Using a mouse model of breast cancer, researchers from Vanderbilt University have now generated evidence to suggest that treatment with TGF-beta inhibitors might help such patients.

In the study, which appears online in advance of publication in the May print issue of the Journal of Clinical Investigation, Carlos Arteaga and colleagues show that treating mice with mammary tumors with either radiation or the chemotherapeutic drug doxorubicin increased the level of TGF-beta in their blood, the number of cancer cells in their blood, and the development of lung metastases. Treatment with an inhibitor of TGF-beta blocked the increased lung metastases. Furthermore, mice whose tumors did not express the receptor for TGF-beta did not develop increased incidence of lung metastases after treatment with radiation, indicating that TGF-beta affects the cancer cells directly, enhancing their metastatic function. This study has important clinical implications as it suggests that monitoring TGF-beta levels after primary therapy might indicate the patients most at risk of developing tumor metastases and that treatment with TGF-beta inhibitors might be of clinical benefit to these individuals.

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The team is currently assessing TGF-beta levels in the serum of patients with breast cancer who are being treated with neoadjuvant chemotherapy to shrink the tumor prior to surgery.

"We'll be looking to see in what proportion of patients the serum and tumor TGF-beta goes up, and whether the increase correlates with the inability of the therapy to eliminate the cancer in the breast," Arteaga said.

Increased circulating and/or tumor TGF-beta in response to treatment may be a marker of tumors destined to progress rapidly after therapy, he said. Patients with such tumors might benefit from the addition of TGF-beta inhibitors to the primary therapy. Several TGF-beta inhibitors are currently in early stage clinical trials, some of which are being conducted at Vanderbilt.

"It probably isn't just TGF-beta that is having this effect," Arteaga said. "There are other growth factors and cytokines that have been reported to increase in response to radiation, chemotherapy and surgery, and some of these could also be tumor survival and prometastatic signals. "TGF-beta may be just the tip of the iceberg."

mc.vanderbilt/reporter