Dynamic Nature of Breast Cancer Resistance: The HER2 Switch
Research at Massachusetts General Hospital has provided clues to drug resistance in breast cancer—the smart tumor cells switch between a human epidermal growth factor receptor 2 (HER2)-negative to a HER2-positive state, which can result in disease progression and drug resistance.
For this study, which has been published in the journal Nature, researchers isolated and analyzed circulating tumor cells (CTCs) from 19 women diagnosed with estrogen receptor–positive (ER-positive)/HER2-negative breast cancer and found that 83% of these women had developed CTCs that expressed HER2. While it is known that CTCs in culture maintain distinct subpopulations of HER2-positive and HER2-negative cells, those in the body do not seem to be addicted to HER2 expression. The authors found that 16 women who had developed metastases following treatment for ER-positive/HER2-negative primary breast cancer expressed a mix of HER2-positive and HER2-negative CTCs.
Interestingly, the authors observed activation of Notch and DNA damage signaling pathways in HER2-negative CTCs, which could explain their resistance to chemotherapy. While HER2-positive and HER2-negative CTCs were equally sensitive to HER2 inhibitors, addition of an inhibitor to the insulin-like growth factor receptor 1 proved more toxic to CTCs expressing HER2. HER2-positive CTCs proliferated more rapidly and responded to treatment with standard chemotherapy drugs, while HER2-negative CTCs were more resistant to chemotherapy drugs but sensitive to Notch inhibitors.
A mouse model developed by injecting either HER2-positive or HER2-negative breast tumor cells into mouse mammary fat pads resulted in tumors that had a mixed population of both types of cells. However, tumors that predominantly expressed HER2 responded to paclitaxel and presented with tumor shrinkage; however, tumor recurrence was characterized by an increase in HER2-negative cells that were insensitive to paclitaxel. However, adding a Notch inhibitor like gamma secretase to the mix seemed to work better in restricting tumors that expressed a mixed population of cells.
“Not only did we observe the acquisition of HER2 positivity in patients with ER-positive/HER2 negative breast tumors, we also found that this population of tumor cells is able to spontaneously oscillate between HER2-positive and HER2-negative states, which contributes to tumor progression and resistance," Shyamala Maheswaran, PhD, one of the senior authors on the study, said in a statement.
“The ability of these two populations of tumor cells to convert back and forth highlights the importance of treating tumors with drugs that would simultaneously target both populations,” she added.
Jordan NV, Bardia A, Wittner BS, et al. HER2 expression identifies dynamic functional states within circulating breast cancer cells [published online August 24, 2016]. Nature. doi:10.1038/nature19328.