Location, location, location: the BRMS1 protein and melanoma progression

Abstract

The metastasis suppressor, BRMS1, has been demonstrated to cause dramatic regression of metastatic lesions without blocking orthotopic tumor growth. The role of BRMS1 is well-documented for several non-melanoma malignancies, such as breast cancer, ovarian cancer and non-small-cell lung cancer. However, its role in melanoma is just beginning to be understood, with a recent article by Slipicevic et al. highlighting the levels of expression of BRMS1 in benign nevi, primary and metastatic melanoma samples. Their findings emphasize that the intracellular location of BRMS1 protein (cytoplasmic or nuclear), appears to have a significant impact upon the metastatic capacity of melanoma cells. Interestingly, this selective localization translates into a statistically significant decrease in the relapse-free period in melanoma patients, further associated with a thicker Breslow's depth of primary melanomas. However, and more importantly, this study begins to define a clearer role for BRMS1 in melanoma that is strictly dependent upon its cellular location, with nuclear expression associated with invasive and metastatic capacity and cytoplasmic expression resulting in repressive effects upon progression and metastasis.

Figure 1

Location(s) of BRMS1 and corresponding activities. BRMS1 is a transcription co-repressor and can shuttle between nucleus and cytoplasm. BRMS1 levels are governed by ubiquitin-mediated degradation. In the nucleus, it shows inhibition of some transcripts and up-regulation others. However, some of these regulations may be due to its cytoplasmic activities (such as deacetylation of NFκB members). The ultimate impact of BRMS1 on a specific tumor cell appears to be tumor type and context-dependent. Abbreviations: BRMS1, breast cancer metastasis suppressor-1; FABP7, fatty acid binding protein-7; ING-4, inhibitor of growth family, member-4; Cul3, Cullin-3; SPOP, speckle-type POZ domain protein; mSin3, mammalian Sin3; HDAC, histone deacetylase; Cx32, 43, connexin-32, -43; uPA, urokinase-type plasminogen activator; OPN, osteopontin; miR, micro ribonucleic acid; Nexin6, sorting nexin-6.