F344/NTac Rats Chronically Exposed to Bromodichloroacetic Acid Develop Mammary Adenocarcinomas With Mixed Luminal/Basal Phenotype and Tgfβ Dysregulation.
Breast cancer is the most common cancer and the second-leading cause of cancer mortality in women in the United States. A recent 2-year National Toxicology Program carcinogenicity study showed an increased incidence of proliferative mammary lesions (hyperplasia, fibroadenoma, adenocarcinoma) in F344/NTac rats exposed to bromodichloroacetic acid (BDCA), a disinfection by-product in finished drinking water with widespread human exposure. We hypothesized that the increase in mammary tumors observed in BDCA-exposed F344/NTac rats may be due to underlying molecular changes relevant for human breast cancer. The objective of the study was to compare (1) gene and protein expression and (2) mutation spectra of relevant human breast cancer genes between normal untreated mammary gland and mammary tumors from control and BDCA-exposed animals to identify molecular changes relevant for human cancer. Histologically, adenocarcinomas from control and BDCA-exposed animals were morphologically very similar, were estrogen/progesterone receptor positive, and displayed a mixed luminal/basal phenotype. Gene expression analysis showed a positive trend in the number of genes associated with human breast cancer, with proportionally more genes represented in the BDCA-treated tumor group. Additionally, a 5-gene signature representing possible Tgfβ pathway activation in BDCA-treated adenocarcinomas was observed, suggesting that this pathway may be involved in the increased incidence of mammary tumors in BDCA-exposed animals.
Investigative Pathology Group, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA North Carolina State University College of Veterinary Medicine, Raleigh, NC, USA.
J B
JB
Harvey
Investigative Pathology Group, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
H-H L
HH
Hong
Investigative Pathology Group, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
S
S
Bhusari
Investigative Pathology Group, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
T-V
TV
Ton
Investigative Pathology Group, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA Special Techniques Group, Cellular and Molecular Pathology Branch, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
Y
Y
Wang
Investigative Pathology Group, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA Special Techniques Group, Cellular and Molecular Pathology Branch, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
J F
JF
Foley
Biostatistics Branch, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
S D
SD
Peddada
Program Operations Branch, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
M
M
Hooth
General Toxicology Group, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
M
M
DeVito
Integrated Laboratory Systems, Inc., Research Triangle Park, NC, USA.
A
A
Nyska
Investigative Pathology Group, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA Experimental Pathology Laboratories, Research Triangle Park, NC, USA.
A R
AR
Pandiri
Investigative Pathology Group, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA hoenerho@med.umich.edu.
M J
MJ
Hoenerhoff
D000085:Acetates / Q000009:adverse effects*; D000230:Adenocarcinoma / Q000139:chemically induced / Q000473:pathology*; D000818:Animals; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000473:pathology*; D010641:Phenotype; D051381:Rats; D011916:Rats, Inbred F344; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D000085:Acetates; D016212:Transforming Growth Factor beta; C100580:bromodichloroacetic acid
F344/NTac rat; basal; breast cancer; environmental pollutants; gene expression; luminal; transforming growth factor beta