Inhibiting a Key Protein Found to Restore Hormone Sensitivity in Breast Cancer

Cold Spring Harbor Laboratory scientists have identified a potential path toward preventing recurrence in estrogen receptor-positive (ER+) breast cancer, the form that makes up roughly three-quarters of all breast cancer cases. Although hormone therapy is a mainstay treatment that includes drugs such as tamoxifen, many patients eventually relapse with tumors that no longer respond to this therapy. The new findings suggest that suppressing a specific protein could reinstate hormonal control over these resistant cancers.

The research, led by Camila dos Santos, demonstrates that inhibiting the BPTF protein in mouse models slows the spread of ER+ cancer and restores responsiveness to hormone-based drugs. Michael Ciccone, first author of the study published in Nature Communications, explained that their work may redirect how the disease is targeted: “We’re not curing cancer, but we’re forcing it into an avenue that we’re good at, which is targeting it with hormone therapies.”

Earlier studies had shown that removing BPTF reduced tumor growth but did not stop cancer from forming, leading many pharmaceutical developers to overlook the protein as a viable target. The CSHL team revisited this question by breeding a conventional breast cancer mouse line with one lacking BPTF. They discovered that the resulting tumors stayed ER-positive throughout their development—an outcome never seen before in existing mouse models.

“There isn’t any mouse model that maintains a hormone-positive cancer throughout the cycle of the tumor,” Ciccone noted. When these mice received tamoxifen treatments, “the tumors were responding and not growing,” leading the team to realize that blocking BPTF sustained the cancers’ vulnerability to hormone therapy.

To further test the concept, they combined BPTF loss with tamoxifen in organoid systems, human breast cancer cell lines, and hormone-resistant mouse models. In each system, the intervention restored drug sensitivity and reduced tumor progression.

Co-author Dhivyaa Anandan pointed to the team’s comprehensive approach as a factor underlying their success. “Cancer is often studied in a binary way,” she says. “Is it there or not? Did the tumors grow or shrink? This study showed there is far more nuance. If we don’t look at the types of tumors that are growing, how they’re growing, and where they’re spreading—all the very nuanced analyses we did—we miss so much.”