While recent reports have shown that, overall, cancer incidence and mortality are decreasing, they have also revealed a disturbing trend: although lung cancer incidence in men has been steadily decreasing since its peak in the late 1980s, it continued to increase in women after this time and didn't take a downward turn until 2000. The number of men dying from the disease has been falling, but lung cancer deaths among women have held relatively steady.

Incidence and mortality aren't the only differences when it comes to lung cancer. Among those who smoke, women are more likely to get small-cell lung cancer, a particularly aggressive form of the disease, than they are to get non-small-cell lung cancer (NSCLC), while their male counterparts have an equal risk of developing the two. Female smokers are also more likely to develop adenocarcinoma, a glandular form of lung cancer similar to that found in the breast, than are men. And among people who have never smoked but developed lung cancer, more than twice as many of them are women as are men.

"These patterns suggest that there might be different pathways through which the disease develops in men and women," says Dr. Jill Siegfried, a professor in the pharmacology department and head of the NCI-funded Lung SPORE at the University of Pittsburgh Cancer Institute. To identify the point of divergence, Dr. Siegfried and her SPORE team are looking at one of the most basic factors in female physiology: the estrogen receptor.

Estrogen receptors, which stimulate cell growth and division in the presence of the hormone estrogen, are most commonly found in female reproductive organs such as the ovaries and the breasts. But these receptors are found in other tissues, too, including the hypothalamus in the brain, the esophagus, the colon, the nervous system, and the lungs. The receptor comes in two forms (alpha and beta) and they differ not only in function, but also in tissue prevalence. In lung tissue, beta receptors are the most common and may play a role in the development of alveoli, the clusters of tiny sacs in the lung where gasses are exchanged between blood and inhaled air.

Research indicates that estrogen doesn't necessarily initiate malignancy in lung tissue, but rather may fuel subsequent tumor growth by heightening cell proliferation and hindering apoptosis. In vitro studies showed that exposure to the hormone increased tumor size, while exposure in the presence of estrogen receptor blockers did not. There's also evidence that estrogen receptors can interact with oncogenes and other growth factor pathways, such as that of the epidermal growth factor receptor (EGFR), which are linked to cancer. But Dr. Siegfried warns that this is still very new territory in lung cancer research. "If you think about breast cancer, researchers have been studying estrogen receptors for 40 years," she says. "We've only just opened this window."

While it isn't clear just how estrogen receptors are linked to lung cancer, the Pittsburgh Lung SPORE has found that estrogen-blocking drugs hold promise for slowing the disease. In vitro studies testing fulvestrant (Faslodex), an estrogen receptor blocker, with gefitinib (Iressa), the EGFR blocker, showed that the combination decreased NSCLC proliferation by up to 90 percent while increasing apoptosis twofold. Now the Lung SPORE is testing these two drugs in a phase I clinical trial. "So far, we've had no adverse effects," says Dr. Siegfried, "and we have seen some clinical responses, some lasting for quite a while." The next step is to plan a phase II trial comparing another EGFR blocker, erlotinib (Tarceva), alone and in combination with fulvestrant. "We're hoping to show that there will be at least a 50 percent increase, if not a doubling, in the response rate" to erlotinib with the addition of the estrogen receptor blocker, Dr. Siegfried says.

As more is learned about the etiology of lung cancer and the role of estrogen receptors, it is likely that researchers will find new ways to manipulate and block the various destructive pathways that underscore this disease. "That's the promise of the future," says Dr. Siegfried. And while her research on estrogen receptors is currently limited to women, because of studies showing that lung tumors can synthesize estrogen directly, drugs that work against lung cancer by blocking estrogen receptors may also hold promise for men with the disease.

By Brittany Moya del Pino