LAUSR

Malignant pleural mesothelioma (MPM) is an asbestos-associated aggressive cancer that arises from the mesothelial lining of the pleura. Although the use of asbestos has been banned in many countries, the potentially hazardous exposure to asbestos is still present with locally high incidences of mesothelioma [1]. Chemotherapy for MPM has remained unchanged since 2003 [2], when the combination of cisplatin and pemetrexed became the standard firstline therapy for patients who are not suitable for aggressive surgery, or in whom chemotherapy is recommended as part of a multimodality regimen. Unfortunately, the disease recurs in over 80% of the patients at the 2-year followup mark. In the second-line setting, a variety of cytotoxic agents have been tested, either as single or combined treatment [3], but none of these have been adopted as standard therapy. Advances in the understanding of MPM biology bring, however, hope that novel agents will be identified that improve patient outcomes. The observation that women diagnosed with MPM respond better to treatments and live longer than men, prompted us to assess the role of estrogens and their receptors in this cancer. Estrogens play important roles in several physiological and pathological processes. The existence of an estrogen receptor (ER) was demonstrated in 1958 [4] and the corresponding gene was cloned in 1985. It was considered the only receptor responsible for mediating estrogen action until the gene coding for a second ER subtype, ERβ, was cloned in 1996 [5]. This second receptor is expressed in many human tissues, including some that traditionally are considered non target for estrogens. One of the more interesting observations about ERβ is that it exerts antiproliferative effects in different preclinical in vitro and in vivo models of human cancers [6–8]. We analyzed the expression of the two ER subtypes, α and β, in tumor biopsies from MPM patients and in normal pleura from healthy controls [9]. Nuclear ERβ immunoreactivity was detected in normal pleura and in the majority of the 78 analyzed MPM samples, although with reduced presence and intensity, compared with normal pleura. The cumulative probability of survival after 2 years of follow-up was 80% for subjects with high ERβ expression versus 31% for subjects with negative of low ERβ expression (p = 0.02, log-rank test). Importantly, multivariate analysis of overall survival demonstrated the prognostic significance of ERβ staining. Different from other lung cancers, none of 78 MPM biopsies or normal pleura stained positive for ERα. MPM cells represent, therefore, a powerful model to study the ERβ role and function.