Professor Jan Brosens
Research in the Uterine Biology Group, headed by Professor Jan Brosens, focuses on the molecular responses in the human endometrium, especially in the context of prevalent reproductive disorders, such as infertility and early pregnancy loss, endometriosis and endometrial cancer. Our work centres on unravelling the signals, pathways and downstream mediators that underpin the preparation of the womb for pregnancy, a process termed ‘decidualization’. These basic molecular investigations provide the platform to identify and validate novel biomarkers and therapeutic targets for common reproductive disorders. To achieve these goals, the Uterine Biology Group works closely together with clinical specialists as well as scientific collaborators.
Decidualization of the endometrium
‘Decidualization’ denotes the maternal response to pregnancy, characterized by the transformation of endometrial stromal fibroblast into secretory, epitheloid decidual cells, influx of specialized uterine immune cells and vascular remodelling. Decidualization bestows unique characteristics on the endometrium essential for pregnancy, including the ability to regulate placenta formation, to modulate local vascular and immune responses, and to resist environmental and oxidative stress. The ovarian hormone progesterone is the major trigger for the differentiation of endometrial cells into specialized decidual cells. Our work has been instrumental in unravelling how progesterone signalling coordinates gene expression that underpin the specialised decidual cell functions, through a variety of mechanism, including interaction with key decidua-specific transcription factors.
Some relevant publications
• B. Cloke, et al. The Poly(C)-binding protein PCBP1 Regulates the Expression of the Androgen Receptor in Decidualizing Human Endometrial Stromal Cells. Endocrinology. 2010. In press
• Leitao B, et al. Silencing of the JNK pathway maintains progesterone receptor activity in decidualizing human endometrial stromal cells exposed to oxidative stress signals. FASEB J. 2009 Dec 21. [Epub ahead of print]
• B. Cloke, et al. The androgen and progesterone receptors regulate distinct gene networks and cellular functions in decidualizing endometrium. Endocrinology. 2008 Sep;149(9):4462-74
• Jones MC, Fusi L, Higham JH, Abdel-Hafiz H, Horwitz KB, Lam WW-F, Brosens JJ. Regulation of the SUMO pathway sensitizes differentiating human endometrial stromal cells to progesterone. PNAS, 2006 Oct 31;103(44):16272-7
Infertility and early pregnancy loss
Reproductive failure is caused by infertility or persistent pregnancy loss, two prevalent but distinct disorders. Conception delay of 12 months or more affects approximately 10% of couples in both developed and less developed countries. Miscarriage, on the other hand, is the most common complication of pregnancy and 1-2% of couples experience recurrent pregnancy loss when defined as 3 or more consecutive pregnancy losses before 24 weeks gestation. Using large-scale profiling techniques on well-defined clinical samples, we have identified major factors and potentially therapeutic targets implicated in unexplained implantation failure. Moreover, in a large collaborative study with centres in the UK and Utrecht (the Netherlands), we discovered an entirely novel mechanism that accounts for miscarriages, irrespective of whether the embryo is chromosomally normal or not. First, we found that the lining of the womb is capable of recognizing and responding to developmentally abnormal embryos but only when adequately prepared (decidualized) for pregnancy. Second, we showed that the ability of the endometrium to decidualize is grossly defective in women suffering from recurrent miscarriages. Combined these observations indicate that impaired decidualization and lack of embryo quality control at the time of implantation is the primary cause of miscarriage.
Some relevant publications
• Teklenburg G, et al. Natural selection of human embryos: decidualizing endometrial stromal cells serve as sensors of embryo quality upon implantation. PLoS One 2010, April 22
• Salker M, et al. Natural selection of human embryos: Impaired decidualization of endometrium disables embryo-maternal interactieons and causes recurrent pregnancy loss. PLoS One 2010, April 22
• Brosens JJ, et al. Proteomic analysis of endometrium from fertile and infertile patients suggests a role for apolipoprotein A-I in embryo implantation failure and endometriosis. Mol Hum Reprod. 2010 Apr;16(4):273-85
• Feroze-Zaidi F, et al. Role and Regulation of the Serum and Glucocorticoid Regulated Kinase 1 in Fertile and Infertile Human Endometrium. Endocrinology 2007 Oct;148(10):5020-9.
Endometriosis
Decidualization of the endometrium in the absence of pregnancy invariably causes menstruation, a rare biological phenomenon that happens only in a handful of mammalian species. When perturbed, cyclic menstruation can cause a number of important disorders, including pelvic endometriosis and uterine adenomyosis. These are common and debilitating disorders, often associated with pain, infertility or both. Key to the efficient management of endometriosis is early diagnosis, which unfortunately still requires an invasive procedure (laparoscopy). Our work therefore not only focuses on understanding the role of cyclic menstruation in normal and abnormal reproductive events but also on identifying and validating non-invasive markers that could be used for early diagnosis.
Some relevant publications
• Brosens JJ, Parker MG, McIndoe A, Pijnenborg R, Brosens IA. A role for menstruation in preconditioning the uterus for successful pregnancy.Am J Obstet Gynecol. 2009 Jun;200(6):615.e1-6.
• Brosens JJ, Hodgetts A, Feroze-Zaidi F, Sherwin JR, Fusi L, Salker MS, Higham J, Rose GL, Kajihara T, Young SL, Lessey BA, Henriet P, Langford PR, Fazleabas AT. Proteomic analysis of endometrium from fertile and infertile patients suggests a role for apolipoprotein A-I in embryo implantation failure and endometriosis. Mol Hum Reprod. 2010 Apr;16(4):273-85
• Purohit A, Fusi L, Brosens JJ, Woo LWL, Potter BVL, Reed MJ. Inhibition of steroid sulphatase activity in endometriotic implants by 667 COUMATE: A potential new therapy. Hum Reprod 2008 Feb;23(2):290-7.
Endometrial cancer
The cyclical waves of endometrial proliferation, differentiation, shedding, and regeneration occur on average 400 times during reproductive life and are unparalleled in any other tissue of the body. Not surprisingly, endometrial cancer is the most common malignancy of the female reproductive tract and its incidence is increasing in Europe and North America. We identified a master transcription factor, FOXO1, which play a major role in ensuring that cellular responses in the endometrium upon the rise and fall in ovarian hormone levels are kept in check. In collaboration with Dr Eric Lam, Professor of Molecular Cancer at Imperial College London, we found that FOXO1 expression is often lost in endometrial hyperplasia and cancer, thereby revealing its potential as a therapeutic target. Ongoing studies suggest that loss of FOXO1 in endometrial cancer may involve several mechanisms, including promoter inhibition and increased mRNA instability or silencing by microRNA.
Some relevant publications
• Takano M, et al. Transcriptional cross-talk between the forkhead transcription factor FOXO1 and the progesterone receptor coordinates cell cycle regulation and differentiation in human endometrial stromal cells. Mol Endocrinol. 2007 Oct;21(10):2334-49.
• Myatt SS, Wang J, Monteiro LJ, Christian M, Ho KK, Fusi L, Dina RE, Brosens JJ, Ghaem-Maghami S, Lam EW. Definition of microRNAs that repress expression of the tumor suppressor gene FOXO1 in endometrial cancer. Cancer Res. 2010 Jan 1;70(1):367-77.T
• Goto, A Albergaria, M Takano, J Briese, KM Pomeranz, B Cloke, F Feroze-Zaidi, N Maywald, M Sajin, RE Dina, O Ishihara, S Takeda, EW-F Lam, AM Bamberger, S Ghaem-Maghami and JJ Brosens. Mechanism and functional consequences of loss of FOXO1 expression in endometrioid endometrial cancer cells. Oncogene 2008 Jan 3;27(1):9-19.
Clinical collaborators
Our work is based foremost on clinical samples. We therefore work in close partnership with clinical specialists within Imperial College NHS Trust and elsewhere, including Mr Fusi (gynaecologist), Professor Tom Bourne (early pregnancy specialist), Mr Trew (fertility specialist), Mr Lavery (fertility specialist), Professor Regan (recurrent miscarriage), Mr Rai (recurrent miscarriage), Professor Higham (gynaecologist), Mr Miskry (endometriosis specialist), Ms Rose (endometriosis), Dr Ghaem-Maghami (cancer specialist), and many more. We are also very indebted to all the patients who have and continue to participate in our research.
Scientific collaborators
Our research benefits greatly from strong national and international collaborations. Over the last decade or so, we had the privilege to be able to work closely with outstanding researchers from around the globe, including with Professor Eric Lam (Cancer Medicine, Imperial College), Dr Birgit Gellersen (Endokrinologikum, Hamburg), Professor Julie Kim (Northwestern University, Chicago, US), Professor Gareth Owen (Pontificia Universidad Católica de Chile, Chile), Professor Asgi Fazleabas (Michigan State University, US), Professor Matti Poutanen (Turku Centre for Disease Modelling, Finland), Professor Vikki Abrahams (Yale University School of Medicine, US), Professor Satoru Takeda (Juntendo University School of Medicine, Japan), Professor Osamu Ishihara (Saitama Medical University, Japan), Professor Patrick Henriet (de Duve Institute, Brussels, Belgium) and many more.
