Abstract
A natural variation exists in the susceptibility to mammary cancer among wild and domestic mammalian species. Mammary stem/progenitor cells (MaSC) represent a primary target cell for transformation; however, little is known about the intrinsic response of these cells to carcinogenic insults. Polycyclic aromatic hydrocarbons (PAH), such as 7,12-dimethylbenz[a]anthracene (DMBA), are abundantly present in the environment and have been linked to the development of mammary cancer in humans and rodents. We treated MaSC from equine (mammary cancer-resistant) and canine (mammary cancer-susceptible) species with DMBA and assessed cytochrome P450 metabolic activity, DNA damage and viability. Our notable findings were that MaSC from both species showed DNA damage following DMBA treatment; however, equine MaSC initiated cell death whereas canine MaSC repaired this DNA damage. Follow-up studies, based on genome-wide transcriptome analyses, revealed that DMBA induced activation of both the intrinsic and extrinsic apoptotic pathways in equine, but not canine, MaSC. Based on these findings, we propose a hypothetical model in which undergoing apoptosis in response to an oncogenic event might contribute to a lower incidence of mammary cancer in certain mammalian species. Such a mechanism would allow for the elimination of DNA-damaged MaSC, and hence, reduce the risk of potential tumor-initiating mutations in these cells.
Highlights
Peto’s paradox describes the lack of correlation between body size and cancer risk [1]
Polycyclic aromatic hydrocarbons (PAH), such as 7,12-dimethylbenz[a]anthracene (DMBA), act as carcinogens by binding to DNA after a multi-step metabolic activation via the cytochrome P450 (CYP450) enzymes CYP1A1 and CYP1B1, which results in the creation of DNA adducts [20]
We first explored the effects of DMBA treatment on the expression and activity of CYP1A1 and CYP1B1 in equine and canine mammary stem/progenitor cells (EqMaSC and canine MaSC (CaMaSC), respectively)
Summary
Peto’s paradox describes the lack of correlation between body size and cancer risk [1]. With more cells in their body compared to smaller animals, do not have an increased cancer risk as would be expected. Elephants are one such example of a species with a greater than average body size and a less than average cancer incidence [2]. Additional species for which the underlying mechanisms of cancer resistance have been studied are the naked mole rat and the blind mole rat. Both are long-lived rodents with exceptionally low cancer incidences. In response to progrowth signals, blind mole rat cells trigger a necrotic cell death response, and this concerted cell death has been attributed to this species’ resistance to cancer [5]
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