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Secreted sphingomyelins modulate low mammary cancer incidence observed in certain mammals.

ABSTRACT: Determining mechanisms that naturally protect species from developing cancer is critical in order to prevent and treat cancer. Here, we describe a novel cancer-suppressing mechanism, via the secretion of bioactive factors by mammary cells, that is present in domesticated mammals with a low mammary cancer incidence. Specifically, these bioactive factors induced triple-negative breast cancer cell (TNBC) death in vitro and reduced tumorigenicity in a xenograft TNBC mouse model in vivo. RNA deep sequencing showed significant downregulation of genes associated with breast cancer progression in secretome-cultured TNBC cells. Further in-depth multi-omics analysis identified sphingomyelins as key secreted factors, and their role was confirmed via inhibition of the sphingomyelin signaling pathway. We speculate that secreted sphingomyelins in the mammary gland of mammals with a naturally low incidence of mammary cancer mediate the elimination of cancer cells. This study contributes to the growing list of protective mechanisms identified in cancer-proof species.

SUBMITTER: Ledet MM

PROVIDER: S-EPMC7689471 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Secreted sphingomyelins modulate low mammary cancer incidence observed in certain mammals.

Ledet Melissa M MM Harman Rebecca M RM Fan Jennifer C JC Schmitt-Matzen Emily E Diaz-Rubio Maria Elena ME Zhang Sheng S Van de Walle Gerlinde R GR

Scientific reports 20201125 1

Determining mechanisms that naturally protect species from developing cancer is critical in order to prevent and treat cancer. Here, we describe a novel cancer-suppressing mechanism, via the secretion of bioactive factors by mammary cells, that is present in domesticated mammals with a low mammary cancer incidence. Specifically, these bioactive factors induced triple-negative breast cancer cell (TNBC) death in vitro and reduced tumorigenicity in a xenograft TNBC mouse model in vivo. RNA deep seq ...[more]

PMID: 33239740

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Project description:BackgroundThe aetiology of Africa's easterly-lying corridor of squamous cell oesophageal cancer is poorly understood. Micronutrient deficiencies have been implicated in this cancer in other areas of the world, but their role in Africa is unclear. Without prospective cohorts, timely insights can instead be gained through ecological studies.MethodsAcross Africa we assessed associations between a country's oesophageal cancer incidence rate and food balance sheet-derived estimates of mean national dietary supplies of 7 nutrients: calcium (Ca), copper (Cu), iron (Fe), iodine (I), magnesium (Mg), selenium (Se) and zinc (Zn). We included 32 countries which had estimates of dietary nutrient supplies and of better-quality GLOBCAN 2012 cancer incidence rates. Bayesian hierarchical Poisson lognormal models were used to estimate incidence rate ratios for oesophageal cancer associated with each nutrient, adjusted for age, gender, energy intake, phytate, smoking and alcohol consumption, as well as their 95% posterior credible intervals (CI). Adult dietary deficiencies were quantified using an estimated average requirements (EAR) cut-point approach.ResultsAdjusted incidence rate ratios for oesophageal cancer associated with a doubling of mean nutrient supply were: for Fe 0.49 (95% CI: 0.29-0.82); Mg 0.58 (0.31-1.08); Se 0.40 (0.18-0.90); and Zn 0.29 (0.11-0.74). There were no associations with Ca, Cu and I. Mean national nutrient supplies exceeded adult EARs for Mg and Fe in most countries. For Se, mean supplies were less than EARs (both sexes) in 7 of the 10 highest oesophageal cancer ranking countries, compared to 23% of remaining countries. For Zn, mean supplies were less than the male EARs in 8 of these 10 highest ranking countries compared to in 36% of other countries.ConclusionsEcological associations are consistent with the potential role of Se and/or Zn deficiencies in squamous cell oesophageal cancer in Africa. Individual-level analytical studies are needed to elucidate their causal role in this setting.

Dataset Information

Secreted sphingomyelins modulate low mammary cancer incidence observed in certain mammals.

Publications

Secreted sphingomyelins modulate low mammary cancer incidence observed in certain mammals.

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