Lung cancer in women: role of estrogens

Abstract

The incidence of lung cancer in females is increasing, in contrast to that seen in males. In addition, the proportion of lung cancer cases in women attributable to smoking is approximately half of that seen in males. Female sex hormones, especially estrogen, may play a key role in this. Estrogen receptors ERalpha and ERbeta have been detected on lung cancer cells and there is new evidence suggesting that hormone-replacement therapy may increase both the incidence of, and mortality from, lung cancer in women. Laboratory evidence lends credence to the carcinogenic effects of estrogens in lung cancer. This article summarizes the current evidence on their role in lung cancer.

Figure 1. Estrogen receptor-mediated signaling in lung cancer

Lung cancer cells predominantly express ERβ. The full-length ERα, the primary functional receptor in breast cancer cells, is not expressed in most lung cancer cells and tissues. Instead, they express a variant of ERα that lacks the exon 4 at the amino terminus (which contains the nuclear localization signal. As a result, ERα is expressed in the cytoplasm of non-small-cell lung cancer (NSCLC) cells and tissues, while ERβ predominantly localizes to the cytoplasm and is believed to mediate the transcriptional effects of estrogen in NSCLC. Estrogen (17-β estradiol or E2β) present in the extracellular space diffuses through the cell membrane and binds to cytosolic ERs, α or β. The ERs in the cytoplasm are normally kept inactive by binding of a complex containing HSP90. Binding with estrogen causes the inhibitory complex to dissociate, thereby activating the receptor. The ligand-bound receptor then either dimerizes and is imported into the nucleus (classical pathway [I] mediated by ERβ) or translocates to the cell membrane where it associates with receptor tyrosine kinases like the EGFR (alternate pathway [II] mediated by either ERα and/or ERβ). The ER proteins have been shown to colocalize in caveolae, which are plasma membrane-associated lipid rafts that provide the appropriate environment for interaction with cell surface receptors like EGFR. This interaction with EGFR forms the basis of employing EGFR tyrosine kinase inhibitors in combination with anti-estrogens (e.g., fulvestrant, a competitive antagonist of estrogen binding to the ER) for the treatment of lung cancer. In the case of ERα, palmitoylation of a cysteine residue (Cys477) is crucial for its localization to the plasma membrane. The activation of EGFR by ERα or β (bound to the ligand E2β) leads to phosphorylation of the adaptor protein Shc, which in turn associates with the GRB2–SOS complex, activating the Ras/Raf/MAPK pathway. The activated ERK (p44/p42 MAPK) then migrates to the nucleus where it activates the transcription of genes that promote proliferation and invasion of NSCLC cells. In addition, the ligand-bound ERβ receptor, upon translocating to the nucleus, binds directly to gene promoters containing the ERE where it recruits the p160 coactivator GRIP1/TIF2 and thus activates genes that promote cell cycle progression (Id-2 and cyclin D1) and therefore induces proliferation of NSCLC cells. EGFR: EGF receptor; ER: Estrogen receptor; ERE: Estrogen response element; ERK: Extracellular signal-regulated kinase; GRB: Growth factor receptor-bound protein; GRIP: Glutamate receptor interacting protein; HSP: Heat-shock protein; SOS: Son of sevenless.