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Paracrine Signaling by Progesterone ⇑ Renuga Devi Rajaram, Cathrin Brisken

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Paracrine Signaling by Progesterone ⇑ Renuga Devi Rajaram, Cathrin Brisken View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Infoscience - École polytechnique fédérale de Lausanne Molecular and Cellular Endocrinology xxx (2011) xxx–xxx Contents lists available at SciVerse ScienceDirect Molecular and Cellular Endocrinology journal homepage: www.elsevier.com/locate/mce Review Paracrine signaling by progesterone ⇑ Renuga Devi Rajaram, Cathrin Brisken Ecole Polytechnique Fédérale de Lausanne (EPFL), ISREC – Swiss Institute for Experimental Cancer Research, NCCR Molecular Oncology, SV2832 Station 19, CH-1015 Lausanne, Switzerland article info abstract Article history: Steroid hormones coordinate and control the development and function of many organs and are impli- Available online xxxx cated in many pathological processes. Progesterone signaling, in particular, is essential for several impor- tant female reproductive functions. Physiological effects of progesterone are mediated by its cognate Keywords: receptor, expressed in a subset of cells in target tissues. Experimental evidence has accumulated that pro- Progesterone receptor gesterone acts through both cell intrinsic as well as paracrine signaling mechanisms. By relegating the Paracrine signaling hormonal stimulus to paracrine signaling cascades the systemic signal gets amplified locally and signal- Uterus ing reaches different cell types that are devoid of hormone receptors. Interestingly, distinct biological Ovaries responses to progesterone in different target tissues rely on several tissue-specific and some common Mammary gland Carcinogenesis paracrine factors that coordinate biological responses in different cell types. Evidence is forthcoming that the intercellular signaling pathways that control development and physiological functions are important in tumorigenesis. Crown Copyright Ó 2011 Published by Elsevier Ireland Ltd. All rights reserved. Contents 1. Introduction . ....................................................................................................... 00 2. Mammary gland ....................................................................................................... 00 2.1. Role of Wnt signaling in mammary gland development . ....................................................... 00 2.2. RANKL/RANK in mammary gland development . ....................................................... 00 2.3. Calcitonin involvement in mammary gland development . ....................................................... 00 3. Mammary tumorigenesis. .................................................................................... 00 4. Human breast . ....................................................................................................... 00 4.1. Proliferation and stem/progenitor cell activation . ....................................................... 00 5. Breast cancer . ....................................................................................................... 00 5.1. Role of Wnts in breast cancer. .......................................................................... 00 5.2. RANKL/RANK in breast cancer . .......................................................................... 00 5.3. Calcitonin involvement in breast cancer . .......................................................................... 00 6. Ovaries . ....................................................................................................... 00 7. Ovarian cancer . ....................................................................................................... 00 8. Uterus . ....................................................................................................... 00 9. Endometrial cancer . .................................................................................... 00 Abbreviations: ADAM8, a disintegrin and metalloproteinase 8; ADAMTS-1, a disintegrin and metalloproteinase with thrombospondin motif-1; BrdU, bromodeoxyuridine; CHiP, chromatin immunoprecipitation; COC, cumulus oocyte complex; CT, calcitonin; CTR, calcitonin receptor; DKK3, dickkopf-3; DMBA, dimethylbenz(a)anthracene; Dvl, dishevelled; ECM, extra cellular matrix; EGF, epidermal growth factor; EGFR, epidermal growth factor family receptor; ER, estrogen receptor; ET-2, endothelin2; ETR, endothelin2 receptor; FACS, fluorescent activated cell sorting; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; FSH, follicle stimulating hormone; HGF, hepatocyte growth factor; HMECs, human mammary epithelial cells; IHH, Indian hedgehog; LH, luteinizing hormone; LHR, luteinizing hormone receptor; MaSC, mammary stem cell; MECs, mammary epithelial cells; MGC, mural granulosa cells; MPA, medroxyprogesterone; PR, progesterone receptor; PRAKO, progesterone receptor isoform-A knock out; PRBKO, progesterone receptor isoform-B knock out; PRKO, progesterone receptor knock out; P4, progesterone; RANK, receptor activator of NF-jB; P4, progesterone; RANKL, receptor activator of NF-jB Ligand; SFRP-1, secreted frizzled-related protein-1; TNF, tumor necrosis factors family; WIF1, Wnt inhibitory factor-1; Wnt-1, wingless-type MMTV integration site family, member 1; Wnt-4, wingless-type MMTV integration site family, member 4; WT, wild type. ⇑ Corresponding author. Tel.: +41 0 21 693 07 81/62; fax: +41 0 21 693 07 40. E-mail address: cathrin.brisken@epfl.ch (C. Brisken). 0303-7207/$ - see front matter Crown Copyright Ó 2011 Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.mce.2011.09.018 Please cite this article in press as: Rajaram, R.D., Brisken, C. Paracrine signaling by progesterone. Molecular and Cellular Endocrinology (2011), doi:10.1016/ j.mce.2011.09.018 2 R.D. Rajaram, C. Brisken / Molecular and Cellular Endocrinology xxx (2011) xxx–xxx 10. Progesterone signaling in non-reproductive tissues . ....................................................................... 00 11. Conclusions.......................................................................................................... 00 Acknowledgements . .......................................................................................... 00 References . .......................................................................................................... 00 1. Introduction strong and diversified biological effects? Extensive studies addressing how progesterone affects reproductive tissues using The steroid hormone progesterone plays a prominent role in fe- in vitro and in vivo approaches, which include genetically engi- male reproductive tissues; its levels rise cyclically during men- neered-mouse models such as mice that lack PR and mice deficient strual cycles and are high throughout pregnancy. The hormone for either PR-A or PR-B isoforms have provided evidence that pro- exerts its effects by binding to its cognate receptor, the progester- gesterone acts by paracrine signaling as reviewed below. one receptor (PR) that acts as a transcription factor and is ex- pressed only in a subset of cells in the target organs. The major functions of PR signaling are to trigger the release of the mature 2. Mammary gland oocytes from the ovaries, to prepare the uterus for implantation of the blastocysts, and to increase the complexity of the milk duct The mammary gland is a branching organ that undergoes most system in the mammary gland essential for the expansion of secre- of its development postnatally under control of female reproduc- tory surface for milk production. Progesterone signaling also af- tive hormones. Progesterone is a key player in the adult mammary fects non-reproductive organs like thymus, bone and blood gland where it triggers the formation of side branches from the vessels, and impinges on the central nervous system. It exerts dis- preexisting mammary ducts during estrus cycles and early preg- tinct biological functions in different target tissues that can be nancy (Brisken and O’Malley, 2010). Analysis of mutant mice that quite opposed. For instance, in the adult mammary gland proges- lack either PR-A or PR-B isoform revealed that PR-B function is terone signaling is mitogenic whereas it is anti-proliferative in essential for mammary gland development (Mulac-Jericevic et al., the uterine epithelium. How can a single hormone elicit such 2003, 2000). The mammary ducts are composed of an inner layer Fig. 1. Paracrine signaling induced by progesterone in mouse mammary gland and human breast. Progesterone binds to PR expressed in a subset of luminal mammary epithelial cells, and induces the expression of paracrine factors. In mouse mammary gland, RANKL, CT and Wnt-4 are induced which in turn act on their respective target cells to induce stem cell activation, cell proliferation, and tissue remodeling thereby increasing the complexity of the mammary gland. In human breast model that responds to progesterone, the hormone induces genes involved in Notch signaling pathway (shown in dashed frame) and was suggested to communicate with bipotent progenitors to increase the complexity of the breast (for details see text). Please cite this article in press as: Rajaram, R.D., Brisken, C. Paracrine signaling by progesterone. Molecular and Cellular Endocrinology (2011), doi:10.1016/ j.mce.2011.09.018 R.D. Rajaram, C. Brisken / Molecular and Cellular Endocrinology xxx (2011) xxx–xxx 3 of luminal epithelium and an outer layer of myoepithelial cells that Wnt-4 being a direct target of PR signaling, PR and Wnt-4 mRNAs are surrounded by a basal lamina and stromal fibroblasts and are show a similar expression pattern in the
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