Functional analysis of two single nucleotide polymorphisms inSLC30A2(ZnT2): implications for mammary gland function and breast disease in women

Abstract

Zinc transporter 2 (ZnT2) plays a major role in zinc (Zn) export from the mammary gland. Recently, we determined that ZnT2 is associated with secretory vesicles reflecting its role in Zn secretion during lactation. Herein, we identified two distinct single nucleotide polymorphisms (SNPs) in SLC30A2, which encodes ZnT2. SNP1 (rs35235055) results in a leucine-to-proline substitution (Leu23Pro), while SNP2 (rs35623192) results in an arginine-to-cysteine substitution (Arg340Cys). We examined the localization and function of each SNP in cells generated to express these polymorphic variants. SNP1 was mislocalized to lysosomes, while SNP2 was mislocalized to the Golgi apparatus. FluoZin-3 fluorescence illustrated increased lysosomal accumulation of Zn in cells expressing SNP1 concomitant with the abrogation of Zn secretion. In contrast, ectopic expression of SNP2 was associated with the expansion of cytoplasmic Zn pools, elevated reactive oxygen species, and increased Zn efflux. Taken together, our data indicate that polymorphic variants in ZnT2 distinctly alter mammary cell Zn metabolism. We speculate that these SNPs may compromise mammary cell function, which may have important implications in human health and breast disease.