Molecular approaches to understanding pregnancy-induced protection against breast cancer

Excerpt

The marked protection against breast cancer afforded women by an early first full-term pregnancy has important clinical implications for designing chemopreventive approaches to breast cancer and, more generally, for understanding how cancer susceptibility can be modulated by normal developmental events. Epidemiologic studies have repeatedly demonstrated that women who undergo an early first full-term pregnancy have a significantly reduced lifetime risk of breast cancer. Similarly, rodents that have previously undergone a full-term pregnancy are highly resistant to carcinogen-induced breast cancer compared with age-matched nulliparous controls. Relatively little progress has been made, however, towards understanding the molecular basis of this phenomenon. We have used microarray expression profiling to identify persistent changes in gene expression in the mouse and rat mammary gland that are induced by an early first full-term pregnancy. Using this approach, we have isolated a panel of genes whose expression is persistently altered in multiple strains of mice and rats by a reproductive event known to reduce breast cancer risk. Additional studies are underway to compare gene expression patterns in mammary tissues from parous and nulliparous mice, rats, and women with parity-induced changes in gene expression that are evolutionarily conserved. Similarly, gene expression patterns in rats that have been treated with hormonal regimens that mimic parity-induced protection are being compared with those induced by non-protective control regimens in order to identify genes whose expression patterns are most closely correlated with protection. Finally, gene expression changes induced by parity in strains of rats that exhibit different levels of susceptibility to carcinogen-induced tumorigenesis are being compared. These gene expression changes suggest novel hypotheses for the mechanisms by which parity may modulate breast cancer risk and will be useful for probing the mechanisms by which the developmental state of the mammary gland modulates the response to an oncogenic stimulus. …