Mammary tumor latency is increased in mice lacking the inducible nitric oxide synthase.
Nitric oxide (NO) and its metabolites are implicated in carcinogenesis and metastasis. Both stimulatory and inhibitory effects of NO have been reported in relation to breast cancer and its role in the development of malignancies and metastasis remains uncertain. We have used the polyomavirus middle T antigen (PyV-mT) targeted to the mouse mammary gland and bred into an inducible NO synthase (iNOS)-deficient C57Bl/6 strain to examine a role for nitric oxide in modulating tumors that develop in the complex environment of the whole animal. The development of hyperplasias was delayed to the extent that the earliest palpable tumors arose 2-4 weeks later in PyV-mT/iNOS(-/-) mice compared with PyV-mT/iNOS(+/+) mice, identifying a role for iNOS in early events in mammary tumor formation. Tumors that did develop in PyV-mT/iNOS(-/-) mice were characteristically well differentiated and had a cribriform pattern. Other tumors were myoepithelial adenocarcinomas with uniform nuclear size. In contrast, mice capable of iNOS activity typically developed solid nodular adenocarcinomas with a high mitotic index and pleomorphic nuclei. No significant effect of iNOS deficiency was found on vascular density in hyperplasias or tumors by examining CD31-positive vessels. The infiltration of lesions by macrophages, cells capable of significant NO production, remained unchanged in PyV-mT/iNOS(-/-) mice. Metastatic potential was retained by PyV-mT-transformed epithelium in the absence of iNOS, indicating that NO production by iNOS is not essential for this process. These results indicate a role for iNOS in tumorigenesis, particularly in the regulation of early events.
Ellies
Lesley G
LG
Department of Medicine, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA. lellies@ucsd.edu
Fishman
Michael
M
Hardison
Joy
J
Kleeman
Jeanine
J
Maglione
Jeannie E
JE
Manner
Cathyryne K
CK
Cardiff
Robert D
RD
MacLeod
Carol L
CL
D000230:Adenocarcinoma / Q000235:genetics; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism; D015153:Blotting, Western; D005260:Female; D006579:Heterozygote; D006965:Hyperplasia; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D015674:Mammary Neoplasms, Animal / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008938:Mitosis; D009362:Neoplasm Metastasis; D019001:Nitric Oxide Synthase / Q000378:metabolism / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D019076:Transgenes
D000952:Antigens, Polyomavirus Transforming; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse