Study reveals factors outside of tumors that steer breast cancer aggressiveness

Cancer researchers have identified key factors in the surroundings of tumor cells that it may be possible to target to improve outcomes for patients with HER2-positive breast cancer.

Co-principal investigator Jim Korkola, Ph.D., said it’s the first comprehensive study of the ways that HER2-positive breast cancer cells are influenced by signals from the non-cancerous cells and tissues around them. Korkola is an assistant professor of biomedical engineering in the OHSU School of Medicine.

Photo: The study team included Tiera Liby, M.Sc., Zuzana Tatarova, Ph.D., Elmar Bucher, B.Sc., Jim Korkola, Ph.D., and Moqing Liu, Ph.D. (OHSU/Kristyna Wentz-Graff)In about one out of four breast cancer cases, gene alterations boost the output of a protein called human epidermal growth factor receptor 2, or HER2, which promotes cancer cell growth. Therapies that block HER2 activity, including the drugs lapatinib and neratinib, have been approved for patients with HER2-positive breast cancer. But not all patients respond to these drugs, and their effect is usually short-lived in advanced cancers.

To uncover the microenvironment effects on tumor response to therapies, the OHSU researchers used an emerging microarray technology. They printed proteins onto plates to form the matrix that cancer cells grow on, and added liquid media containing soluble proteins that tumors encounter in their microenvironment. The method allowed them to measure the effect of more than 2,500 combinations of 56 soluble and 46 matrix microenvironment proteins on the response of cancer cells derived from human breast tumors after treatment with lapatinib or neratinib. The two drugs are in a class called tyrosine kinase inhibitors, or TKIs.

Plots of median cell count versus median EdU-positive ratio for AU565 cells (representing the L-HER2+ subtype) and HCC1954 cells (representing the HER2E subtype) on microenvironment microarrays following lapatinib or DMSO treatments. (Watson et al.)

They found that the matrix or soluble factors conferring resistance to drug treatment differed between luminal-like (L-HER2+) and basal-like (HER2E) breast cancer subtypes. The protein neuregulin1-β1 conferred resistance to L-HER2+ subtype cells, and hepatocyte growth factor conferred resistance in HER2E cells, but not vice versa. The microenvironment-mediated resistance was reversed by co-treatment with the drug pertuzumab in L-HER2+ cells and by co-treatment with crizotinib in HER2E cells.

“These differential responses to microenvironmental factors reflect fundamental differences in signaling network wiring and architecture in the two subtypes,” the researchers wrote in a paper published in the open-access journal Cell Systems.

“Our findings also support the emerging notion that L-HER2+ and HER2E represent distinct diseases. They also suggest clinical studies to test the possibility that differential targeting of resistance factors from the microenvironment in L-HER2+ and HER2E will improve clinical outcome in patients being treated with HER2-targeted TKIs.”

The results raise a red flag for researchers conducting “basket” clinical trials, studies in which all patients with a given gene alteration are treated with the same therapy independently of tumor type or subtype. The new data add to the evidence that factors in the microenvironment can significantly modify the effect of a cancer driver mutation and the response of cancer cells to drugs targeting a driver mutation.

The co-PI on the research is Joe Gray, Ph.D., the Knight Cancer Institute associate director for biophysical oncology and professor of biomedical engineering in the OHSU School of Medicine. The researchers said in a news release that they are pursuing funding options that would allow preliminary testing in patients. That work is a collaboration with a biotechnology company and Zahi Mitri, M.D., an assistant professor of medicine in the OHSU School of Medicine.

Spencer Watson, the first author, worked on the study as part of his Ph.D. thesis in the Department of Biomedical Engineering. He is now working as a post-doctoral researcher in Switzerland.

Further reading:

Area surrounding a tumor impacts how breast cancer cells grow by Amanda Gibbs. OHSU News (March 14, 2018)

Microenvironment-Mediated Mechanisms of Resistance to HER2 Inhibitors Differ between HER2+ Breast Cancer Subtypes by Spencer S. Watson, Mark Dane, Koei Chin, Zuzana Tatarova, Moqing Liu, Tiera Liby, Wallace Thompson, Rebecca Smith, Michel Nederlof, Elmar Bucher, David Kilburn, Matthew Whitman, Damir Sudar, Gordon B. Mills, Laura M. Heiser, Oliver Jonas, Joe W. Gray, James E. Korkola. Cell Systems (March 14, 2018)

This research was funded by the NIH Common Fund Library of Network Cellular Signatures (LINCS) grant HG008100 and the Susan G. Komen Foundation award SAC110012. Spencer Watson was supported by the National Cancer Institute under award number F31CA200322. Additional support was provided by the Knight Cancer Institute NCI grant 5P30CA069533-16, NIH grant CA195469 (Joe Gray) and the Prospect Creek Foundation. Oliver Jonas was supported by the Brigham Research Institute, Director’s Transformative Award.