The HER2 paradox: HER2-positive stem cells found in HER2-negative breast cancer

(Press-News.org) (SACRAMENTO, Calif.) — A multicenter study led by researchers at UC Davis describes new, paradoxical characteristics of the most common type of breast cancer. The findings shed light on how the disease can evade treatment and could improve diagnosis and treatment of breast cancer.

The research, led by Jian Jian Li, director of translational research in the UC Davis Department of Radiation Oncology, examined breast tumors previously thought to lack the HER2 protein, which, when over-expressed, is associated with disease recurrence. Instead, researchers found in the tumors small groups of aggressive, treatment-resistant HER2-positive breast cancer stem cells (BCSCs). The findings will be published Dec. 15 in Clinical Cancer Research.

"These BSCSs are very resistant to traditional treatments, which can lead patients to relapse," said Li, the study lead author. "Despite chemotherapy, radiotherapy or even surgery, the cancer is still recurrent. These findings change our concept of breast cancer because now we know HER2-negative breast cancers can be treated effectively with anti-HER2 treatments."

In the past decade scientists and clinicians have developed a better understanding of how breast cancers differ on the cellular level. Whether a tumor contains HER2, an estrogen receptor protein, a progesterone receptor protein or all three or none can have an enormous impact on the tumor's aggressiveness, the patient's overall prognosis and treatment choices.

HER2-positive breast cancers are routinely treated with drugs that target the HER2 protein, such as Herceptin or Tykerb, with good results. However, until recently, there has been little reason to administer these targeted treatments to patients with HER2-negative cancer.

The team, which included researchers from the University of Michigan Comprehensive Cancer Center, the Holden Comprehensive Cancer Center at the University of Iowa, Emory University School of Medicine and MD Anderson Cancer Center, isolated the HER2-positive BCSCs from irradiated, HER2-negative breast tumors. They also analyzed the stem cells for CD44 and CD24, cell surface proteins that indicate cancer aggressiveness and act as BCSC markers.

The team found that the HER2-positive, CD44 positive, CD24 negative/low BCSCs were more aggressive and highly resistant to radiotherapy. These characteristics were significantly reduced by Herceptin or short interfering RNA. HER2 and CD44 positive BCSCs were found in 57.1 percent of primary tumors and 84.6 percent of recurrent tumors.

In addition to identifying this previously hidden group of HER2-positive stem cells, further examination provided new insights into how these BCSCs maintain their resistance to treatment. A complex network of proteins, including HER2 and STAT3, modulate metastasis, programmed cell death and other functions. As a result, these cells survive the gamut of traditional anti-cancer therapies.

"We feel this research will have a major scientific, as well as clinical, impact," says Li. "We now have a better understanding of how BCSCs resist radiation and other treatments."

While recent research has shown that patients with HER2-negative breast cancer can indeed benefit from HER2 treatments, prior to this work no one understood the mechanisms. This research provides detailed confirmation that HER2 treatment can potentially improve outcomes in HER2-negative breast cancers.

In addition to opening up new treatment options for HER2-negative patients, the research also provides a diagnostic pathway. Markers, such as CD44, could help clinicians identify aggressive, HER2-positive BCSCs in cancers that are ostensibly HER2-negative, individualizing treatment to match each patient's needs. These findings may also advance treatment for other cancers.

"This may open the possibility of treating HER2-positive stem cells in bone, lung or brain cancers, which are all difficult to treat in the later stages," says Li.

### Other authors were Nadire Duru, Ming Fan, Demet Candas, Cheikh Menaa, Hsin-Chen Liu, Danupon Nantajit, Kai Xiao, Angela Eldridge and Kit S. Lam, at UC Davis, Yunfei Wen at MD Anderson, Brett A. Chromy at UC Davis and Lawrence Livermore, Shiyong Li at Emory University, Douglas R. Spitz, Holden Comprehensive Cancer Center and Max S. Wicha at the University of Michigan Comprehensive Cancer Center.

This research was supported by the National Institutes of Health Grant CA133402, CA152313, and by the U.S. Department of Energy Office of Science Grant DE-SC0001271.

UC Davis Comprehensive Cancer Center is the only National Cancer Institute-designated center serving the Central Valley and inland Northern California, a region of more than 6 million people. Its specialists provide compassionate, comprehensive care for more than 9,000 adults and children every year, and access to more than 150 clinical trials at any given time. Its innovative research program engages more than 280 scientists at UC Davis, Lawrence Livermore National Laboratory and Jackson Laboratory (JAX West), whose scientific partnerships advance discovery of new tools to diagnose and treat cancer. Through the Cancer Care Network, UC Davis collaborates with a number of hospitals and clinical centers throughout the Central Valley and Northern California regions to offer the latest cancer care. Its community-based outreach and education programs address disparities in cancer outcomes across diverse populations. For more information, visit cancer.ucdavis.edu.