Mammary gland zinc metabolism: regulation and dysregulation

Abstract

Zinc (Zn) is required for numerous metabolic processes serving both a structural and catalytic role. The mammary gland has a unique Zn requirement resulting from the need to also transfer an extraordinary amount of Zn into milk (~0.5-1 mg Zn/day) during lactation. Impairments in this process can result in severe Zn deficiency in the nursing offspring which has adverse consequences with respect to growth and development. Moreover, dysregulated mammary gland Zn metabolism has recently been implicated in breast cancer transition, progression and metastasis, thus there is a critical need to understand the molecular mechanisms which underlie these observations. Tight regulation of Zn transporting mechanisms is critical to providing an extraordinary amount of Zn for secretion into milk as well as maintaining optimal cellular function. Expression of numerous Zn transporters has been detected in mammary gland or cultured breast cells; however, understanding the molecular mechanisms which regulate mammary Zn metabolism as well as the etiology and downstream consequences resulting from their dysregulation is largely not understood. In this review, we will summarize the current understanding of the regulation of mammary gland Zn metabolism and its regulation by reproductive hormones, with a discussion of the dysregulation of this process in breast cancer.

Zinc and metalloproteinases 2 and 9: What is their relation with breast cancer?

“…Taylor et al 37 and Kelleher et al 38 highlight the implications of deregulation of zinc homeostasis in the pathogenesis of breast cancer. According to these authors, an increase in the expression of transporters of this mineral occurs in cells with malignant tumors, including metallothionein, Zip5, Zip6, Zip7, Zip8, and Zip10, producing an influx of zinc into the neoplastic cells, suggesting that its accumulation inside the breast tumor induces processes dependent on this mineral, for example, the activation of MMPs.…”

Zinc efflux through lysosomal exocytosis prevents zinc-induced toxicity

“…This organellar Zn 2+ export lowers potentially toxic cytoplasmic Zn 2+ concentrations in pathophysiological conditions such as neurodegeneration (Kanninen et al, 2013) and breast cancer . Moreover, it provides Zn 2+ to organellar processes that require it, such as the maturation of enzymes like the lysosomal acid sphingomyelinase (Schissel et al, 1996), and for the secretion of Zn 2+ under normal physiological conditions such as synaptic transmission (Frederickson and Bush, 2001) and lactation (Kelleher et al, 2009).…”

A potential role for zinc transporter 7 in testosterone synthesis in mouse Leydig tumor cells

“…The roles of ZnTs in the pathogenesis of disease have received great attention and monitoring cellular Zn status may have an important impact on disease prevention and treatment (45,46). Several studies have demonstrated that ZnT7 is located in the Golgi apparatus and may participate in the transport of cytoplasmic Zn into the Golgi apparatus (21,47).…”