A naturally occurring protein that tends to be expressed at higher levels in breast cancer cells boosts the effectiveness of some anticancer agents, including doxorubicin, one of the most widely used chemotherapies, and a preclinical drug known as ErSO, researchers report. The protein, FGD3, contributes to the rupture of cancer cells disrupted by these drugs, boosting their effectiveness and enhancing anticancer immunotherapies.
The discovery is described in the Journal of Experimental & Clinical Cancer Research.
The new findings were the happy result of experiments involving ErSO, an experimental drug that killed 95-100% of estrogen-receptor-positive breast cancer cells in a mouse model of the disease. ErSO upregulates a cellular pathway that normally protects cancer cells from stress, said Cancer Center at Illinois (CCIL) member David Shapiro, a professor of biochemistry, who led the new work with Illinois graduate student Junyao Zhu. But when that protective pathway is ramped up, the system goes awry.
“Most anticancer drugs inhibit something that the cell needs to survive, and they either prevent the cell from growing or, in some cases, cause it to die in an orderly way called apoptosis,” Shapiro said. “But ErSO does exactly the opposite. It overactivates the cell pathway and the cancer cells literally swell up and rip open.”
Shapiro and CCIL Deputy Director Paul Hergenrother, a co-author on this new study, first discovered ErSO and reported on it in 2021. In the new study, they wanted to better understand how ErSO worked by identifying the cellular proteins that play a role in “making life-death decisions for the cells,” Shapiro said.
To do this, they tested the drug against breast cancer cell lines, each of which had one of its 18,000 genes deleted. If a deleted gene undermined the efficacy of a drug — in this case ErSO — it was a signal that that gene played a role in the drug’s cancer-killing pathway.
“The top target from the screen with ErSO was the gene for this little-studied protein called FGD3,” Shapiro said. “So, we manipulated levels of FGD3 in cancer cells and saw that it indeed controlled whether ErSO could kill the cells. And in a series of important experiments, Zhu showed that FGD3 weakens the cell’s architecture.”
When not under attack by chemotherapy or other anticancer therapies, FGD3 makes cancer cells more flexible, allowing them to move and change their shape, facilitating their migration and likely increasing their potential to metastasize, the researchers said. But when a drug like ErSO or doxorubicin perturbs the cancer cells, FGD3 causes the swollen cancer cells to rupture.
The research team included, front row, from left: graduate student Junyao Zhu, biochemistry professor David Shapiro, and senior researcher Chengiian Mao; back row, from left: graduate students Abigail Spaulding, Xinyi Dai and Qianjin Jiang. Photo by Fred Zwicky
This rupturing spills out the contents of the cell, alerting the body’s immune system, which sends in natural killer cells and macrophages to finish the job, Shapiro said.
The experiments were conducted in 2D cell culture and in 3D “breast cancer patient-derived organoids,” which more closely mimic the tumor environment, Shapiro said. Study co-author Dr. Olufunmilayo Olopade, the director of the Center for Clinical Cancer Genetics and Global Health at University of Chicago Medicine, developed the organoids.
“Work from a number of laboratories has shown that these organoids can retain the same pattern of protein production that occurs in the original tumor,” Shapiro said.
The team also tested the role of FGD3 in a mouse model of human breast cancer, and they found the same pattern: Higher FGD3 levels enhanced the killing power of ErSO.
“One of the things we saw was that FGD3 dramatically increased the movement to the cancer cell membrane of a protein that stimulates natural killer cells to target a cancer cell for destruction,” Shapiro said. “This has the potential for enhancing immunotherapy for cancer and for reducing the doses of toxic drugs that you need to use. This is especially important in breast cancer because immunotherapy has had limited success against solid tumors such as breast cancer.”
The research team also analyzed a vast trove of human breast cancer data, looking for patterns between FGD3 levels and responses to various chemotherapy agents.
“We found, with all types of chemotherapy and all classes of breast cancer, there’s a very high correlation between the level of FGD3 and whether the patient responds favorably to chemotherapy,” Shapiro said. “Those with a high level are highly responsive; those with a low level are poorly responsive. This will allow us to identify those patients most likely to benefit from these kinds of cancer therapies.”
“We will try to expand FGD3 into a broader context, to show whether it also plays a role in other cancers and cancer therapies,” Zhu said.
In human breast cancer cells treated with the preclinical drug ErSO (shown), or with doxorubicin, the cellular protein FGD3 causes another protein, calreticulin (in red on the right), to display on the cancer cell surface, attracting and activating immune cells. Micrographs by Junyao Zhu
“This is a good example of how a scientific study that starts with one objective can broaden out in unexpected directions,” Shapiro said. “We started with the question of how our compound worked and then we eventually realized that this is a common pathway shared by a number of anticancer drugs.”
Anticancer drugs cause breast cancer cells to swell. The cellular protein, FGD3, alters the disrupted cancer cells, promoting the display of molecules on their surface that recruit immune cells, researchers found. The swollen cancer cells are more likely to burst in the presence of high levels of FGD3. Graphic created in BioRender. Zhu, J. (2025) https://BioRender.com/wq32727
David Shapiro
Professor, Biochemistry
Areas of Research
Biochemistry, Breast Cancer, Cellular Function, Lung Cancer, Ovarian Cancer
Research Program and Theme
- Program: Cancer Engineering and Biological Systems
- Theme: Anticancer Chemistry
Research Focus
David Shapiro’s lab has spent over a decade studying estrogens, acting via estrogen receptor a (ERa), which plays a key role in most breast cancers. The Shapiro laboratory has leveraged its expertise in ERa action in cancer to identify new pathways of hormone action that drive proliferation, metastases, and therapy resistance, and new types of selective anticancer therapeutics. Shapiro’s lab has identified a pathway conserved from insects to humans, and between steroid hormones and peptide hormones in which mitogenic hormones, such as estrogen, and epidermal growth factor (EGF), elicit extremely rapid anticipatory activation of the stress sensor, the unfolded protein response (UPR).
Paul Hergenrother
Kenneth Rinehart Jr. Endowed Chair and Professor, Chemistry
Areas of Research
Brain Cancer, Breast Cancer, Cancer Treatment (General), Drug Design, Head and Neck Cancer, Lung Cancer, Molecular Biology
Research Program and Theme
- Program: Cancer Engineering and Biological Systems
- Theme: Anticancer Chemistry
Research Focus
Paul J. Hergenrother, Ph.D., is a Professor of Chemistry and an Affiliate in Biochemistry, and the Kenneth L. Rinehart Jr. Endowed Chair in Natural Products Chemistry. The Hergenrother laboratory seeks to use small molecules to identify and validate novel targets for treating intractable cancers. Cancer patients are taking an anticancer compound discovered by the Hergenrother lab at the University of Illinois Cancer Center and Johns Hopkins as part of a Phase 1 clinical trial. At the University of Illinois, Professor Hergenrother is the Leader of the IGB Theme “Anticancer Discovery from Pets to People” and is the Director of the NIH Chemistry-Biology Interface Training Grant. Hergenrother is also the co-founder and Chief Scientific Officer of Vanquish Oncology.
Editor’s Notes:
Paul Hergenrother is the Deputy Director, and Shapiro is a member of the Cancer Center at Illinois. Hergenrother also is affiliated with the Carle Illinois College of Medicine and the Carl R. Woese Institute for Genomic Biology at Illinois.
To reach David Shapiro, email djshapir@illinois.edu.
The National Institutes of Health, the Amend Family Charitable Fund and Systems Oncology supported this research.
The paper “FGD3 mediates lytic cell death, enhancing efficacy and immunogenicity of chemotherapy agents in breast cancer” is available online.
DOI: 10.1186/s13046-025-03559-5
This story was first published by the Illinois News Bureau on November 12, 2025 and is available here.