Parity and Neu oncogene activation in breast cancer risk and mammary carcinogenesis

Epidemiological studies have consistently demonstrated that women who undergo their first full-term pregnancy early in life are at a significantly reduced risk of developing breast cancer, in comparison to women who never bear children or who first bear a child after the age of 35. Similarly, rodents that have completed a full-term pregnancy are significantly protected against chemically-induced mammary tumorigenesis, as compared to age-matched nulliparous controls. However, the molecular mechanisms underlying this naturally-occurring protective effect have not been elucidated. To gain insight into the mechanisms that contribute to parity-induced protection, we have used high density oligonucleotide microarrays to analyze global transcription profiles of nulliparous and parous rodent mammary glands. We have identified a robust panel of genes whose expression is persistently altered by early parity. We determined that parity results in the persistent down-regulation of several growth-promoting molecules, and the upregulation of the growth-inhibitory molecule TGFβ3 and several of its transcriptional targets, as well as of molecular differentiation markers and of immune cell markers. Since ultimately we wished to test candidate molecules in vivo for a role in parity-induced protection, we developed a murine model for inducible mammary carcinogenesis using the Neu oncogene. However, we found that within this system parity is not protective against Neu-induced mammary tumorigenesis. Nonetheless, we were able to utilize this model system to study aspects of Neu-induced tumor regression, metastasis, and recurrence. We determined that these mice develop mammary adenocarcinomas with short latency and complete penetrance, and that most also proceed to develop pulmonary metastases. Upon Neu transgene withdrawal, essentially all of the primary tumors as well as the pulmonary metastases regress to an undetectable state, indicating that the vast majority of these tumor cells remain dependent upon Neu for maintenance of the transformed state, even in the most advanced stages of malignancy. However, consistent with clinical experience, most mice ultimately develop tumor recurrences in the absence of transgene expression. These findings parallel the natural history of human cancers and suggest that while therapeutic targeting of a single pathway may result in significant clinical responses, such therapy is unlikely to effect a cure