MUC1* is a determinant of trastuzumab (Herceptin) resistance in breast cancer cells

Abstract

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.

Effect of MUC1 siRNA on Drug Resistance of Gastric Cancer Cells to Trastuzumab

“…In addition, some studies found that the molecular mechanisms promoting trastuzumab resistance of gastric cancer cells may include: (1) excessive activation of the downstream PI3K/Akt signaling pathway (Velho et al, 2005) (2) cell surface proteins such as HSP90 (Citri et al, 2004;Lang et al, 2007) and mucins (Price, Schiavi et al, 2002) decrease the interaction between trastuzumab and the HER2 receptor, thereby blocking the inhibitory actions of the drug. However, recent studies have shown upregulation of mucin-1 (MUC1), a protein with growth factor receptor-like activity (Fessler et al, 2009 ), mediated the growth of tumor cells, especially the trastuzumab-resistant HER2-positive breast cancer cells. The relationship between MUC1 in gastric cancer cells and its effect on the resistance is unknown.…”

Mucin 1 enhances the tumor angiogenic response by activation of the AKT signaling pathway

“…MUC1 overexpression correlates with high metastatic potential and poor survival; therefore, MUC1 antigens have been used as clinical markers to monitor disease progression in cancer patients (Kohno et al, 1992;Duffy et al, 2000). In addition, previous studies have shown that MUC1 has a pivotal role in tumor development, growth, invasion (Sachdeva and Mo, 2010), oncogenic cellular signal transduction (Raina et al, 2004;Wei et al, 2006), responses to hypoxia (Mikami et al, 2009) and resistance to anti-cancer reagents (Fessler et al, 2009). However, the significance of high expression of MUC1 in tumor cells remains to be determined.…”

Two Molecular Markers of Early Non-Small Cell Lung Carcinoma Based on Gene Expression in Peripheral Blood

“…Sample size was calculated taking into account the ratio of positivity for the N. Bahrami et al markers in the two groups based on primary estimates in similar previous studies [24] as well as using sample size estimation formula considering type one error of 5% and type two error of 20%. The data were analyzed using SPSS version 22.…”