Estrogen receptor-beta affects the prognosis of human malignant mesothelioma

Our plain-English summary of Estrogen receptor-beta affects the prognosis of human malignant mesothelioma, by G. Pinton, E. Brunelli, B. Murer, et al (Cancer Research, 2009).

The study

• Authors: G. Pinton, E. Brunelli, B. Murer, R. Puntoni, M. Puntoni, D.A. Fennell, G. Gaudino, L. Mutti, L. Moro
• Journal: Cancer Research
• Published: 2009;69(11):4598-604
• Cited by: 76 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant pleural mesothelioma is an asbestos-related neoplasm with poor prognosis, refractory to current therapies, the incidence of which is expected to increase in the next decades. Female gender was identified as a positive prognostic factor among other clinical and biological prognostic markers for malignant mesothelioma, yet a role of estrogen receptors (ERs) has not been studied. Our goal was to investigate ERs expression in malignant mesothelioma and to assess whether their expression correlates with prognosis. Immunohistochemical analysis revealed intense nuclear ERbeta staining in normal pleura that was reduced in tumor tissues. Conversely, neither tumors nor normal pleura stained positive for ERalpha. Multivariate analysis of 78 malignant mesothelioma patients with pathologic stage, histologic type, therapy, sex, and age at diagnosis indicated that ERbeta expression is an independent prognostic factor of better survival. Moreover, studies in vitro confirmed that treatment with 17beta-estradiol led to an ERbeta-mediated inhibition of malignant mesothelioma cell proliferation as well as p21(CIP1) and p27(KIP1) up-regulation. Consistently cell growth was suppressed by ERbeta overexpression, causing a G(2)-M-phase cell cycle arrest, paralleled by cyclin B1 and survivin down-regulation. Our data support the notion that ERbeta acting as a tumor suppressor is of high potential relevance to prediction of disease progression and to therapeutic response of malignant mesothelioma patients.

In plain English

This Italian study asked whether estrogen receptor-beta (ER-beta), a hormone receptor measured in tumor tissue, was linked to survival in malignant mesothelioma. The authors stained archived tissue from 78 mesothelioma patients and 21 controls from a hospital in Mestre-Venice. ER-beta staining appeared in all normal pleura samples and, less intensely and extensively, in 59 of 78 tumors. Twelve tumors had high levels comparable to normal tissue. No tumor or normal pleura sample stained positive for estrogen receptor-alpha. Over a median follow-up of 1.2 years, 56 patients (72%) died. After adjustment for age, chemotherapy, sex, tumor type and stage, patients with high ER-beta had a lower risk of death than those with negative or low levels (hazard ratio 0.18, 95% CI 0.05 to 0.61). Women compared with men had a hazard ratio of 0.49 (95% CI 0.24 to 1.01). In cell lines, adding ER-beta slowed mesothelioma cell growth, and estradiol slowed growth through ER-beta. The article did not report assessing patients' asbestos exposure. The authors concluded that ER-beta status could be considered a prognostic marker. They noted that few women were included.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Analysis of archival tumor tissue from a patient series, with survival analysis (Kaplan-Meier and multivariate Cox model), plus laboratory (in vitro) cell-line experiments
• Who was studied: 78 malignant mesothelioma cases (59 men, 19 women; median age 63; 57 epithelioid, 14 biphasic, 7 sarcomatoid) and 21 controls, selected from the archival pathology files of the Regional Hospital of Mestre-Venice, Italy. Dates of diagnosis were not given. The laboratory work used immortalized human mesothelial cells and six mesothelioma cell lines.
• Exposure: The article did not report assessing patients' asbestos exposure. The factor examined was expression of estrogen receptor-beta and estrogen receptor-alpha in tumor and normal pleura. The laboratory work used 10 nmol/L estradiol and also increased or silenced the receptors in cells.
• Main results:
  • ER-beta nuclear staining was seen in all normal pleural specimens, and at lower intensity and extent in 59 of 78 (76%) tumor samples
  • 12 tumors had more than 75% stained cells with high intensity, comparable with normal tissue (classed as high ER-beta expression; the other 66 were negative or low)
  • No tumor or normal pleura sample stained positive for estrogen receptor-alpha
  • After a median follow-up of 1.2 years, 56 of the 78 patients (72%) had died
  • Median survival was 2.1 years for women versus 1.1 years for men (P = 0.01)
  • Two-year survival was 80% (95% CI 41-95%) in patients with high ER-beta versus 31% (95% CI 20-43%) in those with negative or low ER-beta (P = 0.02)
  • In the multivariate model (including sex, histologic type, stage and ER-beta, adjusted for age at diagnosis and chemotherapy), high ER-beta expression had HR 0.18 (95% CI 0.05-0.61, P = 0.006) and female sex had HR 0.49 (95% CI 0.24-1.01, P = 0.05). The text reports these as HR 0.2 and HR 0.5.
  • Compared with epithelioid tumors, sarcomatoid tumors (HR 6.8; 95% CI 2.6-17.4) and biphasic tumors (HR 5.1; 95% CI 2.5-10.8) were associated with increased risk of death
  • In a separate analysis of the 57 epithelial tumors only, the result for high ER-beta was similar (HR 0.1; 95% CI 0.01-0.9)
  • In REN mesothelioma cells, estradiol inhibited proliferation through ER-beta; the effect was reversed when the receptor was silenced
  • Overexpressing ER-beta reduced REN cell growth by more than 50% and caused cell cycle arrest at the G2-M phase; overexpressing estrogen receptor-alpha did not affect growth
• The authors' conclusion: The authors concluded that their findings point to a suppressive role of ER-beta in mesothelioma. They wrote that ER-beta status could be considered a prognostic marker, with potential implications for treatment.
• Limitations the authors state:
  • The number of women in the sample was small. The authors raised this when noting they did not find sex differences in receptor expression.
  • ER-beta gene variants, other estrogen receptor forms, and hormone levels were not examined and need further investigation
  • The authors could not tell which of two possible ways of acting (genomic or nongenomic) ER-beta used in the cell experiments
  • The precise mechanism by which estradiol slowed the cell cycle in mesothelioma cells was not determined

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Prognosis, Malignant Mesothelioma, Pleural Mesothelioma, Neoplasm, Pleura, Multivariate Analysis, Disease Progression.

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