Developmental events influence breast cancer risk: Insights from MYC, Stat5, and pregnancy

Epidemiological studies clearly demonstrate that the timing of normal developmental events, such as menarche, menopause, and a first full-term pregnancy, can significantly influence a woman\u27s lifetime risk of breast cancer. Moreover, the developmental stage of the breast at the time of exposure to a carcinogenic insult can also significantly influence breast cancer risk. At present, the biological mechanisms underlying these epidemiological observations are unknown. The goal of this thesis was to identify and characterize potential mechanisms through which mammary developmental processes might alter breast cancer risk. To accomplish this, we employed genetically engineered mice to determine whether mammary developmental events influence the effects of aberrant activation of the MYC oncogene. We determined that the effects of aberrant MYC activation are significantly modified by the developmental stage of the mammary gland at the time of exposure, due to alterations in Prlr-Jak2-Stat5 signaling. In addition, we found that the Prlr-Stat5 pathway plays a critical role in MYC-induced mammary tumorigenesis. Additional studies to investigate how developmental events influence breast cancer risk used gene expression profiling to identify persistent parity-induced changes in gene expression that correlate with the protective effects of an early first full-term pregnancy. Through this analysis, we identified a parity-related gene expression signature that is tightly linked with protection against carcinogen-induced breast cancer and is evolutionarily conserved in four genetically diverse inbred rat strains. Finally, we investigated the basis for the time-dependent effects of pregnancy on breast cancer risk: a first-full-term pregnancy early in life protects against breast cancer, whereas a first full-term pregnancy late in life increases breast cancer risk. Using a rat carcinogenesis model, we determined that it is the timing of pregnancy relative to an initiating carcinogenic event, rather than age at pregnancy per se, that determines whether a pregnancy will promote or protect against breast cancer. These findings have significant implications for how mammary developmental events affect breast cancer risk and suggest potential strategies for breast cancer prevention and treatment