New models of drug-resistant breast cancer hint at better treatments

Breast cancer that spreads to other organs is extremely difficult to treat. Doctors can buy patients time, but a cure remains elusive. Now, researchers at Washington University School of Medicine in St. Louis have shown that human breast tumors transplanted into mice are excellent models of metastatic cancer and could be valuable tools in the search for better treatments.

According to new research published Sept. 19 in Cell Reports, these transplanted tumors maintain the genetic errors that caused the original cancer, even though they are growing in mice. As such, mice carrying human tumors can help identify drivers of tumor growth and serve as excellent test subjects for investigating new drugs.

Senior author Matthew J. Ellis, MD, PhD, said the new paper is a step toward precision medicine, allowing researchers to study model tumors matched to a specific patient whose treatment regimens are well-documented.

"It is so powerful to have a model of Mrs. Jones' cancer or Mrs. Smith's cancer," said Ellis, a breast cancer specialist who treats patients at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University. "First, we have carefully documented information about the patient. We know exactly what drugs she responded to and what drugs she didn't. Second, we have her consent for full genetic analysis. And third, we take the cells from her cancer and grow them in a special strain of mice that has no immune system, so they grow cells from a human without rejection."

Ellis and his colleagues reported that the breast tumors growing in the mouse are startlingly similar to cancers growing in the human. And the changes that do occur in the transfer from human to mouse are often "silent," having no effect on tumor growth.

"We are addressing a fundamental question about how similar or different the tumor is once it's in a mouse," said Elaine Mardis, PhD, co-director of The Genome Institute, which performed the sequencing. "These results give us confidence that pursuing new therapies using the mouse will provide an accurate picture of how that therapy will impact the tumor in the patient."

The analysis showed that mutations occurring at high frequency in the original tumor remained at high frequency in the mouse. Likewise, and somewhat surprisingly, according to Ellis, less common mutations remained at the same low frequency in the mouse.

"A simple growth model says the slower growing clones should go away," Ellis said. "They shouldn't be maintained at the same low frequency, but they are. And this drive for equilibrium is so strong it can survive crossing a species barrier. In maintaining this hierarchy, the genetically different clones in the tumor are interacting, a bit like different cell types within an organ, which is a wild thought because it means that our old models based on competition between the clones may be incorrect."

Ellis emphasized that this approach is fundamentally different from most breast cancer research. Others have grown human tumors in mice, but Ellis' team is the first to sequence whole genomes — the patient's healthy genome, tumor genome and the corresponding mouse genome — to determine how closely the mouse tumor resembles that in the human. Others have tested new drugs in breast cancer cell lines growing in a dish, but these cell lines are far removed from any information about the original patient the cells were taken from and how that patient fared with a particular kind of treatment.