Estrogen receptor signaling in lung cancer

Abstract

Lung cancer has long been thought of as a cancer that mainly affects men, but over the past several decades, because of the high increase in tobacco use by women, there has been a corresponding dramatic increase in lung cancer among women. Since 1998, lung cancer deaths in women have surpassed those caused by breast cancer in the United States. Annual lung cancer deaths among US women currently surpass those caused by breast, ovarian, and cervical cancers combined. Women are more likely than men to be diagnosed with adenocarcinoma and small cell carcinoma of the lung compared to squamous cell carcinoma, and never-smokers diagnosed with lung cancer are almost three times more likely to be female than male. These observations in the population, coupled to the findings that both estrogen receptors (ERs) and aromatase, the enzyme that synthesizes 17beta-estradiol, are expressed by lung tumors, suggest a role for female steroid hormones in control of lung cancer growth. Preclinical data and clinical data are increasingly emerging to support this concept, and to suggest that a local production of estrogen and expression of ERs occurs in lung tumors that arise in men as well as in women. An additional protein that recognizes 17beta-estradiol with high affinity, GPR30, also is expressed in lung tumors at high levels and may be responsible for some of the proliferation signals induced by estrogen.

Figure 1

Available strategies to target the estrogen signaling pathway for lung cancer include 1) inhibition of the final step in the synthesis of estrogen, by inhibiting the enzyme aromatase with the inhibitor anastrozole; 2) down-regulation of classical ERs using the pure antiestrogen fulvestrant; 3) inhibition of GPR30-dependent signaling through the newly identified GPR30 antagonist, G15; 4) targeting the growth factor pathways that are activated by estrogens, mainly the EGF and VEGF pathways using the drugs gefitinib, erlotinib or vandetanib. These strategies can be used alone or in combination.