Abstract
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 (PyVโmT) targeted to the mouse mammary gland and bred into an inducible NO synthase (iNOS)โdeficient 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 2โ4 weeks later in PyVโmT/iNOS^โ/โ^ mice compared with PyVโmT/iNOS^+/+^ mice, identifying a role for iNOS in early events in mammary tumor formation. Tumors that did develop in PyVโmT/iNOS^โ/โ^ 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 CD31โpositive vessels. The infiltration of lesions by macrophages, cells capable of significant NO production, remained unchanged in PyVโmT/iNOS^โ/โ^ mice. Metastatic potential was retained by PyVโmTโtransformed 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. ยฉ 2003 WileyโLiss, Inc.