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(American Journal of Pathology. 2006;168:1365-1374.)
© 2006 American Society for Investigative Pathology

Prolactin Potentiates Transforming Growth Factor Induction of Mammary Neoplasia in Transgenic Mice

Lisa M. Arendt^*, Teresa A. Rose-Hellekant, Eric P. Sandgren and Linda A. Schuler

From the Cellular and Molecular Biology Program,^* the Department of Comparative Biosciences, and the Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin

Prolactin influences mammary development and carcinogenesis through endocrine and autocrine/paracrine mechanisms. In virgin female mice, pro-lactin overexpression under control of a mammary selective nonhormonally responsive promoter, neu-related lipocalin, results in estrogen receptor (ER)-positive and ER-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 (TGF) in bitransgenic mice. Prolactin and TGF cooperated to reduce dramatically the latency of mammary macrocyst development, the principal lesion type induced by TGF. In combination, prolactin and TGF 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 TGF transgenic glands, suggesting that this kinase may be a point of signaling crosstalk. Furthermore, transgenic prolactin also reversed the decrease in ER induced by neu-related lipocalin-TGF. 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 thera-peutic target.

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