What Does Estrogen Have to do With Lung Cancer?

by: Maryann Donovan, MPH, PhD, Scientific Director, CEO-UPCI; Associate Director Research Services, UPCI; Assistant Professor, Department of Pathology, University of Pittsburgh

Lung cancer, the leading cause of cancer-related death in women, is responsible for more than 73,000 deaths each year. For many years, there has been the growing awareness that women may be more susceptible to smoking-related cancers and also may suffer from more aggressive disease. Dr. Jill Siegfried and her colleagues at the University of Pittsburgh Cancer Institute are asking whether the higher levels of estrogen found in women can partially explain why women may be more vulnerable to lung cancer than men. These researchers are also hoping to use estrogen and estrogen receptors as targets to guide the development of more effective treatments for the disease.^{1, 2}

Many of the compounds found in tobacco smoke are known human carcinogens, such as benzene, formaldehyde, and radiation. In addition to the recognized association between smoking and lung cancer, the State of California has declared that both active and passive exposures to tobacco smoke cause breast cancer.

Estrogen, which has long been implicated in breast cancer development, is now being shown to be involved in lung cancer. Estrogen is a hormone that binds to a receptor in certain cells and this bound complex can turn on genes involved in cell growth. Prolonged exposure to natural and synthetic estrogens (hormone replacement therapy, HRT) and to synthetic estrogens or chemicals that act like estrogen (such as the widely used plasticizer bisphenol A, the heavy metal cadmium, and the banned pesticide DDT) have been implicated in the development of endometrial cancer and breast cancer. Dr. Siegfried, in collaboration with Dr. Pamela Hershberger and Dr. Mark Nichols and colleagues, has shown that estrogen binding to estrogen receptors can speed up the growth of human non-small cell lung cancer cells. Based on this work, studies are underway to use drugs that block these receptors as a way to reduce the growth of lung cancer cells.³

Taking advantage of the fact that lung cancer in women involves the estrogen receptor and other hormonally regulated genes, Dr. Siegfried and her colleagues are actively devising better treatment strategies that may reduce the toll of lung cancer in women. Specifi cally, her group has shown that the combination of two drugs-fulvestrant (Faslodex), which is an estrogen receptor antagonist, and gefi tinib (Iressa), which is a selective epidermal growth factor receptor inhibitor-can markedly reduce the growth of non-small cell lung cancer both in experimental cell cultures and in whole animals. The combined treatment is more effective than the result with either single agent alone.⁴ Based on these results, Dr. Siegfried and her colleagues are starting a clinical trial in women with non-small cell lung cancer to determine whether the toll of this disease can be reduced by combining these two agents, and whether response is related to the extent of expression of estrogen receptors.

Sources

1. Stabile LP, Siegfried JM. Estrogen receptor pathways in lung cancer. Curr Oncol Rep. 2004; 6: 259-267.
2. Stabile LP, Siegfried JM. Sex and gender differences in lung cancer. J Gend Specif Med. 2003; 6: 37-48.
3. Hershberger PA, Vasquez AC, Kanterewicz B, Land S, Siegfried JM, Nichols M. Regulation of endogenous gene expression in human non-small cell lung cancer cells by estrogen receptor ligands. Cancer Res. 2005; 65: 1598-1605.
4. Stabile LP, Lyker JS, Gubish CT, Zhang W, Grandis JR, Siegfried JM. Combined targeting of the estrogen receptor and the epidermal growth factor receptor in non-small cell lung cancer shows enhanced antiproliferative effects. Cancer Res. 2005; 65: 1459-1470.

Published September 14, 2006.