Fighting Treatment-Resistant Breast Cancer Using RNA Nanoparticles

        According to the World Health Organization (WHO), breast cancer is the most common cancer among women worldwide, claiming the lives of hundreds of thousands of women each year and affecting countries at all levels of modernization.

Researchers at the University of Cincinnati (UC) College of Medicine have generated multifunctional RNA nanoparticles that could overcome treatment resistance in breast cancer, potentially making existing treatments more effective in these patients.

    Their study ("Overcoming Tamoxifen Resistance of Human Breast Cancer by Targeted Gene Silencing using Multifunctional pRNA Nanoparticles") was published online in the American Chemical Society's ACS Nano. It was led by Xiaoting Zhang, Ph.D., associate professor in the Department of Cancer Biology at the UC College of Medicine, and shows that using a nano delivery system to target human epidermal growth factor receptor 2 (HER2)-positive breast cancer and stop production of the protein MED1, or Mediator Subunit 1, could slow tumor growth, stop cancer from spreading, and sensitize the cancer cells to treatment with tamoxifen, a known therapy for estrogen-driven cancer.

    MED1 is a protein often produced at abnormally high levels in breast cancer cells that, when eliminated, is found to stop cancer cell growth. HER2-positive breast cancer involves the amplification of a gene encoding, or programming, the protein known as human epidermal growth factor receptor 2, which also promotes the growth of cancer cells. MED1 co-produces (co-expresses) and co-amplifies with HER2 in most cases, and Zhang's previous studies have shown their interaction plays critical roles in antiestrogen treatment resistance.

 "Most breast cancers express estrogen receptors, and the antiestrogen drug tamoxifen has been widely used for their treatment," says Dr. Zhang, a member of the Cincinnati Cancer Center and the UC Cancer Institute. "Unfortunately, up to half of all estrogen receptor-positive tumors are either unresponsive or develop resistance to the therapy later. In this study, we have developed a highly innovative design that takes advantage of the co-overexpression of HER2 and MED1 in these tumors."

    Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in the coding, decoding, regulating, and expressing of genes.

Dr. Zhang and researchers in his lab found that these RNA nanoparticles could bind selectively to HER2-overexpressing breast tumors, eliminating MED1 expression and significantly decreasing estrogen receptor-controlled target gene production. The RNA nanoparticles reduced the growth and spread of the HER2-overexpressing breast cancer tumors and sensitized them to tamoxifen treatment.

    "These biosafe nanoparticles efficiently targeted and penetrated HER2-overexpressing tumors after administration in animal models," he says. "In addition, these nanoparticles also led to a dramatic reduction in breast tumors' cancer stem cell content when combined with tamoxifen treatment. Cancer stem cells, as you know, are tumor-causing cells that are known to play essential roles in tumor spread, recurrence, and therapy resistance. Eliminating these cells could represent an improved and more desirable treatment strategy for breast cancer patients.

    "These findings are highly promising for potential clinical treatment of advanced metastatic and tamoxifen-resistant human breast cancer. Further studies are still needed, and hopefully, soon, we'll be able to test our nanoparticles in clinical trials at the UC Cancer Institute's Comprehensive Breast Cancer Center."