Prostate cancer in African American men is associated with downregulation of zinc transporters.

In the United States, prostate cancer is the most commonly diagnosed male cancer and the second leading cause of all male cancer deaths. Furthermore, incidence rates are higher in African Americans than in any other racial group. Our laboratory is attempting to decipher the environmental and molecular mechanisms involved in the development of prostate cancer in African Americans. Because Africa is a mineral-rich continent, and the zinc levels in the water and diet are high, it is hypothesized that Africans may have genetically downregulated their zinc absorption capacity; otherwise, they would absorb abnormally high levels of zinc, resulting in various serious neurodegenerative and biochemical disorders. It is therefore possible that people of African origin may have a lower capacity to absorb zinc when compared with other racial groups because of their inherent downregulation of zinc transporters. Extensive research has shown that low serum levels of zinc are associated with the increased incidence of prostate cancer. We have evaluated 58 prostate cancer tissues in 2 major racial groups (30 from whites and 28 from African Americans) for their ability to express 2 major human zinc transporters, hZIP1 and hZIP2. In all 30 prostate cancer specimens obtained from white people, the degree of expression of these 2 zinc receptors was high when compared with age-matched and Gleason score-matched specimens obtained from African American patients. We also found a significant downregulation of these 2 zinc transporters in normal prostate tissues from African American men when compared with age-matched white men. The loss of the unique ability to retain normal intracellular levels of zinc may be an important factor in the development and progression of prostate cancer. Our observation that the uptake of zinc may be different in racial groups is intriguing and relevant. Once these data are confirmed in larger groups, this finding could have significant application as a preventive maneuver for at least for some people. Because dietary zinc supplements are relatively nontoxic, any efficacy trial would be low-risk.

BRAF and RAS mutations in human lung cancer and melanoma.

BRAF encodes a RAS-regulated kinase that mediates cell growth and malignant transformation kinase pathway activation. Recently, we have identified activating BRAF mutations in 66% of melanomas and a smaller percentage of many other human cancers. To determine whether BRAF mutations account for the MAP kinase pathway activation common in non-small cell lung carcinomas (NSCLCs) and to extend the initial findings in melanoma, we screened DNA from 179 NSCLCs and 35 melanomas for BRAF mutations (exons 11 and 15). We identified BRAF mutations in 5 NSCLCs (3%; one V599 and four non-V599) and 22 melanomas (63%; 21 V599 and 1 non-V599). Three BRAF mutations identified in this study are novel, altering residues important in AKT-mediated BRAF phosphorylation and suggesting that disruption of AKT-induced BRAF inhibition can play a role in malignant transformation. To our knowledge, this is the first report of mutations documenting this interaction in human cancers. Although >90% of BRAF mutations in melanoma involve codon 599 (57 of 60), 8 of 9 BRAF mutations reported to date in NSCLC are non-V599 (89%; P < 10(-7)), strongly suggesting that BRAF mutations in NSCLC are qualitatively different from those in melanoma; thus, there may be therapeutic differences between lung cancer and melanoma in response to RAF inhibitors. Although uncommon, BRAF mutations in human lung cancers may identify a subset of tumors sensitive to targeted therapy.