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

Department of Comparative Biosciences, University of Wisconsin, 2015 Linden Dr., Madison, WI 53706, USA.
American Journal Of Pathology (Impact Factor: 4.59). 05/2006; 168(4):1365-74. DOI: 10.2353/ajpath.2006.050861
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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 alpha (ERalpha)-positive and ERalpha-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 (TGFalpha) in bitransgenic mice. Prolactin and TGFalpha cooperated to reduce dramatically the latency of mammary macrocyst development, the principal lesion type induced by TGFalpha. In combination, prolactin and TGFalpha 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 TGFalpha transgenic glands, suggesting that this kinase may be a point of signaling crosstalk. Furthermore, transgenic prolactin also reversed the decrease in ERalpha induced by neu-related lipocalin-TGFalpha. Our findings demonstrate that locally produced prolactin can strikingly potentiate the carcinogenic actions of another oncogene and modify ovarian hormone responsiveness, suggesting that prolactin signaling may be a potential therapeutic target.

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Available from: Lisa M Arendt, Apr 09, 2014
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    • "In addition to initiating transformation by itself, prolactin also cooperates with other prominent regulators of mammary tumorigenesis. Coexpression of NRL–prolactin and an EGF family growth factor, TGFa, significantly shortens the development of macrocystic lesions and adenocarcinomas (Arendt et al. 2006). Together, these studies highlight an important aspect of prolactin biology: While prolactin/prolactin receptor signaling promotes lactogenic differentiation of mammary epithelial cells, aberrant activation of prolactin/prolactin receptor signaling can transform mammary epithelial cells and induce mammary tumors. "
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    ABSTRACT: Prolactin (PRL) is a peptide hormone that is produced by the pituitary gland and is known to regulate lactogenic differentiation. There is a significant body of evidence that points to autocrine production of prolactin and activation of an autocrine/paracrine signaling pathway to regulate cell proliferation and migration and inhibition of cell death. This perspective highlights the recent study in the October 1, 2012, issue of Genes & Development by Chen and colleagues (pp. 2154-2168) that describes a mechanism for autocrine prolactin production and places the finding in the context of a role for prolactin in breast development and cancer.
    Genes & development 10/2012; 26(20):2253-8. DOI:10.1101/gad.204636.112 · 10.80 Impact Factor
    • "Although this variability is a concern, these mice provide a good model to examine the biology of hormone-dependent breast cancer. Further studies by the same investigators showed co-expression of prolactin with the EGFR ligand and the mammary oncogene, TGF-α, dramatically reduced the latency of pre-neoplastic lesions.[71] The pre-neoplastic lesions common in prolactin transgenic mice were epithelial hyperplasia with high rate of adenocarcinoma formation, whereas, in TGF-α transgenic mice the most common pre-neoplastic lesions were macrocysts with a rare incidence of adenosis. "
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    ABSTRACT: Breast cancer is the most frequent malignancy and second leading cause of cancer-related deaths among women. Despite advances in genetic and biochemical analyses, the incidence of breast cancer and its associated mortality remain very high. About 60 - 70% of breast cancers are Estrogen Receptor alpha (ER-α) positive and are dependent on estrogen for growth. Selective estrogen receptor modulators (SERMs) have therefore provided an effective targeted therapy to treat ER-α positive breast cancer patients. Unfortunately, development of resistance to endocrine therapy is frequent and leads to cancer recurrence. Our understanding of molecular mechanisms involved in the development of ER-α positive tumors and their resistance to ER antagonists is currently limited due to lack of experimental models of ER-α positive breast cancer. In most mouse models of breast cancer, the tumors that form are typically ER-negative and independent of estrogen for their growth. However, in recent years more attention has been given to develop mouse models that develop different subtypes of breast cancers, including ER-positive tumors. In this review, we discuss the currently available mouse models that develop ER-α positive mammary tumors and their potential use to elucidate the molecular mechanisms of ER-α positive breast cancer development and endocrine resistance.
    Journal of Carcinogenesis 12/2011; 10(1):35. DOI:10.4103/1477-3163.91116
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    • "Elevated activities of AP-1 [50,51], AKT [52] and MAP kinases, including ERK1/2 [43], have been implicated in resistance to conventional chemotherapies and anti-estrogens. PRL can activate these signals alone, as well as potently cooperate with growth factors to enhance ERK1/2 and AKT activation in vitro and in vivo [53-55]. In light of the variable levels of Prlr transcripts in these tumors (see below), it is clear that PRL itself may play different roles in ongoing activation of these pathways as they influence lesion progression, tumor phenotype, and treatment sensitivity. "
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    ABSTRACT: Tumors that express estrogen receptor alpha (ERα+) comprise 75% of breast cancers in women. While treatments directed against this receptor have successfully lowered mortality rates, many primary tumors initially or later exhibit resistance. The paucity of murine models of this "luminal" tumor subtype has hindered studies of factors that promote their pathogenesis and modulate responsiveness to estrogen-directed therapeutics. Since epidemiologic studies closely link prolactin and the development of ERα+ tumors in women, we examined characteristics of the aggressive ERα+ and ERα- carcinomas which develop in response to mammary prolactin in a murine transgenic model (neu-related lipocalin- prolactin (NRL-PRL)). To evaluate their relationship to clinical tumors, we determined phenotypic relationships among these carcinomas, other murine models of breast cancer, and features of luminal tumors in women. We examined a panel of prolactin-induced tumors for characteristics relevant to clinical tumors: histotype, ERα/progesterone receptor (PR) expression and estrogen responsiveness, Activating Protein 1 (AP-1) components, and phosphorylation of signal transducer and activator of transcription 5 (Stat5), extracellular signal regulated kinase (ERK) 1/2 and AKT. We compared levels of transcripts in the ERα-associated "luminal" signature that defines this subtype of tumors in women and transcripts enriched in various mammary epithelial lineages to other well-studied genetically modified murine models of breast cancer. Finally, we used microarray analyses to compare prolactin-induced ERα+ and ERα- tumors, and examined responsiveness to estrogen and the anti-estrogen, Faslodex, in vivo. Prolactin-induced carcinomas were markedly diverse with respect to histotype, ERα/PR expression, and activated signaling cascades. They constituted a heterogeneous, but distinct group of murine mammary tumors, with molecular features of the luminal subtype of human breast cancer. In contrast to morphologically normal and hyperplastic structures in NRL-PRL females, carcinomas were insensitive to ERα-mediated signals. These tumors were distinct from mouse mammary tumor virus (MMTV)-neu tumors, and contained elevated transcripts for factors associated with luminal/alveolar expansion and differentiation, suggesting that they arose from physiologic targets of prolactin. These features were shared by ERα+ and ERα- tumors, suggesting a common origin, although the former exhibited transcript profiles reflecting greater differentiation. Our studies demonstrate that prolactin can promote diverse carcinomas in mice, many of which resemble luminal breast cancers, providing a novel experimental model to examine the pathogenesis, progression and treatment responsiveness of this tumor subtype.
    Breast cancer research: BCR 01/2011; 13(1):R11. DOI:10.1186/bcr2819 · 5.49 Impact Factor
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