Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1
Jun Zhang
 -- 1372 2022-12-08 17:51:49 |
2 Format correction
Sirius Huang
 Meta information modification 1372 2022-12-09 02:43:23 |

Video Upload Options

Do you have a full video?
Send video materials Upload full video

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Renteria, M.;  Belkin, O.;  Aickareth, J.;  Jang, D.;  Hawwar, M.;  Zhang, J. Role of Zinc in Breast Cancer Tumorigenesis. Encyclopedia. Available online: https://encyclopedia.pub/entry/38361 (accessed on 27 July 2024).
Renteria M,  Belkin O,  Aickareth J,  Jang D,  Hawwar M,  Zhang J. Role of Zinc in Breast Cancer Tumorigenesis. Encyclopedia. Available at: https://encyclopedia.pub/entry/38361. Accessed July 27, 2024.
Renteria, Mellisa, Ofek Belkin, Justin Aickareth, David Jang, Majd Hawwar, Jun Zhang. "Role of Zinc in Breast Cancer Tumorigenesis" Encyclopedia, https://encyclopedia.pub/entry/38361 (accessed July 27, 2024).
Renteria, M.,  Belkin, O.,  Aickareth, J.,  Jang, D.,  Hawwar, M., & Zhang, J. (2022, December 08). Role of Zinc in Breast Cancer Tumorigenesis. In Encyclopedia. https://encyclopedia.pub/entry/38361
Renteria, Mellisa, et al. "Role of Zinc in Breast Cancer Tumorigenesis." Encyclopedia. Web. 08 December, 2022.
Role of Zinc in Breast Cancer Tumorigenesis
Edit
This entry is adapted from the peer-reviewed paper 10.3390/biom12111672

It is well-known that serum and cellular concentrations of zinc are altered in breast cancer patients. Specifically, there are notable zinc hyper-aggregates in breast tumor cells when compared to normal mammary epithelial cells.

Zinc CmPn signaling network breast cancer

1. Cellular Zinc Level Is Influenced by Dietary Supplementation

1.1. Cellular Zinc Concentrations Depend on Dietary Consumption

Minerals and other trace elements are essential micronutrients for normal physiological functioning and well-being [1]. The daily intake and homeostasis of these micronutrients are largely dependent on dietary habits [1]. Although zinc is the most abundant intracellular micronutrient, the human body is incapable of storing sufficient amounts of zinc; therefore, an inadequate diet can rapidly lead to zinc deficiencies [2][3]. It is estimated that nearly 50% of United States adults over the age of 50 are consuming suboptimal amounts of zinc and nearly two billion people worldwide may be zinc-deficient [2]. In rodents, nutritional zinc deficiencies have shown to predispose subjects to a reversible carcinogenesis, in which the subsequent replenishment of dietary zinc led to a reduction in cellular multiplicity and subsequent progression of the malignancy, likely by altering cellular proliferation and gene expression [4][5]. Epidemiological studies have shown that an inverse relationship exists between dietary zinc consumption and the development of breast cancer [3][6]. Specifically, evidence shows that biopsies of breast tumor cells contained significantly higher intracellular zinc concentrations and increased zinc transmembrane protein expression compared with normal tissue cells [6]. Therefore, the aberrant expression and homeostasis of zinc in breast tumors correlates with malignancy and could contribute to the severity of this cancer subtype [6].

1.2. Zinc Cellular Specific Actions

Zinc has shown to modulate immune system functioning, as well as the regulation of various metabolic, genetic, and cell-signaling pathways [2][7]. Studies have shown that zinc plays a protective role in tumor initiation and development by reducing oxidative stress and protecting DNA from reactive oxygen species (ROS) and the subsequent development of oncogenic mutations [8]. Specifically, zinc’s function as an antioxidant provides genomic stability by decreasing oxidative DNA damage [6]. However, other studies suggest that cytotoxic levels of zinc are also known to cause DNA damage, oxidative stress, and the formation of ROS [9]. Several findings suggest that zinc’s function is largely concentration- and cell-specific and this property of zinc may result in both pro-apoptotic and anti-apoptotic properties of the micronutrient [7]. While zinc has been shown to play a role in numerous malignancies, as a result of the complex nature of zinc homeostasis, a delineated relationship between zinc and tumorigenesis has yet to be established [7].

2. Zinc Plays a Significant Role in Tumorigenesis

2.1. Function of Zinc Contributes to the Progression of Cell Tumorigenesis

The biological effects of zinc can be exerted through the intra- and extracellular zinc regulatory functions and its interactions with proteins [10]. Zinc can act as either extracellular stimuli or intracellular messengers. Therefore, a precise working model of zinc regulatory mechanisms is needed to obtain a better understanding of homeostatic control for transients, subcellular distribution and trafficking, organellar homeostasis, and vesicular storage and exocytosis of zinc ions [11]. The vast majority (95%) of zinc is located intracellularly so that the extracellular concentration available is low. Intracellular zinc homeostatic molecules include cytosolic zinc-binding proteins, transporters localized to cytoplasmic and organellar membranes, and sensors of cytoplasmic free zinc ions [12]. Circulatory zinc is mainly bound to albumin, transferrin, and α2-macroglobulin but remains accessible to zinc transporters to control the cellular zinc balance [13]. Intracellular levels of zinc are largely coordinated by zinc transport channels, which are capable of both zinc influx and efflux [2]. There is evidence suggesting that zinc accumulates in elevated levels in breast cancer cells and other malignant cell lines in comparison to normal mammary epithelial cells [14]. Specifically, breast cancer cells showed a 72% increase in intracellular zinc concentrations in comparison to other, non-malignant breast cells, while serum levels of zinc were decreased from baseline [15]. One meta-analysis of 36 studies containing more than 5700 patients found significantly decreased serum zinc levels in breast cancer patients in comparison to controls and patients with benign breast diseases [16]. The findings of increased intracellular zinc concentrations were also observed at the histological level, suggesting that cellular zinc concentrations may be clinically useful in determining malignancy grading, as well as serving as predictive biomarkers for breast cancers [17]. However, the exact mechanisms that are responsible for the accumulation and dysregulation of zinc in breast tumors are not well understood and it remains unclear as to whether intracellular zinc accumulation causes the disease or is a consequence of this disease [2][14].

2.2. Zinc Transport Protein in Breast Cancer Cells

While the exact mechanisms of zinc’s role in tumorigenesis is not well-understood, there are many speculations. Zinc acts as a signaling molecule, and both its intracellular and extracellular concentrations must be tightly regulated for proper physiological functioning [18]. Therefore, there is a complex regulatory system for the precise homeostatic control of cellular zinc transport, distribution, trafficking, organelle homeostasis, vesicular storage, and exocytosis of zinc ions [11][19]. There are several regulators of free intracellular zinc, such as zinc transporters, inhibitory factors, and sensors. Among the zinc transporters, Zrt-/Irt-like proteins (ZIPs) are most frequently studied [20][21][22]. Cellular zinc levels are strictly controlled by two families of transport proteins: ZIP channels (SLC39A) and ZnT transporters (SLC30A). ZIP channels increase cytosolic zinc levels by importing zinc into cells or releasing zinc from endoplasmic reticulum (ER) [23][24][25]. One subfamily of ZIP, estrogen-regulated LIV-1 (SLC39A6) has been implicated in breast cancer [24][26]. For example, the gene expression levels of LIV-1, a membranous zinc transporter, have been shown to increase four-fold under exposure to estrogen treatment [3][4]. Similarly, increased expression levels of LIV-1 were also observed under progesterone (PRG) treatment [3]. LIV-1 is one of the few zinc transporters identified to contain a metalloproteinase motif, which is responsible for breaking down the basement membrane and allowing for the metastasis of breast cancer cells [5]. Likewise, studies have shown that the expression levels of another zinc transporter, ZIP10, were significantly increased in metastatic breast cancer cell lines (such as MDA-MB-231 and MDA-MB-435S) when compared to less invasive cell lines (such as T47D, MCF7, ZR75-1, and ZR75-30). In addition, attenuating ZIP10 or intracellular zinc chelation in MDA-MB-231 cell lines lead to the inhibition of malignant cell migration [6][27]. Furthermore, ZIP7 was found to be able to release zinc from the ER, which leads to zinc-mediated tyrosine kinase signaling to activate cell migration and growth. This result suggests that ZIP7 might be a novel therapeutic target for breast cancer [28]. Contradicting results for the roles of LIV1 in breast cancer tumorigenesis have been reported: some studies demonstrate that ER-positive(+) breast cancer cells, which, according to the aforementioned mechanism above, have increased LIV-1 and intracellular zinc levels, are associated with better outcomes [29], as they are responsive to anti-estrogenic therapies such as Tamoxifen and aromatase inhibitors [8]. Similarly, ZIP6 deficiency disturbs intracellular Zn(2+) homeostasis, leading to increased cell survival [26]. However, breast samples from patients showed significant increases in both ZIP7 and ZIP6 in tumors, and the Kaplan–Meier curve revealed that high ZIP7 levels are correlated with decreased overall survival of patients [30]. These contradicting results can be explained by the tumor-specific hormonal response for different members of ZIP. Another cellular zinc transport receptor, ZnT2, has been shown to function in zinc sequestration, protecting cells from the cytotoxic effects of excess intracellular zinc, ROS formation, and subsequent apoptosis [10]. This study demonstrated that increased expression levels of ZnT2 transporters in malignant breast cancer cells protects these cells from apoptosis and that, conversely, tumor cells with decreased expression levels of ZnT2 transporters were less viable [10]. As a result, attenuating intracellular zinc-sequestering mechanisms may be a viable strategy for treating malignant breast cancers [10]. One study displayed a correlation between zinc concentration and histological and molecular grading and subtypes, showing elevated zinc levels in TNBC [11]. This study also displayed that increased intracellular levels of zinc were correlated with increased aggressiveness of breast cancers, with the highest zinc concentrations being present in HER2-positive breast cancers and TNBCs [11]. Additional zinc cellular regulatory factors are zinc inhibitory factor (ZIF) and zinc-sensing G-protein coupled receptor (ZnR/GPR39). ZIF reduces free intracellular zinc by inhibiting zinc transport in the oocyte before ovulation [31]. As a G-protein coupled receptor, ZnR/GPR39 triggers intracellular Ca2+ release and subsequently activates downstream MAPK or PI3K/AKT pathways controlling cell proliferation [32]. ZnR/GPR39 activity has been found to be enhanced in breast cancer [33][34][35].

References

  1. Venturelli, S.; Leischner, C.; Helling, T.; Renner, O.; Burkard, M.; Marongiu, L. Minerals and Cancer: Overview of the Possible Diagnostic Value. Cancers 2022, 14, 1256.
  2. Grattan, B.J.; Freake, H.C. Zinc and Cancer: Implications for LIV-1 in Breast Cancer. Nutrients 2012, 4, 648–675.
  3. Skrajnowska, D.; Bobrowska-Korczak, B. Role of Zinc in Immune System and Anti-Cancer Defense Mechanisms. Nutrients 2019, 11, 2273.
  4. Fong, L.Y.Y.; Nguyen, V.T.; Farber, J.L. Esophageal cancer prevention in zinc-deficient rats: Rapid induction of apoptosis by replenishing zinc. J. Natl. Cancer Inst. 2001, 93, 1525–1533.
  5. Fong, L.Y.Y.; Jiang, Y.; Riley, M.; Liu, X.; Smalley, K.J.; Guttridge, D.C.; Farber, J.L. Prevention of upper aerodigestive tract cancer in zinc-deficient rodents: Inefficacy of genetic or pharmacological disruption of COX-2. Int. J. Cancer 2008, 122, 978–989.
  6. Alam, S.; Kelleher, S.L. Cellular mechanisms of zinc dysregulation: A perspective on zinc homeostasis as an etiological factor in the development and progression of breast cancer. Nutrients 2012, 4, 875–903.
  7. Franklin, R.B.; Costello, L.C. The Important Role of the Apoptotic Effects of Zinc in the Development of Cancers. J. Cell Biochem. 2009, 106, 750–757.
  8. Yildiz, A.; Kaya, Y.; Tanriverdi, O. Effect of the Interaction Between Selenium and Zinc on DNA Repair in Association With Cancer Prevention. J. Cancer Prev. 2019, 24, 146–154.
  9. Wang, J.; Zhao, H.; Xu, Z.; Cheng, X. Zinc dysregulation in cancers and its potential as a therapeutic target. Cancer Biol. Med. 2020, 17, 612–625.
  10. Maret, W. Regulation of Cellular Zinc Ions and Their Signaling Functions. In Zinc Signaling; Fukada, T., Kambe, T., Eds.; Springer: Singapore, 2019; pp. 5–22.
  11. Maret, W. Zinc in Cellular Regulation: The Nature and Significance of “Zinc Signals”. Int. J. Mol. Sci. 2017, 18, 2285.
  12. Colvin, R.A.; Holmes, W.R.; Fontaine, C.P.; Maret, W. Cytosolic zinc buffering and muffling: Their role in intracellular zinc homeostasis. Metallomics 2010, 2, 306–317.
  13. Lonergan, Z.R.; Skaar, E.P. Nutrient Zinc at the Host-Pathogen Interface. Trends Biochem. Sci. 2019, 44, 1041–1056.
  14. Chandler, P.; Kochupurakkal, B.S.; Alam, S.; Richardson, A.L.; Soybel, D.I.; Kelleher, S.L. Subtype-specific accumulation of intracellular zinc pools is associated with the malignant phenotype in breast cancer. Mol. Cancer 2016, 15, 2.
  15. Margalioth, E.J.; Schenker, J.G.; Chevion, M. Copper and zinc levels in normal and malignant tissues. Cancer 1983, 52, 868–872.
  16. Feng, Y.; Zeng, J.W.; Ma, Q.; Zhang, S.; Tang, J.; Feng, J.F. Serum copper and zinc levels in breast cancer: A meta-analysis. J. Trace Elem. Med. Biol. 2020, 62, 126629.
  17. Riesop, D.; Hirner, A.V.; Rusch, P.; Bankfalvi, A. Zinc distribution within breast cancer tissue: A possible marker for histological grading? J. Cancer Res. Clin. Oncol. 2015, 141, 1321–1331.
  18. Yamasaki, S.; Sakata-Sogawa, K.; Hasegawa, A.; Suzuki, T.; Kabu, K.; Sato, E.; Kurosaki, T.; Yamashita, S.; Tokunaga, M.; Nishida, K.; et al. Zinc is a novel intracellular second messenger. J. Cell Biol. 2007, 177, 637–645.
  19. Nagamatsu, S.; Nishito, Y.; Yuasa, H.; Yamamoto, N.; Komori, T.; Suzuki, T.; Yasui, H.; Kambe, T. Sophisticated expression responses of ZNT1 and MT in response to changes in the expression of ZIPs. Sci. Rep. 2022, 12, 7334.
  20. Eide, D. Molecular biology of iron and zinc uptake in eukaryotes. Curr. Opin. Cell Biol. 1997, 9, 573–577.
  21. Guerinot, M.L. The ZIP family of metal transporters. Biochim. Biophys. Acta 2000, 1465, 190–198.
  22. Cuajungco, M.P.; Ramirez, M.S.; Tolmasky, M.E. Zinc: Multidimensional Effects on Living Organisms. Biomedicines 2021, 9, 208.
  23. Taylor, K.M.; Morgan, H.E.; Johnson, A.; Nicholson, R.I. Structure-function analysis of HKE4, a member of the new LIV-1 subfamily of zinc transporters. Biochem. J. 2004, 377, 131–139.
  24. Taylor, K.M.; Morgan, H.E.; Smart, K.; Zahari, N.M.; Pumford, S.; Ellis, I.O.; Robertson, J.F.; Nicholson, R.I. The emerging role of the LIV-1 subfamily of zinc transporters in breast cancer. Mol. Med. 2007, 13, 396–406.
  25. Taylor, K.M. A distinct role in breast cancer for two LIV-1 family zinc transporters. Biochem. Soc. Trans 2008, 36, 1247–1251.
  26. Matsui, C.; Takatani-Nakase, T.; Hatano, Y.; Kawahara, S.; Nakase, I.; Takahashi, K. Zinc and its transporter ZIP6 are key mediators of breast cancer cell survival under high glucose conditions. FEBS Lett. 2017, 591, 3348–3359.
  27. Taccioli, C.; Chen, H.; Jiang, Y.; Liu, X.P.; Huang, K.; Smalley, K.J.; Farber, J.L.; Croce, C.M.; Fong, L.Y. Dietary zinc deficiency fuels esophageal cancer development by inducing a distinct inflammatory signature. Oncogene 2012, 31, 4550–4558.
  28. Hogstrand, C.; Kille, P.; Nicholson, R.I.; Taylor, K.M. Zinc transporters and cancer: A potential role for ZIP7 as a hub for tyrosine kinase activation. Trends Mol. Med. 2009, 15, 101–111.
  29. Kasper, G.; Weiser, A.A.; Rump, A.; Sparbier, K.; Dahl, E.; Hartmann, A.; Wild, P.; Schwidetzky, U.; Castanos-Velez, E.; Lehmann, K. Expression levels of the putative zinc transporter LIV-1 are associated with a better outcome of breast cancer patients. Int. J. Cancer 2005, 117, 961–973.
  30. Jones, S.; Farr, G.; Nimmanon, T.; Ziliotto, S.; Gee, J.M.W.; Taylor, K.M. The importance of targeting signalling mechanisms of the SLC39A family of zinc transporters to inhibit endocrine resistant breast cancer. Explor. Target Antitumor Ther. 2022, 3, 224–239.
  31. Lisle, R.S.; Anthony, K.; Randall, M.A.; Diaz, F.J. Oocyte-cumulus cell interactions regulate free intracellular zinc in mouse oocytes. Reproduction 2013, 145, 381–390.
  32. Sharir, H.; Zinger, A.; Nevo, A.; Sekler, I.; Hershfinkel, M. Zinc released from injured cells is acting via the Zn2+-sensing receptor, ZnR, to trigger signaling leading to epithelial repair. J. Biol. Chem. 2010, 285, 26097–26106.
  33. Hershfinkel, M. The Zinc Sensing Receptor, ZnR/GPR39, in Health and Disease. Int. J. Mol. Sci. 2018, 19, 439.
  34. Ventura-Bixenshpaner, H.; Asraf, H.; Chakraborty, M.; Elkabets, M.; Sekler, I.; Taylor, K.M.; Hershfinkel, M. Enhanced ZnR/GPR39 Activity in Breast Cancer, an Alternative Trigger of Signaling Leading to Cell Growth. Sci. Rep. 2018, 8, 8119.
  35. Mero, M.; Asraf, H.; Sekler, I.; Taylor, K.M.; Hershfinkel, M. ZnR/GPR39 upregulation of K(+)/Cl(-)-cotransporter 3 in tamoxifen resistant breast cancer cells. Cell Calcium 2019, 81, 12–20.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Oncology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Mellisa Renteria
,
Ofek Belkin
,
Justin Aickareth
,
David Jang
,
Majd Hawwar
,
Jun Zhang
View Times: 996
Revisions: 2 times (View History)
Update Date: 09 Dec 2022
Table of Contents
    1000/1000
    Hot Most Recent
    Video Production Service
    Feedback