| Epidemiological studies have consistently demonstrated that women who have an early first full-term pregnancy have a reduced lifetime risk of developing breast cancer as compared to women who never bear children. Similarly, the protective effect of parity has also been demonstrated in rodent models in which parous animals are less susceptible to carcinogen-induced tumorigenesis than age-matched nulliparous controls. Despite the long-standing evidence for parity-induced protection against breast cancer, the molecular and cellular basis for this phenomenon is unknown. As a means of addressing the underlying mechanism of parity-induced protection, we have analyzed the expression of 11,000 genes and EST's in the mammary glands of nulliparous and parous mice. From this analysis, we have generated a comprehensive panel of genes whose expression correlates with the protected state of the mammary gland that is associated with parity. Among these genes, we have identified an increase in the expression of markers for mammary epithelial differentiation, as well as an upregulation of markers for cells of the immune system. In addition, we have detected the downregulation of several growth factors and receptors, as well as the upregulation of a growth-inhibitory pathway. To date, these findings provide the most comprehensive analysis of molecular differences between the nulliparous and parous murine mammary gland.;In an effort to test the role of specific oncogenic pathways in parity-induced protection against breast cancer, we have created a novel transgenic mouse model that permits the inducible and reversible expression of c-MYC in the mammary gland of transgenic mice. Using this animal model, we have determined that c-MYC-induced tumorigenesis proceeds via a preferred secondary pathway involving spontaneous K-ras mutations. Interestingly, following abrogation of c-MYC expression, half of the mammary tumors regressed completely, whereas the other half did not. We have demonstrated a strong correlation between tumors that are unable to regress fully and the presence of an activated K-ras or N-ras allele. These findings suggest that by identifying collaborating oncogenic pathways that contribute to neoplastic growth, we will be able to more effectively design genetically targeted chemotherapeutic regimens for human breast cancers. |
