BRCA1 is an essential mediator of vinorelbine-induced apoptosis in mesothelioma

Our plain-English summary of BRCA1 is an essential mediator of vinorelbine-induced apoptosis in mesothelioma, by S. Busacca, M. Sheaff, K. Arthur, et al (The Journal of Pathology, 2012).

The study

• Authors: S. Busacca, M. Sheaff, K. Arthur, S.G. Gray, K.J. O'Byrne, D.J. Richard, A. Soltermann, I. Opitz, H. Pass, D.P. Harkin, J.E. Quinn, D.A. Fennell
• Journal: The Journal of Pathology
• Published: 2012;227(2):200-8
• Cited by: 27 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Therapeutic options for malignant pleural mesothelioma (MPM) are limited despite the increasing incidence globally. The vinca alkaloid vinorelbine exhibits clinical activity; however, to date, treatment optimization has not been achieved using biomarkers. BRCA1 regulates sensitivity to microtubule poisons; however, its role in regulating vinorelbine-induced apoptosis in mesothelioma is unknown. Here we demonstrate that BRCA1 plays an essential role in mediating vinorelbine-induced apoptosis, as evidenced by (1) the strong correlation between vinorelbine sensitivity and BRCA1 expression level; (2) induction of resistance to vinorelbine by BRCA1 using siRNA oligonucleotides; (3) dramatic down-regulation of BRCA1 following selection for vinorelbine resistance; and (4) the re-activation of vinorelbine-induced apoptosis following re-expression of BRCA1 in resistant cells. To determine whether loss of BRCA1 expression in mesothelioma was potentially relevant in vivo, BRCA1 immunohistochemistry was subsequently performed on 144 primary mesothelioma specimens. Loss of BRCA1 protein expression was identified in 38.9% of samples. Together, these data suggest that BRCA1 plays a critical role in mediating apoptosis by vinorelbine in mesothelioma, warranting its clinical evaluation as a predictive biomarker.

Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

In plain English

This was a laboratory study of malignant pleural mesothelioma, a cancer of the pleura (the lining around the lungs). It did not study asbestos exposure. The authors asked whether the protein BRCA1 affects how mesothelioma cells respond to the drug vinorelbine. Across six mesothelioma cell lines, lower BRCA1 levels went with greater resistance to the drug (Pearson r = −0.7379). When BRCA1 was reduced by RNA interference in three cell lines, the drug killed fewer cells. In control cells, the share of dying cells rose 2.77-, 3.53- and 6.25-fold. With BRCA1 reduced, the rises were 1.45-, 1.86- and 2.88-fold. Cells grown to resist vinorelbine lost BRCA1, and putting BRCA1 back restored much, though not all, of the drug's effect. Of 144 archived tumour samples, 56 (38.9%) were classified BRCA1-negative: absent or very low BRCA1, with fewer than 10% of cells showing nuclear staining. Differences between tumour subtypes were not statistically significant. The authors lacked enough suitable samples to test whether BRCA1 predicts patients' response to vinorelbine. The authors concluded that BRCA1-negative tumours may be expected to resist vinorelbine, a question for a prospective clinical study.

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: Laboratory (in vitro) study of human mesothelioma cell lines, plus a retrospective immunohistochemistry analysis of archived tumour samples
• Who was studied: Six human mesothelioma cell lines (REN, E58, MSTO-211H, H2461, H2591, MM98) and 144 surgically resected primary mesothelioma tumour specimens on three tissue microarrays plus whole sections. The article does not state where or when the patients were treated.
• Exposure: No asbestos exposure was studied. Cells were treated with the chemotherapy drug vinorelbine at 5 nM to 500 nM for 48 h. BRCA1 expression was reduced with siRNA (RNA interference) or re-expressed with a BRCA1 construct.
• Main results:
  • Across the six cell lines, BRCA1 protein level correlated with vinorelbine response (Pearson r = −0.7379). H2461 and MM98 had the lowest BRCA1 and the greatest resistance.
  • In REN, E58 and MSTO-211H cells, the vinorelbine-induced rise in the dying (subG1) cell population was 2.77-, 3.53- and 6.25-fold with control siRNA. With BRCA1 silenced (siBRCA1#1), it was 1.45, 1.86 and 2.88.
  • Caspase 3 activity (a marker of cell death) after vinorelbine in REN, E58 and MSTO-211H with BRCA1 silenced (siBRCA1#1) was 0.71, 0.97 and 2.4
  • Cell lines selected for vinorelbine resistance (RVR from REN, MVR from MSTO-211H) lost BRCA1 expression. Their caspase 3 rise after vinorelbine was 1.029-fold (RVR) and 1.176-fold (MVR), compared with 1.62-fold (REN) and 4.96-fold (MSTO-211H) in the parental lines.
  • Re-expressing BRCA1 in the resistant lines raised the dying cell population compared with control vector: 1.53 versus 3.17 in RVR cells, and 1.77 versus 3.02 in MVR cells
  • BRCA1 was classified as immunonegative in 38.9% of the 144 tumour samples (56 of 144 in Table 1). Immunonegative meant absent or very low expression, with fewer than 10% of cells showing nuclear staining.
  • BRCA1 negativity was 30.77% in epithelioid (16 of 52), 45.50% in sarcomatoid (5 of 11) and 43.20% in biphasic (35 of 81) tumours. The differences were not statistically significant.
• The authors' conclusion: The authors concluded that BRCA1 mediates vinorelbine-induced cell death in mesothelioma, and that BRCA1-immunonegative tumours may be expected to resist vinorelbine. They said this should be tested in a prospective clinical study and that BRCA1 warrants clinical evaluation as a predictive biomarker.
• Limitations the authors state:
  • The authors could not test whether BRCA1 in patients' tumours correlated with clinical response to vinorelbine, because they had too few suitable samples and limited statistical power
  • Re-expressing BRCA1 did not fully restore sensitivity to the level of the parental cells. The authors noted that other resistance mechanisms may be involved.
  • The authors stated that their data do not support a causal link between BRCA1 expression and vinorelbine treatment (the article does not explain this further)

Topics

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

Medical terms in this study, explained in our Lexicon: Vinorelbine, Apoptosis, Mesothelioma, Pleural Mesothelioma, Biomarker, Immunohistochemistry.

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