Prolactin influences mammary development and carcinogenesis through endocrine and autocrine/paracrine mechanisms. In virgin female mice, prolactin overexpression under control of a mammary selective nonhormonally responsive promoter, neurelated lipocalin, results in estrogen receptor α (ERα)-positive and ERα-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 α (TGFα) in bitransgenic mice. Prolactin and TGFα cooperated to reduce dramatically the latency of mammary macrocyst development, the principal lesion type induced by TGFα. In combination, prolactin and TGFα 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 TGFα transgenic glands, suggesting that this kinase may be a point of signaling crosstalk. Furthermore, transgenic prolactin also reversed the decrease in ERα induced by neurelated lipocalin-TGFα. 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.
Bibliographical noteFunding Information:
Supported in part by the National Institutes of Health (grants R01 CA78312 to L.A.S.; K01 RR00145 to T.A.R.-H.; and T32 AG00265), the University of Wisconsin Center for Women's Health and Women's Health Research; and the University of Wisconsin School of Veterinary Medicine.