Zinc Signaling in the Mammary Gland: For Better and for Worse

Abstract

Zinc (Zn2+) plays an essential role in epithelial physiology. Among its many effects, most prominent is its action to accelerate cell proliferation, thereby modulating wound healing. It also mediates affects in the gastrointestinal system, in the testes, and in secretory organs, including the pancreas, salivary, and prostate glands. On the cellular level, Zn2+ is involved in protein folding, DNA, and RNA synthesis, and in the function of numerous enzymes. In the mammary gland, Zn2+ accumulation in maternal milk is essential for supporting infant growth during the neonatal period. Importantly, Zn2+ signaling also has direct roles in controlling mammary gland development or, alternatively, involution. During breast cancer progression, accumulation or redistribution of Zn2+ occurs in the mammary gland, with aberrant Zn2+ signaling observed in the malignant cells. Here, we review the current understanding of the role of in Zn2+ the mammary gland, and the proteins controlling cellular Zn2+ homeostasis and signaling, including Zn2+ transporters and the Gq-coupled Zn2+ sensing receptor, ZnR/GPR39. Significant advances in our understanding of Zn2+ signaling in the normal mammary gland as well as in the context of breast cancer provides new avenues for identification of specific targets for breast cancer therapy.

Zinc’s Association with the CmPn/CmP Signaling Network in Breast Cancer Tumorigenesis

“…Serum and intracellular zinc concentrations are altered in breast cancer patients, and it remains unclear if this redistribution is a direct consequence of zinc nutrient alteration or a tissue-specific response [ 21 ]. Zinc signaling directly controls mammary gland development and aberrant signaling has been observed in malignant cells during breast cancer progression, accumulation, or the redistribution of zinc in the mammary gland [ 22 ].…”

Determination of metal ion transport rate of human ZIP4 using stable zinc isotopes

“…Daily tuning of the instrument was accomplished using manufacturer supplied tuning solution containing Li, Co, Y, Ce, and Tl. Global tune optimization was based on optimizing intensities for 7 Li, 89 Y, and 205 Tl while minimizing oxides ( 140 Ce 16 O/ 140 Ce < 1.5%) and doubly charged species ( 140 Ce++/ 140 Ce+ < 2%). Following global instrument tuning, gas mode tuning was accomplished using the same manufacturer supplied tuning solution in KED mode (using 100% UHP He, Airgas).…”

“…As an essential trace element, zinc ions play catalytic, structural, and regulatory roles in biological systems (1), including cell signaling (2)(3)(4) and cell cycle control during meiosis and mitosis (5)(6)(7)(8)(9)(10)(11)(12). Zinc fluxes are also associated with numerous physio-pathological processes (3,5,9,(13)(14)(15)(16)(17)(18)(19). In humans, dietary zinc is absorbed in the small intestine where its transport is primarily mediated by ZIP4, a zinc transporter belonging to the Zrt/Irt-like protein (ZIP) metal transporter family (20)(21)(22)(23).…”

Cross‐talk between zinc and calcium regulates ion transport: A role for the zinc receptor, ZnR/GPR39

“…3), expressed on the basolateral membrane of mouse colon epithelial cells (colonocytes), as well as human colonocytes (Sunuwar, Asraf et al., 2017). In breast cancer cells, ZnR/GPR39 activated another member of the KCC family, KCC3 (Chakraborty & Hershfinkel, 2021; Mero et al., 2019). Similar to the pathway activated by Zn 2+ to enhance KCC2 activity, increases in KCC1‐ or KCC3‐dependent transport were abolished in ZnR/GP39 knockout cells and tissues, indicating that KCC family members are regulated by ZnR/GPR39 signalling.…”

“…Importantly, KCC3 was localized to cellular protrusions, probably formed by local perturbations of cell volume mediated by KCC3 activity (Chakraborty et al., 2021). These protrusions can promote the migration of breast cancer cells and, indeed, both ZnR/GPR39 and KCC3 are required to enhance breast cancer cell invasion through Matrigel (Chakraborty & Hershfinkel, 2021; Chakraborty et al., 2021). Importantly, a role for this pathway in breast cancer is also supported by increased expression of ZnR/GPR39 in tissue biopsies of higher‐grade compared to lower‐grade tumours (Ventura‐Bixenshpaner et al., 2018).…”