Breast Cancer Cells Can Switch HER2 On and Off, Requiring Combination Treatment Interview with:

Shyamala Maheswaran, PhD Associate Professor of Surgery Harvard Medical School Assistant Molecular Biologist Center for Cancer Research

Dr. Shyamala Maheswaran

Shyamala Maheswaran, PhD
Associate Professor of Surgery
Harvard Medical School
Assistant Molecular Biologist
Center for Cancer Research What is the background for this study? What are the main findings?

Response: About 85% hormone receptor positive HER2 negative metastatic breast cancer patients show that cancer cells acquire HER2 expression during disease progression. These HER2 positive cells coexist with HER2 negative cancer cells, and these two populations are able to spontaneously oscillate between these two states; in culture and in cancers established in mice. Both HER2 positive and HER2 negative cells form tumors when injected into mice, but HER2 positive cancer cells form tumors more rapidly than HER2 negative tumors. At a molecular level, several growth factor pathways are activated in HER2 positive cancer cells, while activation of the Notch pathway, an embryonic signaling event, is observed in HER2 negative cells. Thus the HER2 positive and HER2 negative cancer cells exhibit differential sensitive to drugs: the HER2 positive cells, which are more proliferative and non-responsive to HER2-targeting agents, are responsive to chemotherapy drugs whereas the HER2 negative tumor cells are sensitive to Notch inhibitors. A combination of chemotherapeutic drugs and notch inhibitors effectively eliminate tumors formed by a mixture of these two population of cancer cells compared to either drug alone. These findings highlight the importance of tumor heterogeneity in cancer progression and drug responses and suggest that targeting all the different populations within cancers is necessary to effectively manage cancer progression. What should readers take away from your report?

Response: These findings show that dynamic changes in the characteristics tumor cells can generate heterogenous populations of tumor cells that need to be targeted with a combination of drugs. What recommendations do you have for future research as a result of this study?

Response: Future studies will focus on the mechanisms that are enable the spontaneous transition of cancer cells between a HER2 positive and HER2 negative states. Is there anything else you would like to add?

Response: We would also like to determine whether additional levels of heterogeneity exist within cancers and how they influence tumor growth and therapeutic responses. Thank you for your contribution to the community.


Nicole Vincent Jordan, Aditya Bardia, Ben S. Wittner, Cyril Benes, Matteo Ligorio, Yu Zheng, Min Yu, Tilak K. Sundaresan, Joseph A. Licausi, Rushil Desai, Ryan M. O’Keefe, Richard Y. Ebright, Myriam Boukhali, Srinjoy Sil, Maristela L. Onozato, Anthony J. Iafrate, Ravi Kapur, Dennis Sgroi, David T. Ting, Mehmet Toner, Sridhar Ramaswamy, Wilhelm Haas, Shyamala Maheswaran, Daniel A. Haber.HER2 expression identifies dynamic functional states within circulating breast cancer cells. Nature, 2016; DOI:10.1038/nature19328

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

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