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BMC Cancer. 2012; 12: 73.
Published online Feb 22, 2012. doi:  10.1186/1471-2407-12-73
PMCID: PMC3341185
Cytoplasmic BRMS1 expression in malignant melanoma is associated with increased disease-free survival
Ana Slipicevic,1 Ruth Holm,1 Elisabeth Emilsen,1 Anne Katrine Ree Rosnes,1 Danny R Welch,2 Gunhild M Mælandsmo,3,4 and Vivi Ann Flørenescorresponding author1
1Department of Pathology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
2Department of Cancer Biology, The Kansas University Medical Center, Kansas City, USA
3Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital The Norwegian Radium Hospital, Oslo, Norway
4Department of Pharmacy, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway
corresponding authorCorresponding author.
Ana Slipicevic: Ana.Slipicevic/at/rr-research.no; Ruth Holm: Ruth.Holm/at/oslo-universitetssykehus.no; Elisabeth Emilsen: Elisabeth.Emilsen/at/oslo-universitetssykehus.no; Anne Katrine Ree Rosnes: Anne.Katrine.Rosnes/at/rr-research.no; Danny R Welch: DWelch/at/KUMC.edu; Gunhild M Mælandsmo: Gunhild.Mari.Malandsmo/at/rr-research.no; Vivi Ann Flørenes: Vivi.Ann.Florenes/at/radiumhospitalet.no
Received October 24, 2011; Accepted February 22, 2012.
Abstract
Background/aims
Breast cancer metastasis suppressor 1 (BRMS1) blocks metastasis in melanoma xenografts; however, its usefulness as a biomarker in human melanomas has not been widely studied. The goal was to measure BRMS1 expression in benign nevi, primary and metastatic melanomas and evaluate its impact on disease progression and prognosis.
Methods
Paraffin-embedded tissue from 155 primary melanomas, 69 metastases and 15 nevi was examined for BRMS1 expression using immunohistochemistry. siRNA mediated BRMS1 down-regulation was used to study impact on invasion and migration in melanoma cell lines.
Results
A significantly higher percentage of nevi (87%), compared to primary melanomas (20%) and metastases (48%), expressed BRMS1 in the nucelus (p < 0.0001). Strong nuclear staining intensity was observed in 67% of nevi, and in 9% and 24% of the primary and metastatic melanomas, respectively (p < 0.0001). Comparable cytoplasmic expression was observed (nevi; 87%, primaries; 86%, metastases; 72%). However, a decline in cytoplasmic staining intensity was observed in metastases compared to nevi and primary tumors (26%, 47%, and 58%, respectively, p < 0.0001). Score index (percentage immunopositive celles multiplied with staining intensity) revealed that high cytoplasmic score index (≥ 4) was associated with thinner tumors (p = 0.04), lack of ulceration (p = 0.02) and increased disease-free survival (p = 0.036). When intensity and percentage BRMS1 positive cells were analyzed separately, intensity remained associated with tumor thickness (p = 0.024) and ulceration (p = 0.004) but was inversely associated with expression of proliferation markers (cyclin D3 (p = 0.008), cyclin A (p = 0.007), and p21Waf1/Cip1 (p = 0.009)). Cytoplasmic score index was inversely associated with nuclear p-Akt (p = 0.013) and positively associated with cytoplasmic p-ERK1/2 expression (p = 0.033). Nuclear BRMS1 expression in ≥ 10% of primary melanoma cells was associated with thicker tumors (p = 0.016) and decreased relapse-free period (p = 0.043). Nuclear BRMS1 was associated with expression of fatty acid binding protein 7 (FABP7; p = 0.011), a marker of invasion in melanomas. In line with this, repression of BRMS1 expression reduced the ability of melanoma cells to migrate and invade in vitro.
Conclusion
Our data suggest that BRMS1 is localized in cytoplasm and nucleus of melanocytic cells and that cellular localization determines its in vivo effect. We hypothesize that cytoplasmic BRMS1 restricts melanoma progression while nuclear BRMS1 possibly promotes melanoma cell invasion.
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