Marginal zinc intake reduces the protective effect of lactation on mammary gland carcinogenesis in a DMBA-induced tumor model in mice

Abstract

Breastfeeding can reduce breast cancer risk; however, unknown factors modify this protective effect. Zinc (Zn) modulates an array of cellular functions including oxidative stress, cell proliferation, motility and apoptosis. Marginal Zn intake is common in women and is associated with breast cancer. We reported that marginal Zn intake in mice leads to mammary gland hypoplasia and hallmarks of pre-neoplastic lesions. In the present study, we tested the hypothesis that marginal Zn intake confounds the protective effect of lactation on breast cancer. Nulliparous mice fed control (ZA, 30 mg Zn/kg) or a marginal Zn diet (ZD, 15 mg Zn/kg), were bred and offspring were weaned naturally. Post-involution, mice were gavaged with corn oil or 7,12-dimethylbenz(a)anthracene (DMBA, 1 mg/wk for 4 weeks) and tumor development was monitored. A ZD diet led to insufficient involution, increased fibrosis and oxidative stress. Following DMBA treatment, mice fed ZD had higher oxidative stress in mammary tissue that correlated with reduced levels of peroxiredoxin-1 and p53 and tended to have shorter tumor latency and greater incidence of non-palpable tumors. In summary, marginal Zn intake creates a toxic mammary gland microenvironment and abrogates the protective effect of lactation on carcinogenesis.

Early-in-life dietary zinc deficiency and supplementation and mammary tumor development in adulthood female rats

“…and large (N8.5 cm 3 ). adult female C57/Bl6 mice, leading to shorter tumor latency, and greater incidence of tumors in these animals, when DMBA was administered to dams [20,37]. Although some studies have indicated that nutritionally induced poor early growth is linked to increased susceptibility of mammary tumor development in female Wistar rats [38,39], the altered body weight and mammary gland outgrowth induced by dietary zinc deficiency did not alter the development of chemically induced mammary tumors in our study.…”

“…These findings may be explained by the evidence that the intracellular increase of zinc is essential for cell proliferation, since its absence is related to tumor cells arrest in S-phase [41,42]. On the other hand, excessive intracellular zinc accumulation is cytotoxic and presents a potential prooxidant activity leading to cellular oxidative stress and increased risk of mammary cancer development in mice [20,37,43]. In the present study, the dietary zinc supplementation (~fivefold more than the control) could have been cytotoxic to the mammary tissue, corroborating to other studies [44,45] and modifying carcinogenic action of DMBA on this tissue leading to higher number of mammary tumors in this group.…”

Immune and metabolic responses in early and late sepsis during mild dietary zinc restriction

“…Feeding the ZM diet for this length of time to mice alters whole-body Zn balance by affecting fertility, testicular Zn concentration, sperm activity, and Zn concentration in milk of lactating female 22–24 . Although this specific ZM diet does not appear to alter plasma Zn levels 22–25 , it has been reported to lower hepatic Zn content in the non-stressed state 22 . Body weights and food intake were recorded weekly during the diet protocol.…”

The emerging role of zinc transporters in cellular homeostasis and cancer

“… 164 , 171 In support of this, the incidence of mammary tumors in primiparous mice exposed to a carcinogen is lower in mice fed a zinc adequate diet than in mice fed a marginally zinc-deficient diet, similar to the zinc-deficient diets often consumed by humans. 172 …”