Research Papers:

Differential signaling pathway activation in 7,12-dimethylbenz[a] anthracene (DMBA)-treated mammary stem/progenitor cells from species with varying mammary cancer incidence

Melissa M. Ledet, Meghan Oswald, Robyn Anderson and Gerlinde R. Van de Walle _

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Oncotarget. 2018; 9:32761-32774. https://doi.org/10.18632/oncotarget.25988

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Melissa M. Ledet1, Meghan Oswald1, Robyn Anderson1 and Gerlinde R. Van de Walle1

1Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca 14853, NY, USA

Correspondence to:

Gerlinde R. Van de Walle, email: [email protected]

Keywords: mammary stem/progenitor cells; DMBA; mammary cancer; DNA damage; apoptosis

Received: May 16, 2018     Accepted: July 31, 2018     Published: August 28, 2018


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.

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