Targeting aromatase and estrogen signaling in human non-small cell lung cancer

Ann N Y Acad Sci. 2009 Feb;1155:194-205. doi: 10.1111/j.1749-6632.2009.04116.x.

Abstract

Lung cancer has become increasingly common in women, and gender differences in the physiology and pathogenesis of the disease have suggested a role for estrogens. In the lung recent data have shown local production of estrogens from androgens via the action of aromatase enzyme and higher levels of estrogen in tumor tissue as compared with surrounding normal lung tissue. High levels of aromatase expression are also maintained in metastases as compared with primary tumors. Consistent with these findings, clinical studies suggest that aromatase expression may be a useful predictive biomarker for prognosis in the management of non-small cell lung cancer (NSCLC), the most common form of lung malignancy. Low levels of aromatase associate with a higher probability of long-term survival in older women with early stage NSCLC. Treatment of lung NSCLC xenografts in vivo with an aromatase inhibitor (exemestane) alone or combined with standard cisplatin chemotherapy elicits a significant reduction in tumor progression as compared to paired controls. Further, lung cancer progression is also governed by complex interactions between estrogen and growth factor signaling pathways to stimulate the growth of NSCLC as well as tumor-associated angiogenesis. We find that combination therapy with the multitargeted growth factor receptor inhibitor vandetanib and the estrogen receptor antagonist fulvestrant inhibit tumor growth more effectively than either treatment administered alone. Thus, incorporation of antiestrogen treatment strategies in standard antitumor therapies for NSCLC may contribute to improved patient outcome, an approach that deserves to be tested in clinical trials.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use
  • Aromatase / metabolism*
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Division / physiology
  • Cell Line, Tumor
  • Disease Progression
  • Epidermal Growth Factor / physiology
  • Estrogen Receptor Modulators / therapeutic use
  • Estrogens / metabolism*
  • Estrogens / physiology
  • Humans
  • Immunohistochemistry
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Nude
  • Neoplasm Metastasis
  • Signal Transduction*
  • Transplantation, Heterologous

Substances

  • Antineoplastic Agents
  • Estrogen Receptor Modulators
  • Estrogens
  • Epidermal Growth Factor
  • Aromatase