Cellular mechanisms of zinc dysregulation: a perspective on zinc homeostasis as an etiological factor in the development and progression of breast cancer

Abstract

Worldwide, breast cancer is the most commonly diagnosed cancer among women and is the leading cause of female cancer deaths. Zinc (Zn) functions as an antioxidant and plays a role in maintaining genomic stability. Zn deficiency results in oxidative DNA damage and increased cancer risk. Studies suggest an inverse association between dietary and plasma Zn levels and the risk for developing breast cancer. In contrast, breast tumor biopsies display significantly higher Zn levels compared with normal tissue. Zn accumulation in tumor tissue also correlates with increased levels of Zn importing proteins. Further, aberrant expression of Zn transporters in tumors correlates with malignancy, suggesting that altered metal homeostasis in the breast could contribute to malignant transformation and the severity of cancer. However, studies have yet to link dysregulated Zn transport and abnormal Zn-dependent functions in breast cancer development. Herein, we summarize studies that address the multi-modal role of Zn dyshomeostasis in breast cancer with respect to the role of Zn in modulating oxidative stress, DNA damage response/repair pathways and cell proliferation/apoptosis, and the relationship to aberrant regulation of Zn transporters. We also compare Zn dysregulation in breast tissue to that of prostate, pancreatic and ovarian cancer where possible.

Keywords: DNA damage/repair; apoptosis; breast cancer; cell cycle; cell signaling; oxidative stress; proliferation; transcription; zinc homeostasis; zinc transport.

Figure 1

Homeostatic role of Zn in cellular functions which potentially link to initiation and progression of breast cancer. Zn is a biologically essential metal and is a cofactor for more than 300 enzymes and proteins involved in the defense against oxidative stress, including metallothionein, proteins controlling responses to DNA damage and repair (p53; ATM/MRN), intracellular signaling enzymes, more than 2000 transcription factors that require Zn for their structural stability and binding to DNA, also known as Zn-finger proteins, including MTF-1, which controls transcription of Zn regulatory proteins such as metallothionein (MT), and matrix metalloproteinases (MMPs), a family of Zn-dependent endopeptidases which regulate tissue remodeling. Zn also functions as an intracellular second messenger, cytosolic levels of which are tightly controlled by coordinate regulation of ZnTs and ZIPs. In addition, Zn is critical for cell proliferation, cell cycle regulation, differentiation and apoptosis. Cumulatively, the antioxidant and anti-carcinogenesis mechanisms associated with Zn homeostasis appear to play an inhibitory role on neoplastic cell growth.