Prolactin potentiates transforming growth factor α induction of mammary neoplasia in transgenic mice

Prolactin influences mammary development and carcinogenesis through endocrine and autocrine/ paracrine mechanisms. In virgin female mice, prolactin overexpression under control of a manunary selective nonhormonally responsive promoter, neurelated lipocalin, results in estrogen receptor a (ER alpha)-positive and ER alpha-negative adenocarcinomas. However, disease in vivo occurs in the context of dysregulation of multiple pathways. In this study, we investigated the ability of prolactin to modulate carcinogenesis when co-expressed with the potent oncogene transforming growth factor alpha (TGF alpha) in bitransgenic mice. Prolactin and TGFa cooperated to reduce dramatically the latency of mammary macrocyst development, the principal lesion type induced by TGFa. In combination, prolactin and TGFa also increased the incidence and reduced the latency of other preneoplastic lesions and increased cellular turnover in structurally normal alveoli and ducts compared with single transgenic females. Bitransgenic glands contained higher levels of phosphorylated ERK1/2 compared with single TGFa transgenic glands, suggesting that this kinase may be a point of signaling crosstalk. Furthermore, transgenic prolactin also reversed the decrease in ER alpha induced by neurelated lipocalin-TGF alpha. Our findings demonstrate that locally produced prolactin can strikingly potentiate the car-cinogenic actions of another oncogene and modify ovarian hormone responsiveness, suggesting that prolactin signaling may be a potential therapeutic target.