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Background: The survival rates from breast cancer in Africa are poor and yet the incidence rates are on the rise. In this study, we hypothesized that, in Africa, a continent with great disparities in socio-economic status, race, tumor biology, and cultural characteristics, the survival rates from breast cancer vary greatly based on region, tumor biology (hormone receptor), gender, and race. We aimed to conduct the first comprehensive systematic review and meta-analysis on region, gender, tumor-biology and race-specific 5-year breast cancer survival rates in Africa and compared them to 20-year survival trends in the United States. Methods: We searched MEDLINE, EMBASE, and Cochrane Library to identify studies on breast cancer survival in African published before October 17, 2018. Pooled 5-year survival rates of breast cancer were estimated by random-effects models. We explored sources of heterogeneity through subgroup meta-analyses and meta-regression. Results were reported as absolute difference (AD) in percentages. We compared the survival rates of breast cancer in Africa and the United States. Findings: There were 54 studies included, consisting of 18,970 breast cancer cases. There was substantial heterogeneity in the survival rates (mean 52.9%, range 7–91%, I2 = 99.1%; p for heterogeneity <0.0001). Meta-regression analyses suggested that age and gender-adjusted 5-year survival rates were lower in sub-Saharan Africa compared to north Africa (AD: –25.4%; 95% CI: –34.9 - –15.82%), and in predominantly black populations compared to predominantly non-black populations (AD: –25.9%; 95% CI: 35.40 - –16.43%). Survival rates were 10 percentage points higher in the female population compared to male, but the difference was not significant. Progesterone and estrogen receptor-positive breast cancer subtypes were positively associated with survival (r = 0.39, p = 0.08 and r = 0.24, p = 0.29 respectively), but triple-negative breast cancer was negatively associated with survival. Survival rates are increasing over time more in non-black Africans (55% in 2000 versus 65% in 2018) compared to black Africans (33% in 2000 versus 40% in 2018); but, the survival rates for Africans are still significantly lower when compared to black (76% in 2015) and white (90% in 2015) populations in the United States. Conclusion: Regional, sub-regional, gender, and racial disparities exist, influencing the survival rates of breast cancer in Africa. Therefore, region and race-specific public health interventions coupled with prospective genetic studies are urgently needed to improve breast cancer survival in this region. [ABSTRACT FROM AUTHOR]

Background: Zinc (Zn) hyper-accumulates in breast tumors and malignant cell lines compared to normal mammary epithelium. The mechanisms responsible for Zn accumulation and the consequence of Zn dysregulation are poorly understood. Methods: Microarrays were performed to assess differences in the expression of Zn transporters and metallothioneins (MTs) in human breast tumors and breast cancer cell lines. Real-time PCR and immunoblotting were employed to profile Zn transporter expression in representative luminal (T47D), basal (MDA-MB-231), and non-malignant (MCF10A) cell lines. Zn distribution in human tumors was assessed by X-ray fluorescence imaging. Zn distribution and content in cell lines was measured using FluoZin-3 imaging, and quantification and atomic absorption spectroscopy. Functional consequences of ZnT2 over-expression in MDA-MB-231 cells including invasion, proliferation, and cell cycle were measured using Boyden chambers, MTT assays, and flow cytometry, respectively. Results: Gene expression profiling of human breast tumors and breast cancer cell lines identified subtype-specific dysregulation in the Zn transporting network. X-ray fluorescence imaging of breast tumor tissues revealed Zn hyper-accumulation at the margins of Luminal breast tumors while Zn was more evenly distributed within Basal tumors. While both T47D and MDA-MB-231 cells hyper-accumulated Zn relative to MCF10A cells, T47D cells accumulated 2.5-fold more Zn compared to MDA-MB-231 cells. FluoZin-3 imaging indicated that Zn was sequestered into numerous large vesicles in T47D cells, but was retained in the cytoplasm and found in fewer and larger, amorphous sub-cellular compartments in MDA-MB-231 cells. The differences in Zn localization mirrored the relative abundance of the Zn transporter ZnT2; T47D cells over-expressed ZnT2, whereas MDA-MB-231 cells did not express ZnT2 protein due to proteasomal degradation. To determine the functional relevance of the lack of ZnT2 in MDA-MB-231cells, cells were transfected to express ZnT2. ZnT2 over-expression led to Zn vesicularization, shifts in cell cycle, enhanced apoptosis, and reduced proliferation and invasion. Conclusions: This comprehensive analysis of the Zn transporting network in malignant breast tumors and cell lines illustrates that distinct subtype-specific dysregulation of Zn management may underlie phenotypic characteristics of breast cancers such as grade, invasiveness, metastatic potential, and response to therapy. [ABSTRACT FROM AUTHOR]

Abstract: Prolactin receptor (PRL-R) activation regulates cell differentiation, proliferation, cell survival and motility of breast cells. Prolactin (PRL) and PRL-R over-expression are strongly implicated in breast cancer, particularly contributing to tumor growth and invasion in the more aggressive estrogen-receptor negative (ER−) disease. PRL-R antagonists have been suggested as potential therapeutic agents; however, mechanisms through which PRL-R antagonists exert their actions are not well-understood. Zinc (Zn) is a regulatory factor for over 10% of the proteome, regulating critical cell processes such as proliferation, cell signaling, transcription, apoptosis and autophagy. PRL-R signaling regulates Zn metabolism in breast cells. Herein we determined effects of PRL-R attenuation on cellular Zn metabolism and cell function in a model of ER-, PRL-R over-expressing breast cancer cells (MDA-MB-453). PRL-R attenuation post-transcriptionally increased ZnT2 abundance and redistributed intracellular Zn pools into lysosomes and mitochondria. ZnT2-mediated lysosomal Zn sequestration was associated with reduced matrix metalloproteinase 2 (MMP-2) activity and decreased invasion. ZnT2-mediated Zn accumulation in mitochondria was associated with increased mitochondrial oxidation. Our results suggest that PRL-R antagonism in PRL-R over-expressing breast cancer cells may reduce invasion through the redistribution of intracellular Zn pools critical for cellular function. [Copyright &y& Elsevier]

Zinc (Zn) regulates numerous cellular functions. Zn deficiency is common in females; ∼80% of women and 40% of adolescent girls consume inadequate Zn. Zn deficiency enhances oxidative stress, inflammation and DNA damage. Oxidative stress and inflammation is associated with breast disease. We hypothesized that Zn deficiency increases oxidative stress in the mammary gland, altering the microenvironment and architecture. Zn accumulated in the mammary glands of Zn deficient mice and this was associated with macrophage infiltration, enhanced oxidative stress and over-expression of estrogen receptor α. Ductal and stromal hypercellularity was associated with aberrant collagen deposition and disorganized e-cadherin. Importantly, these microenvironmental alterations were associated with substantial impairments in ductal expansion and mammary gland development. This is the first study to show that marginal Zn deficiency creates a toxic microenvironment in the mammary gland impairing breast development. These changes are consistent with hallmarks of potential increased risk for breast disease and cancer. [ABSTRACT FROM AUTHOR]