Epidemiologic studies have demonstrated that increased
prolactin (PRL) exposure raises the risk of invasive
estrogen receptor alpha (
ERalpha)-positive
breast cancer in women. However, the mechanism(s) whereby this occurs and the interactions with
estrogen itself in this disease remain poorly understood. In order to investigate the role of ovarian
hormones in the disease process, we employed a transgenic model neu-related
lipocalin (NRL)-PRL in which transgenic PRL is directed to mammary epithelial cells by the PRL- and
estrogen-insensitive NRL promoter, mimicking the endogenous PRL expression within the breast observed in women. This high local exposure leads to mammary lesion development and eventually
carcinomas.
Ovariectomy (ovx), shortly after puberty, did not alter the incidence or latency of PRL-induced mammary
carcinomas, consistent with the independence of PRL from circulating
estrogens as a risk factor for invasive
breast cancer in women. However, chronic
estrogen administration to ovx NRL-PRL females decreased the latency of both
ERalpha-positive and -negative
tumors. We identified multiple mechanisms that may underlie this observation. Elevated
estrogen exposure cooperated with PRL to increase epithelial proliferation and myoepithelial abnormalities, increasing the incidence of preneoplastic lesions. Critical components of the extracellular matrix secreted by the myoepithelium were reduced with age, and transgenic PRL raised transcripts for
tenascin-C and
maspin, both associated with
tumor progression and poor prognosis in subclasses of clinical
breast tumors. Mammary pERK1/2 and pAkt, but not phosphorylated Stat5, were markedly elevated by local PRL. Together, these findings indicate that PRL employs multiple mechanisms to promote mammary
tumorigenesis.