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Carcinogenesis Advance Access published online on October 4, 2007
Carcinogenesis, doi:10.1093/carcin/bgm224
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Comparative Genomics of Susceptibility to Mammary Carcinogenesis among Inbred Rat Strains: Role of Reduced Prolactin Signaling in Resistance of the Copenhagen Strain

Xuefeng Ren1,2,*, Xun Zhang1,2,*, Andrea S. Kim1,*, Andrei M. Mikheev1, Mingzhu Fang4, Robert Sullivan1, Roger Bumgarner5 and Helmut Zarbl1,2,3,4

1 Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
2 Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA
3 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle
4 Environmental and Occupational Health Sciences Institute, University of Medicine and Dentistry of New Jersey and Rutgers University, Piscataway, NJ, USA
5 Department of Microbiology and Center for Expression Arrays, University of Washington, Seattle

Correspondent Author's Address: Helmut Zarbl, Department of Environmental and Occupational Medicine, Robert Wood Johnson Medical School, Environmental and Occupational Health Sciences Institute, UMDNJ/ Rutgers, 170 Freylinghuysen Road, Room 236D, Piscataway NJ 08854. Phone:(732)445-0350; FAX: (732)445-0131; Email: Zarbl{at}eohsi.rutgers.edu

To elucidate the molecular basis for differential susceptibilities to mammary carcinogenesis, we compared the transcriptomes of normal mammary glands from pubescent, female rats of the resistant Cop strain to those of the susceptible F344, ACI, Buf/N, and WF strains, and (Cop X F344) F1 progeny. Gene expression profiles in mammary tissue within each rat strain were remarkably similar, indicating that gene expression was determined by genetic background. We next identified the subset of genes that were differentially expressed in all susceptible strains relative to the resistant Cop strain. Among these, the mRNAs encoding prolactin and its cell surface receptor were significantly elevated in all susceptible strains. The expression levels of several prolactin-regulated genes were also significantly elevated, indicating the presence of increased prolactin signaling in mammary glands of all susceptible strains. Pathway analysis of gene expression profiles further identified the prolactin activated Jak/Stat signaling pathway among the pathways that most distinguished sensitive rat strains from the resistant Cop rat. To test the hypothesis that reduced levels of the prolactin signaling in mammary tissue partially contributed to the genetic resistance to mammary carcinogenesis, we used the neuroleptic drug, Perphenazine, to transiently elevate serum prolactin levels in the Cop strain. Whereas Cop rats are resistant to NMU-induced mammary carcinogenesis, ~5% of pubescent Cop females treated with Perphenazine and NMU exposure developed mammary adenocarcinomas with latencies comparable to those sensitive strains. Together these finding indicated that in the rat, the molecular mechanisms underlying genetic susceptibility to mammary carcinogenesis include deregulation of prolactin signaling.

Key Words: Gene expression profiling • genetic susceptibility • rat mammary carcinogenesis • Perphenazine • prolactin receptor

* Note: These three authors made equally significant contribution to this study.

Received February 7, 2007; revised September 20, 2007; accepted September 21, 2007.


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