A recent study offers new insights into how breast cancer may spread to nearby lymph nodes and also suggests that a drug commonly used to treat heart failure, digoxin, may be able to interrupt the process. The findings were reported September 10 in the Proceedings of the National Academies of Sciences (PNAS).

The lymphatic system is an important route through which cancer cells reach the circulatory system and travel to distant organs, where they develop into metastatic tumors. Metastasis—which is responsible for most cancer deaths—is not well understood, and few treatments actively target it. In breast cancer, nearly all women with metastatic disease have lymph node involvement.

Using mice, Dr. Gregg Semenza of Johns Hopkins University and his colleagues showed that hypoxia-inducible factor-1 alpha (HIF-1α) plays a direct role in the spread of breast cancer cells to the lymph nodes. HIF-1 α is a subunit of the HIF-1 protein, which promotes blood vessel formation under low-oxygen conditions, such as those in tumors. HIF-1α, the researchers found, activates the PDGF-B gene, which codes for platelet-derived growth factor (PDGF-B).

When mice with tumors formed from injected human breast cancer cells were treated with digoxin (which inhibits HIF-1α) or with imatinib (Gleevec; which inhibits PDGF-B), cancer cell spread was dramatically reduced.

In addition, mice with tumors formed from breast cancer cells that were genetically modified to block production of HIF-1α had 75 percent fewer lymph node metastases than mice with tumors formed from unmodified breast cancer cells.

In biopsy samples from human breast cancers, the authors also found that

• PDGF-B was highly active in cells that were starved of oxygen,
• HIF-1α directly activated transcription of PDGF-B,
• the HIF-1α and PDGF-B proteins were found near each other in almost all of the biopsy samples they studied, and
• levels of expression of these proteins in biopsy samples correlated with tumor grade.

Other studies have linked HIF-1α and PDGF-B to metastatic spread. “But this is the first time that anybody has connected all the dots in a single cancer,” Dr. Semenza explained.

Later this year, the Hopkins researchers plan to launch an early-phase clinical trial to test digoxin in women with operable breast cancer, Dr. Semenza said. Digoxin, an off-patent drug, will be given for about 2 weeks before surgery, and the researchers will analyze pre- and post-surgical tumor samples to determine whether the drug is inhibiting HIF-1 and its downstream target genes.

If the trial suggests that the drug is having the intended molecular effects, an early-phase trial combining digoxin with other standard treatments would likely be launched.

Source: NCI