A new study offers a potential treatment strategy for basal-like breast tumors. Researchers found that disrupting platelet-derived growth factor signaling—either genetically or with an antibody that blocks one form of the growth factor—can cause tumors to change to the luminal subtype, which is susceptible to antiestrogen therapies.

A new mouse study shows that basal-like breast tumors can be converted into a subtype of breast cancer that is susceptible to estrogen receptor (ER)–targeting therapies.

Because they are ER-positive, luminal-type breast tumors often respond to drugs that disrupt estrogen signaling, such as tamoxifen and fulvestrant (Faslodex; AstraZeneca). In contrast, basal-like tumors can lack receptors for estrogen, progesterone, and HER2, making them difficult to treat. Patients with these tumors have the highest disease recurrence rate and the lowest overall survival.

In previous studies, Kristian Pietras, PhD, of Lund University in Sweden, and colleagues found that platelet-derived growth factor (PDGF) boosts tumor growth in several cancer types by altering the function of nearby fibroblasts. In the new work, they probed the role of PDGF in breast cancer. When they tested tissue from patients, they discovered that basal-like breast cancer cells release the PDGF-CC isoform of PDGF. To determine its effects, the team followed tumor growth in control mice and in mice lacking one or both copies of the gene that encodes PDGF-CC. After 14 weeks, mammary tumors were more than twice as large in controls as in mice that were missing PDGF-CC, the researchers found. They also discovered that angiogenesis and collagen levels—a sign of fibroblast activity in the tumor microenvironment—were reduced in tumors that didn't produce the growth factor.

The scientists then characterized the PDGF-CC–lacking tumors by measuring gene expression. They found dramatically increased expression of the transcription factor FOXA1, which predominantly occurs in luminal tumors. Moreover, the researchers determined that tumor cells missing PDGF-CC overexpress other luminal markers, including ERα.

Pietras and colleagues next tried to induce tumors to change subtype. They implanted either patient-derived xenografts or a basal-like breast cancer cell line into mice and injected the animals with 6B3, an antibody that blocks PDGF-CC. In both groups of animals, the tumors began expressing ERα, suggesting that the tumors had switched to the luminal subtype. To confirm that finding, the scientists gave the mice tamoxifen, which slowed tumor growth.

Pietras says that the study indicates that the tumor cells release PDGF-CC, which stimulates fibroblasts in the surrounding tissue. In turn, “they secrete factors that make the tumor cells basal-like,” he says.

The study “shows the tumor environment plays a central role in determining tumor phenotype,” says Xiaojiang Cui, PhD, of Cedars-Sinai Medical Center in Los Angeles, CA, who wasn't connected to the research. He notes that the effect of interfering with PDGF-CC appears to be modest—combining 6B3 and tamoxifen slowed tumor growth but didn't stop it. Nonetheless, he says, “clinically it could provide an avenue for developing a novel therapeutic strategy.”

Pietras says the key question now is: “Can we use pharmacological interventions to change the tumors’ subtype and make them susceptible to available drugs?” He and his colleagues are working to develop 6B3 into a drug candidate. In addition, he says, two approved drugs, imatinib (Gleevec; Novartis) and sunitinib (Sutent; Pfizer), impair PDGF signaling and may drive basal-like tumors to make the change. –Mitch Leslie