle bioassay is a versatile and trustworthy new platform for analyzing protein-protein interactions and high-throughput screening of small-molecule inhibitors.
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