SYNERGISTIC INTERACTION OF TRANSFORMING GROWTH-FACTOR-ALPHA AND C-MYCIN MOUSE MAMMARY AND SALIVARY-GLAND TUMORIGENESIS

The c-myc oncogene is commonly amplified in breast cancer and is known to interact synergistically with transforming growth factor alpha (TG F alpha) in vitro to promote phenotypic transformation of mammary epit helial cells. In addition, both genes are under sex steroid hormone re gulation in breast cancer. We have used a bitransgenic mouse approach to test the relevance of Myc-TGF alpha interaction in mammary gland tu morigenesis of virgin animals in vivo. We mated single transgenic TGF alpha and c-myc mouse strains to yield double transgenic offspring for TGF alpha and c-myc. All (20 of 20) double transgenic TGF alpha/c-myc animals developed synchronous mammary tumors at a mean age of 66 days . An unexpected finding was that tumor latency and frequency in males and virgin females were identical. Thus, two gene products that are kn own to be coinduced in breast cancer by the sex hormones estrogen and progesterone strongly synergize to induce synchronous mammary tumors, independent of sex. The tumors, despite being estrogen receptor positi ve, were readily transplanted as highly malignant s.c. cancers in ovar iectomized nude mice. Although approximately one-half of single transg enic c-myc virgin females also eventually developed mammary gland tumo rs, these were stochastic and arose after a long latency period of 9-1 2 months. Single transgenic virgin TGF alpha females and males, c-myc males, and transgene-negative littermates did not develop tumors (ages up to 15 months). The salivary glands of double transgenic animals al so coexpress the two transgenes and show pathological abnormalities ra nging from hyperplasias to frank adenocarcinomas. In contrast, the sal ivary glands of single transgenic and wild-type animals showed only mi ld hyperplasias or metaplasias, but tumors were not observed. In situ hybridization analysis of mammary and salivary glands revealed that hy perplastic and tumorous areas colocalize with regions that overexpress both the TGF alpha and c-myc transgenes. This indicates that there is a requirement for the presence of both proteins for transformation of these glands. In summary, TGF alpha and c-Myc synergize in an extreme ly powerful way to cause breast and salivary gland tumorigenesis in ma les and virgin females without a requirement for pregnancies.