Mammary gland zinc metabolism: regulation and dysregulation
© Springer-Verlag 2009
Received: 31 October 2008
Accepted: 17 March 2009
Published: 2 April 2009
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 (Zn) is the second most abundant trace element in the human body . As an essential mineral, Zn is required for numerous metabolic processes including the regulation of many proteins involved in DNA and protein synthesis, mitosis and cell division serving both a structural and catalytic role. In addition to regulating basic cellular function, tight regulation of Zn transport in the mammary gland is critical for optimal Zn transfer into milk during lactation. Adequate Zn transfer into milk is particularly important as neonatal Zn requirements are high during this period of rapid growth and development and Zn deficiency in infants results in impaired immune function and decreased growth. In addition, dysregulation of mammary gland Zn metabolism has recently been associated with breast cancer. Recent epidemiological studies have illustrated a relationship between high breast tissue Zn levels and breast cancer . Unfortunately, the link between the regulation of Zn homeostasis and breast cancer has been thus far indirect; however, the limited information available supports the postulate that dysregulation of Zn metabolism may be associated with aberrant cellular function and cancer progression. Thus, 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 in the mammary gland.
The second family of mammalian Zn transporters (Zip1-14) has been identified as a result of gene sequence homology with known Zn transporters (ZRT1, IRTl-like protein) found in plants and yeast . Zip proteins have been shown to facilitate cellular Zn uptake in transfected cell models [24, 106]. Members of this family can be subdivided into four sub-families based on sequence similarity  and share a 12 amino acid signature sequence (HSVFEGLAVGLQ) present in the putative fourth transmembrane domain. Thus far, expression of all Zip proteins with the exception of Zip4, Zip9 and Zip11 has been documented in mammary tissue or cultured mammary cells; however, their specific contribution to mammary gland Zn metabolism is not well understood. Zip1 is ubiquitously expressed and localized to the plasma membrane  or to intracellular compartments in a cell-specific manner . In prostate Zip1 localizes primarily to the luminal (apical) membrane , which suggests its role in Zn import from systemic circulation is limited. Like several Zip proteins, Zip1 is rapidly endocytosed in response to Zn exposure  illustrating the reliance on post-translational regulation. Targeted deletion of the mouse ZIP1 gene illustrates that Zip1 is not biologically essential but does result in increased sensitivity to Zn deficiency . Targeted deletion of the mouse ZIP3 gene revealed that it is not essential for viability and fertility and under normal growth conditions homozygous ZIP3 knockout mice exhibited no obvious phenotypic effect . However, mice lacking Zip3 during pregnancy or at weaning showed impaired adaptation to Zn deficiency, suggesting that like Zip1, Zip3 plays an ancillary role during Zn deficiency and may transport several trace minerals other than Zn . Zip5 expression has been detected in cultured human breast cells  although Zip5 function in this cell type has not been characterized. In enterocytes, Zip5 is localized to the basolateral membrane , where it likely imports Zn from systemic circulation. A novel aspect of Zip5 regulation is the documentation that while Zip5 transcription is not regulated by Zn exposure, Zip5 protein translation is Zn-responsive . Zip6 (LIV-1) is primarily expressed in hormonally controlled tissues including the mammary gland, prostate and brain [14, 101, 102]. Zip6 was first identified as a putative marker for breast cancer although this relationship is not well understood. Immunohistochemistry of human breast biopsies indicates that Zip6 is localized to the plasma membrane and within an intracellular compartment ; however, the relevance of this observation to mammary gland Zn metabolism is not understood. Zip7 is a ubiquitously expressed transporter that exports Zn from the Golgi into the cytoplasm . Similar to Zip5, Zip7 translation appears to be regulated by Zn exposure as opposed to transcriptional or post-translational mechanisms . Zip8 expression has been documented in breast cancer cells and similar to Zip3, Zip8 is capable of importing other minerals including cadmium and manganese . Zip8 expression and localization are responsive to TNF-α suggesting a role in modulating inflammatory response . Although expression of Zip10 and Zip12 has been detected in cultured breast cancer cells, little is known regarding their function or regulation. Studies indicate that Zip10 is positively regulated by thyroid hormones in intestine and kidney  and expression is positively correlated with invasive breast carcinomas . Zip12 localization or function has not been delineated. Zip14 expression has also been detected in breast cancer cells . Zip14 is alternatively spliced, giving rise to two isoforms Zip14A (primarily expressed in liver, duodenum, kidney, and testis) and Zip14B (primarily expressed in liver, duodenum, brain, and testis) . Similar to Zip8, Zip14 transports iron  and cadmium as well as Zn and expression is upregulated by inflammation and LPS . Similar to Zip12, Zip14 expression has been detected in MCF-7 human breast cancer cells  although the distinction between Zip14 isoform expression and function in the mammary gland has not yet been investigated.
Together the integration of Zn import, Zn sequestration and Zn export mechanisms in the mammary gland coordinates not only the secretion of optimal amounts of Zn into milk during lactation but also tightly controls intracellular Zn pools thus regulating cellular function. Understanding the mechanisms which regulate mammary gland Zn transport as well as the etiology and consequences of dysregulated Zn metabolism in breast tissue will provide critical knowledge regarding the complex regulation of Zn metabolism in highly specialized, hormonally responsive tissues and may ultimately yield important therapeutic interventions.
Mammary gland zinc metabolism and lactation
To provide optimal Zn to the offspring, the mammary gland must import a substantial amount of Zn from maternal circulation and then secrete it into milk (0.5–1 mg Zn/day). This process facilitates the movement of almost twice the amount of Zn that is transferred daily across the placenta to the fetus during the third trimester of pregnancy  which illustrates the extraordinary capacity of the mammary gland for Zn transport. Moreover, milk Zn concentration is maintained over a wide range of dietary Zn intake [54, 81], which further suggests that mammary gland Zn import and export are tightly regulated in order to provide adequate Zn to the nursing infant. The essentiality of optimal Zn intake during the neonatal period is evidenced by observations of early neonatal death associated with low milk Zn levels in “lethal milk” (lm) mice . Dysregulation of this process in humans also results in a condition referred to as “transient neonatal Zn deficiency” which results in severe Zn deficiency in the nursing infant. How the mammary gland is able to transport and regulate such extraordinary Zn transfer into milk to provide optimal Zn for neonatal growth and development is not well understood.
Expression of three Zn transporters which may play a role in intracellular Zn accumulation or Zn export from the lactating mammary gland has been characterized. Both ZnT1 mRNA expression and protein abundance increase through lactation and ZnT1 is appropriately localized to the luminal membrane, suggesting a role in Zn secretion into milk. However, increased ZnT1 expression occurs concomitant with a decline in milk Zn concentration . This may be explained by the observation that ZnT1 associated with luminal membrane is particularly high during early lactation and is detected within the mammary cell as lactation continues. Expression of several Zn transporters that participate in intracellular Zn compartmentalization has been detected. ZnT2 is localized proximal to the luminal membrane of the mammary epithelial cell [49, 50, 61]. Association of ZnT2 with the luminal membrane also declines as lactation continues suggesting that ZnT2 plays a significant role in mediating the Zn transfer into milk during early lactation as well. We have recently determined that there are two functional ZnT2 isoforms which are localized to either the plasma membrane or exocytotic vesicles in mammary cells . Similar to Zip3, ZnT2 expression is regulated by lactogenic hormones which we have recently documented at least in part, results from transcriptional regulation through prolactin signaling mechanisms . ZnT4 is expressed ubiquitously, but abundantly expressed in mammary gland, brain and kidney [3, 4, 41, 49, 69]. ZnT4 is localized to intracellular vesicles and to the trans-Golgi network of normal rat kidney cells . In the mammary gland, ZnT4 was most abundant in cells surrounding the alveolar ducts  and resides in an intracellular compartment but does not co-localize with labile Zn pools but perhaps instead with milk-protein containing vesicles . Currently the role of ZnT4 in milk Zn secretion is not understood despite the fact that a mutation in the gene that encodes ZnT4 (SLC30A4) is responsible for the “lethal milk” (lm − /lm − ) phenotype which is associated with reduced Zn secretion into milk during lactation [38, 91]. Observations that milk from lm − /lm − mice still contains ~50% of normal milk Zn concentration  and that pup survival can be improved by maternal Zn supplementation illustrate the complex redundancy in mammary gland Zn secretion mechanisms. Interestingly, localization might depend upon the stage of lactation as ZnT4 shifts its relative distribution from the luminal membrane during early lactation to more of a homogeneous intracellular distribution during late lactation possibly reducing its overall contribution to milk Zn secretion as lactation progresses.
Dysregulation of zinc metabolism during lactation
The importance of optimal mammary gland Zn transfer is recognized by a condition known as “transient neonatal Zn deficiency” that results in severe Zn deficiency in nursing infants  and the early death from severe Zn deficiency of pups suckled from “lethal milk” mice . “Transient neonatal Zn deficiency” has been documented in both premature and term newborns . Numerous case reports have documented this condition [2, 4, 77, 89, 108] as a consequence of low milk Zn concentration in nursing mothers, which cannot be corrected by maternal Zn supplementation [89, 108]. Term breast-fed infants with this condition usually experience severe eczema and decreased growth by 2–3 months of age; premature infants experience eczema and decreased growth earlier due to their lower Zn stores at birth . “Transient neonatal Zn deficiency” resembles some aspects of the phenotype observed in “lethal milk” mice. However, “transient neonatal Zn deficiency” in humans is clinically distinct from symptoms in lm − /lm − mice in that no maternal symptoms, other than low breast milk Zn concentration, have been reported in affected humans, whereas lm − /lm − mice develop Zn deficiency with age and lack utricular otoconia, resulting in abnormalities in the balance system . The mutation in SLC30A4 which results in the “lethal milk” phenotype is presumed to result in early translational termination and truncation of the ZnT4 protein. Interestingly, Murgia et al.  determined that ZnT4 mRNA is absent in “lethal milk” mice, suggesting nonsense mediated decay as a secondary level of post-transcriptional control of ZnT4 mRNA in lm − /lm − mice. Numerous reports clearly demonstrate that this mutation is not responsible for “transient neonatal Zn deficiency” in human infants [63, 95]. Recently we have found a family in which two exclusively breast-fed infants developed “transient neonatal Zn deficiency” that was associated with low milk Zn concentration in both women . This condition was not associated with mutations in ZnT4 or Zip3 but did result from a mis-sense mutation in ZnT2 which substitutes an arginine for a conserved histidine residue (H54R) in the N-terminal domain resulting in decreased Zn secretion from the mammary gland during lactation in the mothers of infants suffering from this condition. The incidence and penetrance of this mutation are currently unknown. Together, observations gleaned from studies documenting mutations in ZnT4 and ZnT2 illustrates a role for at least ZnT2 and ZnT4 in facilitating Zn secretion into milk.
Regulation by the lactogenic hormone prolactin
The mammary gland is comprised of numerous cell types including mammary epithelial cells which are highly specialized secretory cells that line an alveolar lumen and are responsible for the synthesis and/or secretion of milk components. These cells tightly coordinate the accumulation, production and secretion of milk components in a vectorial manner. This process requires both continuous and episodic stimulation in response to the hormone prolactin following binding of prolactin to prolactin receptors on the mammary epithelial cell . Initial differentiation of proliferating mammary epithelial cells to a fully functional, secreting cell-type is regulated by prolactin and is essential for lactogenesis (initiation of lactation)  to occur. Moreover, galactopoiesis (maintenance of established lactation) requires both continuous as well as episodic prolactin signaling . During lactation, prolactin is primarily secreted by the anterior pituitary gland [41, 63, 64], and is responsible for maintaining a secretory phenotype [5, 76], increasing nutrient transport into the mammary gland  and ultimately regulating milk protein production and secretion [65, 85].
Circulating prolactin levels are very high during early lactation then decline as lactation proceeds. This pattern is positively associated with declining milk Zn concentrations throughout lactation , suggesting prolactin is involved in the secretion of Zn from the mammary gland. In fact, several studies directly implicate prolactin in the stimulation of Zn transport in mammary [51, 52] and prostate cells . The mechanisms through which prolactin regulates Zn transport or Zn transporters are not currently understood. Zinc deficiency has been associated with hyperprolactinemia in men [3, 10, 69] and several in vitro studies have documented the inhibitory effects of physiological Zn concentrations on the synthesis and secretion of prolactin from the pituitary gland . Zinc deficiency during lactation increases production and secretion of prolactin in rodents . These observations may be at least partially responsible for the inverse relationship between low plasma Zn concentration and high milk Zn levels in women from developing countries as a reflection of restricted food intake  or malnutrition . Taken together, data suggest that Zn itself may have a role in the in vivo regulation of prolactin release and thus play an indirect role in regulating Zn transporting mechanisms in hormonally responsive tissues.
Mammary gland zinc metabolism and breast cancer
Breast cancer is one of the leading causes of death among women with ductal carcinomas representing ~30% of all diagnoses. The etiology of breast cancer is multifactorial and generally not understood; however, compelling evidence implicates dysregulated Zn homeostasis in breast cancer development [11, 17, 58, 73, 93]. While little is known regarding the relevance of dysregulated mammary gland Zn metabolism in breast cancer, biopsies taken from mastectomies or lumpectomies have revealed significantly higher Zn levels compared with normal breast tissue [32, 33, 73, 93]. Moreover, recent studies have found a correlation between high levels of Zn in breast tissue and the onset of carcinogenesis . As previously mentioned, Zn homeostasis is a coordinated effort between members of the SLC39A and SLC30A gene families. The significance of dysregulated Zn transporting processes may reflect the fact that tight regulation of cellular Zn metabolism plays a regulatory role in modulating cell proliferation  and programmed cell death , processes which are uncoupled in cancer. Thus understanding the relationship between dysregulated Zn homeostasis and cellular function in breast cancer may provide important clues with respect to the prevention, diagnosis and management of breast cancer.
Dysregulation in zinc transporting mechanisms
Thus far, mounting evidence has linked dysregulation of Zn transporter abundance with the transition or progression of breast cancer. This postulate is evidenced by aberrant expression of proteins in breast cancer biopsies or cultured cells that are responsible for maintaining Zn homeostasis, such as metallothionein (MT) [43, 44], Zip6 , Zip7 , Zip8  and Zip10 . While these data implicate the importance of tight regulation of Zn transport in mammary gland function, we still lack specific information linking breast cancer etiology directly with either (1) abnormal Zn transport regulation; or (2) aberrant cellular functions resulting from dysregulated Zn transporter function.
Studies in animal models have begun to delineate the expression pattern and function of Zn homeostatic mechanisms on tumor growth. Studies using N-methyl-N-nitrosourea-induced mammary tumors in rats revealed that Zn concentrations in mammary tumors were 12-times higher than in normal mammary gland tissue, similar to what has been reported in biopsies of breast tissue from humans . As a consequence MT mRNA and protein levels were significantly increased, similar to observations from breast biopsies from cancer patients [44, 48, 94]. Interestingly, MT mRNA expression has also been positively correlated with more aggressive and higher-grade tumors [30, 44]. This suggests that the severity of excess cellular Zn accumulation, perhaps as a consequence of decreased expression of critical Zn exporting or sequestering mechanisms such as ZnT1  may exacerbate cellular dysfunction.
Most of our knowledge regarding the dysregulation of Zn transporters associated with breast cancer comes from studies in cultured cell models. Zip6 has been suggested to be prognostic marker for breast cancer [48, 98]. Studies in ZR-75-1 and MCF-7 human breast cancer cell lines [22, 26, 70] and in normal mammary cells (Lopez and Kelleher, unpublished data) have demonstrated that Zip6 is positively regulated by estrogen suggesting that aberrant estrogen receptor signaling may play a modulating role in Zn metabolism dysregulation. Somewhat counter intuitively, studies have detected a negative correlation between Zip6 protein abundance and tumor size, grade and stage, implicating high Zip6 protein levels with less aggressive tumors . In conjunction with these observations are reports demonstrating that Zip6 attenuation in breast cancer cells significantly increased cell growth and reduced cell–cell interaction through reduced E-cadherin expression  further implicating Zip6 in “tumor suppression”. Interestingly, elevated Zip6 mRNA levels have been associated with lymph node involvement and potentially metastatic spread [71, 72], illustrating the disconnect often observed between Zn transporter mRNA and protein abundance and the complex regulation of Zn transport regulation. Taken together, these data suggest that Zip6 plays a role in modulating breast cancer transition and/or metastasis; however, direct mechanisms through which this occurs requires further delineation.
Recently, Zip7 expression has been linked to abnormal cell growth. It has been observed that tamoxifen-resistant breast cancer cells have significantly increased intracellular Zn concentration compared with non-tamoxifen-resistant cells. This observation coincides with the over-expression of Zip7 and epidermal growth factor receptor (EGFR) activation . It is interesting to note that activation of the EGFR has been implicated in the neoplastic transformation of solid tumors and over-expression of EGFR correlates with poor survival . Attenuation of Zip7 expression diminished intracellular Zn levels and significantly reduced cell migration presumably through inactivation EGFR-mediated mechanisms . Based on these data, the relationship between aberrant Zn influx and the activation of downstream cell signaling pathways in the pathogenesis of breast cancer is of critical interest and requires more examination. Finally, elevated Zip10 mRNA expression has been linked with lymph node metastasis and in highly invasive breast cancer cell lines such as MDA-MB-231 and MDA-MB-435S . In vitro, Zip10 gene attenuation and treatment with the Zn-chelator TPEN revealed diminished cell motility in MDA-MB-231 cells, supporting the essentiality of Zip10 for cell migration in breast cancer cells . Beyond these cursory observations, we know little with respect to the underlying mechanisms or down-stream consequences. With that said, the significance of these findings begins to elucidate possible mechanisms by which alterations in cellular Zn metabolism as a result of dysregulation of Zn importers modulate oncogenesis. Taken together, these data suggest that Zn importers may play a significant role in the progression of breast cancer. More studies are critically needed to explore effects of anti-hormone therapies on Zn transporter regulation since these processes are largely hormonally regulated and anti-hormone therapy is the conventional breast cancer treatment.
Downstream consequences of Zn dysregulation
Understanding the down-stream effects of dysregulated Zn transport is critical to our understanding of the cellular processes that are affected and may provide important therapeutic interventions. One characteristic of cancerous cells is their inability to undergo programmed cell death or apoptosis. Zinc has been long appreciated to play important roles in cellular function, as both a deficiency and excess in cellular Zn level result in apoptosis . Alterations in Zn homeostasis in breast cells likely dysregulates intrinsically mediated apoptogenic mechanisms. The intrinsic pathway of apoptosis is typically triggered following fluctuations in cellular microenvironment resulting in mitochondria damage. In support of the relationship between Zn and intrinsic apoptosis, recently, it has been shown that Zn chelation induced apoptosis in MCF-7 and MDA-MB468 breast cancer cells by promoting mitochondria permeability, cytochrome C release and activation of caspase-9 activity . Moreover, these effects were determined to be independent from the death-receptor dependent pathway . Additionally, understanding effects of dysregulated Zn homeostasis on signaling events which are initiated upstream of apoptogenesis may be equally as critical as constitutive influx and/or the inability to modulate Zn efflux would activate a plethora of biological pathways. For example, Zn exposure increases ERK phosphorylation and cell viability in the breast cancer cell line MCF-7 and pre-treatment with the ERK inhibitor PD98059 resulted in cell death through increased mitochondrial permeability . This suggests that the over-expression of Zn importers may result in hyper-accumulation of Zn pools in breast cells and may play a role in suppressing apoptotic mechanisms increasing cell proliferation. An interesting question is which comes first; does increased cell proliferation increase cellular Zn requirements and consequently Zn import or does increased Zn import result in increased cellular proliferation? There is evidence that in 3T3 cells (a fibroblast cell line) the initiation of cellular proliferation results in increased Zn retention, Zip1, ZnT1 and ZnT4 mRNA expression , supporting the concept that Zn transporter expression may be responding to increased cellular needs but not necessarily potentiating cellular Zn requirements in cancerous cells.
In summary, the mammary gland is a highly specialized hormonally responsive tissue that has a unique requirement for Zn resulting from the need to import, redistribute and secrete an extraordinary amount of Zn into milk to provide optimal Zn to the newborn offspring. The uncoupling of this process during lactation results in severe Zn neonatal deficiency illustrating the essentiality of tight regulation of Zn transporting mechanisms in the mammary gland. Furthermore, the dysregulation of Zn transporting mechanisms in the non-lactating mammary gland may either result from or precipitate breast cancer transition or progression. The relationship between dysregulation of Zn transporting mechanisms and breast cancer may yield interesting avenues of investigation into novel therapeutic targets.
Conflict of interest
The authors declare no conflict of interests.
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