Daria Martin, Schering Stiftung Projektraum

 

Progestins and the mammary gland – from basic science to clinical applications

Dr. Dr. Christiane Otto, CRBA Gynecology & Andrology - Female Healthcare, Bayer Schering Pharma AG, Berlin, Germany
Prof. Dr. Orla Conneely, Baylor College, Houston, TX, USA

Berlin, March 21 - 23, 2007

The series of scientific symposia organized by the Ernst Schering Foundation (ESF) opened in 2007 with the workshop „Progestins and the mammary gland – from basic science to clinical application“. Scientists from around the world met to exchange their views on the latest findings in progestin research. The main focus of the discussions of experts from bench to bedside, was the effects of progesterone on the mammary gland.

Progesterone belongs to a class of hormones called progestogens, and is the major naturally occurring human progestogen. It is a steroid hormone produced by adrenal glands, the gonads, specifically after ovulation in the corpus luteum, and, during pregnancy, in the placenta. In women, progesterone levels are relatively low during the preovulatory phase of the menstrual cycle, rise after ovulation, and are elevated during the luteal phase. If pregnancy occurs, progesterone levels are maintained at luteal levels initially. With the onset of the luteal-placental shift in progesterone support of the pregnancy levels rise even further. After delivery of the placenta and during lactation, progesterone levels are very low. Eventually, after menopause progesterone levels stay low. Progesterone as well as its synthetic analogues, the progestins, is used in oral contraception and hormone combinations to treat postmenopausal women. Both molecules specifically bind to the progesterone receptor (PR), which is an intracellular steroid receptor, controlling transcription of various target genes.

Professor Bert W. O’Malley of Baylor College of Medicine in Houston, Texas, USA is one of the first researchers in endocrinology, pioneering the basic molecular science in this field. „During the last 40 years, we have been able to gain a lot of insight into the effects of hormones and the relationship between hormones and cancer“, explains O’Malley. „Initially we were most interested in the endocrine signal pathways and the effects of steroids in target cells. Today we are focusing on gene expression profiles.“ His talk at the ESF symposium in Berlin titled „Coactivators ‚Master’ Regulators of Genes“ focused on progesterone receptor and its steroid receptor coactivators (SRC), which control gene transcription in vivo. In order to find out, which interaction of PR-SRC communicates progesterone effects in the mammary gland and the uterus, his lab constructed a PR-activity-indicator mouse (=PRAI-mouse). In the PRAI mouse the DNA binding domain of PR is substituted for the transcription factor domain GAL4. Thus progesterone activity in vivo can be monitored through luciferase activity, which is controlled by the GAL4 binding site. Recombination of PRAI mice with SRC-1 or SRC-3 deficient mice results in two different phenotypes. SRC-1 deficient PRAI mice show PR activity in the mammary gland but not in the uterus. In contrary SRC-3 deficient mice still have PR activity in the uterus, however the mammary gland tissue shows no PR activity. With this transgenic mouse model O’Malley showed the effects of progesterone being transmitted via the SRC-3 coactivator in the mammary gland and via the SRC-1 co-activator in the uterus.

„Mouse models are generally very effective for understanding the molecular mechanisms and signaling pathways, which are controlled by PR in the mammary gland“, explains Orla M. Conneely, co-organizer of the symposium and professor at Baylor College of Medicine in Houston, Texas, USA. She works on rodent models of normal and malignant breast development. „Despite the differences in hormone dependency of tumor genesis in rodents and humans, their signaling pathways are very similar“, says Conneely. The Texan professor is mostly interested in the specific role of the two progesterone receptor isoformes PR-A and PR-B in the female reproductive system.

Daniel Medina, also professor at Baylor College of Medicine in Houston, Texas, USA, is interested in the effects of steroid hormones on female breast tissue. His work focuses on the hormonal prevention of breast cancer. It is widely known that approximately half of all human tumors show genetic changes in the tumor suppressor gene p53. The mutation inhibits its natural role of regulating the cell cycle, thus resulting in uncontrolled proliferation of cells with damaged DNA. Since p53 is also dysfunctional in breast cancer cells, Medina studies a mouse model, which simulates the loss of function of p53. He was able to show that a two week treatment of young Trp53-/--mice with estrogen and/ or progesterone could reduce the rate of tumors occurring by 70 percent. The protective effect for the mammary tissue could also be demonstrated in older animals. Hormone treatment of mice was able to down regulate the overexpression of the HER2/neu oncogene and thus the incidence of breast cancer occurring. However it remains to be shown whether the findings from the mouse model hold in humans, due to composition differences in the stroma in which breast epithelial cells are embedded.

Starting off at the basic molecular mechanisms of tissue specific progesterone effects, the ESF symposium went all the way to the development of progesterone receptor ligands, which allow detailed imaging of breast tumors via new imaging technology. Professor John Katzenellenbogen of the University of Illinois, Urbana, USA, introduced new PR-ligands for tumor diagnostics via positron emission tomography (PET). To conduct the scan, a short-lived radioactive tracer isotope, i.e. 18Fluorodeoxyglukose (18F-FDG), is injected into the living subject. The glucose analogue 18F-FDG-6 is phosphorylated like normal glucose, resulting in 18F-FDG-6-phosphate. 18F-FDG-6-phosphate however is not further processed and thus starts accumulating in cells of metabolically active organs like the brain or kidney but also cancer cells. Thus PET is used to illustrate the differences in metabolic activity within the body. „PET is highly sensitive compared to other imaging techniques“, says Katzenellenbogen. „Given a specific design of imaging agents, metabolically active cells, like those occurring in malignant tumors, can be closely monitored.“ Katzenellenbogen sees the decision of US health insurances of reimbursement of FDG-imaging via PET costs as one of the major factors in paving its way into mainstream oncology in the US. The development as well as the response to administered therapies can be closely monitored by this non-invasive technology, thus showing any response of the tumor long before x-rays or computer tomography can pick up reduction in tumor size.

The first ESF symposium 2007 did not only look at the latest findings in progesterone research, however it still managed to tie in with last years „Cancer Stem Cells“ symposium, with a talk given by Dr. Robert Clarke of Manchester University, UK. He and his team looked at the hierarchy of cells within the breast epithelial tissue. Clarke thinks of tumors as a hierarchical system of cells, rather than a homogenous cell population, which would respond to any treatment identically. „We are mostly interested in how steroid hormones regulate the hierarchy of cells, since progesterone as well as estrogen are key players in normal breast development as well as in tumor genesis“, Clarke explains. „For me personally, there were a lot of new and interesting things learned at this workshop. I am also hopeful that our angle of stem cell research will help the development of new strategies and targets for breast cancer therapy and prevention.“

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