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New Clues for Overcoming Tamoxifen-Resistant Breast Cancer

Estrogen receptor activators help mediate resistance (Nov. 2)

Researchers at the University of Cincinnati have found that an estrogen receptor co-activator — MED1 — plays a central role in mediating tamoxifen resistance in human breast cancer. The team reported its findings in Cancer Research.

The new discovery may help overcome resistance to endocrine (hormone) therapy in patients with estrogen-positive breast cancer.

According to the National Cancer Institute, nearly 227,000 women are diagnosed with breast cancer annually in the U.S. About 75% of these women have estrogen-positive tumors and require adjuvant hormone-therapy drugs, such as tamoxifen, which works by interfering with the ability of estrogen to stimulate the growth of breast cancer cells.

Despite advances in hormone treatments, cancer surveillance research has shown that 50% of patients will develop drug resistance and will experience relapse.

The hormones estrogen and progesterone stimulate the growth of some breast cancers, and hormone therapy is used to stop or slow the growth of these tumors. Hormone-sensitive (i.e., positive) breast cancer cells contain specific proteins (hormone receptors) that become activated once hormones bind to them, leading to cancer growth.

Based on the new findings, the researchers believe that tamoxifen resistance may be driven by a molecular "crosstalk” point between the estrogen and HER2 (human epidermal growth factor receptor 2) signaling pathways.

Testing in both preclinical models and human breast-cancer tissue samples showed that MED1 co-amplifies and co-expresses with HER2 — a gene that has an increased presence in 20% to 30% of invasive human breast cancer and that plays a major role in tamoxifen resistance.

HER2 over-expression led to MED1 activation, whereas the reduction of MED1 caused breast cancer cells that were otherwise tamoxifen-resistant to respond and stop dividing. Further mechanistic studies showed that HER2 activation of MED1 resulted in the recruitment of co-activators instead of co-repressors by the tamoxifen-bound estrogen receptor. This drove the expression of not only traditional estrogen receptor-positive cancer target genes, but also HER2 and the estrogen receptor target genes abnormally activated by HER2.

“Together, these findings suggest this ‘crosstalk’ could play a central role in mediating tamoxifen resistance in human breast cancer, especially because recent published data also indicated that high MED1 expression levels correlate with poor treatment outcome and disease-free survival of patients who underwent endocrine therapy,” explained researcher Xiaoting Zhang, PhD.

“We are currently utilizing RNA-based nanotechnology to target MED1 in an effort to simultaneously block both estrogen and HER2 pathways to overcome endocrine-resistant breast cancer,” he said.

Source: University of Cincinnati; November 2, 2012.

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