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Differential Expression Of The A And B Isoforms Of Progesterone Receptor In Human Endometrial Cancer Cells. Only Progesterone Receptor B Is Induced By Estrogen And Associated With Strong Transcriptional Activation., Kimberly Leslie, N. Kumar, J. Richer, G. Owen, G. Takimoto, K. Horwitz, C. Lange
Differential Expression Of The A And B Isoforms Of Progesterone Receptor In Human Endometrial Cancer Cells. Only Progesterone Receptor B Is Induced By Estrogen And Associated With Strong Transcriptional Activation., Kimberly Leslie, N. Kumar, J. Richer, G. Owen, G. Takimoto, K. Horwitz, C. Lange
Kimberly K. Leslie
No abstract provided.
Endocrine Cancer Risks For Women During The Perimenopause And Beyond., Kimberly Leslie, N. Kumar
Endocrine Cancer Risks For Women During The Perimenopause And Beyond., Kimberly Leslie, N. Kumar
Kimberly K. Leslie
Cancer and its link to reproductive hormones is an area of intense concern for our patients and has been the subject of much speculation. But if estrogen causes breast cancer, for example, most women would eventually develop the disease. We know this is not the case! Actually, estrogen and progesterone have been linked to a decrease as well as an increase in cancer, depending upon the type of tumor under investigation. The purpose of this manuscript is to review the data supporting those relationships.
Selective Down-Regulation Of Progesterone Receptor Isoform B In Poorly Differentiated Human Endometrial Cancer Cells: Implications For Unopposed Estrogen Action., N. Kumar, J. Richer, G. Owen, E. Litman, K. Horwitz, Kimberly Leslie
Selective Down-Regulation Of Progesterone Receptor Isoform B In Poorly Differentiated Human Endometrial Cancer Cells: Implications For Unopposed Estrogen Action., N. Kumar, J. Richer, G. Owen, E. Litman, K. Horwitz, Kimberly Leslie
Kimberly K. Leslie
The uterine endometrium responds to unopposed estrogen stimulation with rapid cell proliferation. Progesterone protects the endometrium against the hyperplastic effects of estradiol (E2) through progesterone receptors (PRs), of which two isoforms are expressed: human (h) PRA and PRB. hPRB has a longer NH2 terminus and may function differently from hPRA. Thus, the relative expression of hPRA:hPRB is likely to be important for the action of progesterone. We hypothesized that the hPRA:hPRB ratios may be abnormal in endometrial cancer, leading to a lack of normal progesterone protection against the growth-promoting effects of E2. To test this hypothesis, well-differentiated Ishikawa endometrial cancer …
Estrogen Receptors Are Present In Human Granulosa Cells., B. Hurst, M. Zilberstein, J. Chou, B. Litman, J. Stephens, Kimberly Leslie
Estrogen Receptors Are Present In Human Granulosa Cells., B. Hurst, M. Zilberstein, J. Chou, B. Litman, J. Stephens, Kimberly Leslie
Kimberly K. Leslie
Recent studies failed to detect estrogen receptors in primate follicles. This study was initiated to determine whether estrogen receptor (ER) messenger ribonucleic acid (mRNA) is present in human granulosa cells and, further, if functional ER proteins are present. To evaluate the presence of ER, RNA from human granulosa cells obtained at the time of oocyte retrieval for assisted reproduction was extracted, and complementary DNA synthesis was performed by the reverse transcriptase-polymerase chain reaction. Oligonucleotide primers were used to amplify basepairs 570-852 in the B- and C- domains of the ER mRNA. Southern blotting was performed and confirmed that the amplified …
The Role Of Oestrogen In Follicular Development., B. Hurst, Kimberly Leslie
The Role Of Oestrogen In Follicular Development., B. Hurst, Kimberly Leslie
Kimberly K. Leslie
Most of our knowledge of ovarian physiology is based upon studies that have demonstrated functional oestrogen receptors in the ovaries of lower animal species. The presence of oestrogen receptors in primate granulosa cells has been questioned by some investigators. However, we have found oestrogen receptor messenger RNA in human granulosa cells by reverse transcriptase-PCR assay. Furthermore, using immortalized granulosa cell lines transfected with a plasmid containing an oestrogen response element, a functional oestrogen receptor was confirmed. These experiments strongly support the hypothesis that human granulosa cells express biologically active oestrogen receptor.
Estrogen Receptors Are Identified In The Glioblastoma Cell Line U138mg., Kimberly Leslie, D. Keefe, S. Powell, F. Naftolin
Estrogen Receptors Are Identified In The Glioblastoma Cell Line U138mg., Kimberly Leslie, D. Keefe, S. Powell, F. Naftolin
Kimberly K. Leslie
OBJECTIVE: The antiestrogen tamoxifen has been found to be effective in decreasing glioblastoma cell proliferation, but the mechanism underlying this effect and whether it is through the estrogen receptor (ER) is controversial. The objective of this study was to determine whether ERs are present in three human glioblastoma cell lines--HS683, U138MG, and JHN J889H--using the most sensitive techniques available. METHODS: Ligand binding and flow cytometry were employed to identify estrogen and progesterone receptors. The reverse transcriptase-polymerase chain reaction was used to identify ER mRNA, and a novel reporter gene transfection assay demonstrated that the ER was capable of activating gene …
Molecular Tools To Reestablish Progestin Control Of Endometrial Cancer Cell Proliferation., D. Dai, N. Kumar, D. Wolf, Kimberly Leslie
Molecular Tools To Reestablish Progestin Control Of Endometrial Cancer Cell Proliferation., D. Dai, N. Kumar, D. Wolf, Kimberly Leslie
Kimberly K. Leslie
OBJECTIVE: Endometrial cancers often arise in a setting of estrogen stimulation unopposed by the differentiating effects of progesterone. Our laboratory and others have previously shown that progesterone receptor down-regulation or perturbation of progesterone receptor isoform A or B expression is associated with the development of poorly differentiated endometrial cancers that are not growth inhibited by progestins. The purpose of these studies was to reestablish high progesterone receptor isoform A and B gene expressions in such endometrial cancer cells and to examine the effects of progestin treatment on cell growth and metastatic potential after this transformation. STUDY DESIGN: To induce high …
A Randomized Controlled Trial Of Interleukin-1 Receptor Antagonist In A Rabbit Model Of Ascending Infection In Pregnancy., R. Mcduffie, J. Davies, Kimberly Leslie, S. Lee, M. Sherman, R. Gibbs
A Randomized Controlled Trial Of Interleukin-1 Receptor Antagonist In A Rabbit Model Of Ascending Infection In Pregnancy., R. Mcduffie, J. Davies, Kimberly Leslie, S. Lee, M. Sherman, R. Gibbs
Kimberly K. Leslie
OBJECTIVE: To determine whether treatment with interleukin-1 receptor antagonist (IL1-ra) would affect amniotic fluid concentrations of tumor necrosis factor alpha (TNF-alpha) and prostaglandins or clinical or microbiological outcomes in a model of ascending bacterial infection in pregnancy. METHODS: Timed pregnant New Zealand white rabbits at 70% of gestation underwent endoscopic inoculation of the cervices with 10(6) - 10(7) cfu Escherichia coli. Animals were randomly assigned in a blinded manner to a 5-h intravenous infusion of human IL1-ra (10 mg/kg) or placebo beginning 1-2 h after inoculation. Blood was drawn from the does for assay of serum IL1-ra concentration before inoculation, …
Functional Analysis Of A Mutant Estrogen Receptor Isolated From T47dco Breast Cancer Cells., Kimberly Leslie, D. Tasset, K. Horwitz
Functional Analysis Of A Mutant Estrogen Receptor Isolated From T47dco Breast Cancer Cells., Kimberly Leslie, D. Tasset, K. Horwitz
Kimberly K. Leslie
OBJECTIVE: Estrogen receptor-positive cancers that initially respond to hormone therapy often progress to a resistant state. The breast cancer cell line T47Dco is a model for such resistance. It is a polymorphic line, composed of multiple cell populations that demonstrate the presence of mutant estrogen receptors by cloning and sequencing techniques. Our objective was to isolate and analyze the structural and functional characteristics of the T47Dco mutant estrogen receptor complementary deoxyribonucleic acid clones. STUDY DESIGN: We constructed two independent T47Dco complementary deoxyribonucleic acid libraries. We isolated and sequenced T47Dco estrogen receptors and have identified a mutant receptor that is truncated …
Immunomodulatory And Transcriptional Effects Of Progesterone Through Progesterone A And B Receptors In Hec50co Poorly Differentiated Endometrial Cancer Cells, S. Davies, Donghai Dai, D. Wolf, Kimberly Leslie
Immunomodulatory And Transcriptional Effects Of Progesterone Through Progesterone A And B Receptors In Hec50co Poorly Differentiated Endometrial Cancer Cells, S. Davies, Donghai Dai, D. Wolf, Kimberly Leslie
Kimberly K. Leslie
OBJECTIVE: Derivatives of progesterone, progestins, are used to treat endometrial cancer; however, the pathways activated by the hormone have not been fully investigated. Progesterone acts through two receptor isoforms, progesterone receptors A and B (PRA and PRB), transcription factors that control the expression of downstream genes leading to endometrial differentiation. The purpose of this study was to perform an expression analysis to identify the mechanisms underlying progesterone's growth suppressive and immunomodulatory effects in endometrial cancer. METHODS: To study the molecular effects of progesterone, PRs were introduced into Hec50co cells. Expression array analyses followed by confirmatory semiquantitive reverse-transcriptase polymerase chain reaction …
Progesterone Regulation Of Activating Protein-1 Transcriptional Activity: A Possible Mechanism Of Progesterone Inhibition Of Endometrial Cancer Cell Growth, Donghai Dai, E. Litman, E. Schonteich, Kimberly Leslie
Progesterone Regulation Of Activating Protein-1 Transcriptional Activity: A Possible Mechanism Of Progesterone Inhibition Of Endometrial Cancer Cell Growth, Donghai Dai, E. Litman, E. Schonteich, Kimberly Leslie
Kimberly K. Leslie
The uterine endometrium and cancers derived from it are classic models of hormone action: estrogen promotes growth and progesterone inhibits proliferation and results in differentiation. We have now identified a major pathway through which progesterone causes these growth-limiting effects. Ligand-bound progesterone receptors modulate the composition and transcriptional activity of members of the activating protein-1 (AP-1) family, and in particular, c-Jun. First, a dominant negative form of c-Jun inhibits the constitutive growth of Hec50co cells in a manner similar to the effects of progesterone through progesterone B receptors. Second, progesterone inhibits the transcriptional activity of the AP-1 complex in reporter gene …
Effect Of Tamoxifen On Endometrial Histology, Hormone Receptors, And Cervical Cytology: A Prospective Study With Follow-Up, Kimberly Leslie, S. Walter, K. Torkko, J. Stephens, C. Thompson, M. Singh
Effect Of Tamoxifen On Endometrial Histology, Hormone Receptors, And Cervical Cytology: A Prospective Study With Follow-Up, Kimberly Leslie, S. Walter, K. Torkko, J. Stephens, C. Thompson, M. Singh
Kimberly K. Leslie
OBJECTIVES: Our major hypothesis for these studies was that tamoxifen's varied effects on the endometrium might be due in part to differences in effect on estrogen and progesterone receptors [ER, progesterone receptor isoform A (PRA), and progesterone receptor isoform B (PRB)]. We aimed to evaluate the changes in histology in serial endometrial biopsies (Em bx), Papanicolaou smears (Pap smears), and endometrial ultrasounds as well as changes in the expression of ER, PRA, and PRB in response to tamoxifen. We propose that understanding and correlating the dynamics of receptor expression with histologic and cytologic changes will help us better understand the …
Relationship Of Estrogen And Progesterone Receptors To Clinical Outcome In Metastatic Endometrial Carcinoma: A Gynecologic Oncology Group Study, M. Singh, R. Zaino, V. Filiaci, Kimberly Leslie
Relationship Of Estrogen And Progesterone Receptors To Clinical Outcome In Metastatic Endometrial Carcinoma: A Gynecologic Oncology Group Study, M. Singh, R. Zaino, V. Filiaci, Kimberly Leslie
Kimberly K. Leslie
INTRODUCTION: The goal of this study was to explore the relationship between the expression of hormone receptors in metastatic endometrial tumors and clinical response to daily tamoxifen citrate and intermittent weekly medroxyprogesterone acetate. STUDY DESIGN: Patients with measurable recurrent or advanced endometrial cancer were enrolled on a clinical trial, Gynecologic Oncology Group Study 119. A pretreatment tumor biopsy was obtained and subjected to immunohistochemical analyses. Estrogen receptor-alpha (ER-alpha) and progesterone receptor (PR) were assessed on frozen tissues, and PR isoforms A and B were detected on fixed tissues. The receptors were scored using a semi-quantitative HSCORE, with a cut off …
Progesterone: The Ultimate Endometrial Tumor Suppressor, S. Yang, K. Thiel, Kimberly Leslie
Progesterone: The Ultimate Endometrial Tumor Suppressor, S. Yang, K. Thiel, Kimberly Leslie
Kimberly K. Leslie
The uterine endometrium is exquisitely sensitive to steroid hormones that act through well-described nuclear receptors. Estrogen drives epithelial proliferation, and progesterone inhibits growth and causes cell differentiation. The importance of progesterone as a key inhibitor of carcinogenesis is reflected by the observation that women who ovulate and produce progesterone almost never get endometrial cancer. In this review we describe seminal research findings that define progesterone as the major endometrial tumor suppressor. We discuss the genes and diverse signaling pathways that are controlled by progesterone through progesterone receptors (PRs) and also the multiple factors that regulate progesterone/PR activity. By defining these …
Gpr30: A Novel Indicator Of Poor Survival For Endometrial Carcinoma, H. Smith, Kimberly Leslie, M. Singh, C. Qualls, C. Revankar, N. Joste, E. Prossnitz
Gpr30: A Novel Indicator Of Poor Survival For Endometrial Carcinoma, H. Smith, Kimberly Leslie, M. Singh, C. Qualls, C. Revankar, N. Joste, E. Prossnitz
Kimberly K. Leslie
OBJECTIVE: This study was undertaken to evaluate the relationship between GPR30, classical steroidal receptor expression, and clinical outcome in patients with endometrial carcinoma. STUDY DESIGN: Immunohistochemistry was used to investigate the expression of GPR30, estrogen, progesterone, epidermal growth factor receptors and Ki-67 in 47 consecutive consenting patients with endometrial carcinoma diagnosed between 1997 and 2001. Results were correlated with clinical and pathologic predictors of adverse outcome and survival. RESULTS: GPR30 correlated positively with epidermal growth factor receptor (P = .005), but negatively with progesterone (P = .05) receptor expression. GPR30 overexpression occurred more frequently in tumors with deep myometrial invasion, …
Identification Of A Novel Mechanism Of Nf-Kappab Inactivation By Progesterone Through Progesterone Receptors In Hec50co Poorly Differentiated Endometrial Cancer Cells: Induction Of A20 And Abin-2, S. Davies, Donghai Dai, I. Feldman, G. Pickett, Kimberly Leslie
Identification Of A Novel Mechanism Of Nf-Kappab Inactivation By Progesterone Through Progesterone Receptors In Hec50co Poorly Differentiated Endometrial Cancer Cells: Induction Of A20 And Abin-2, S. Davies, Donghai Dai, I. Feldman, G. Pickett, Kimberly Leslie
Kimberly K. Leslie
OBJECTIVE: Nuclear factor kappa B (NFkappaB) is a strong anti-apoptotic factor, which is constitutively active in human endometrial cancer cells. Progesterone is the principal growth inhibitory hormone in the endometrial epithelium and promotes apoptosis. To identify the pathways through which progesterone controls NFkappaB function, we explored its genomic and non-genomic effects in endometrial cancer cells. METHODS: PR-negative Hec50co endometrial cancer cells were engineered to express high levels of the A or B isoform of PR (PRA or PRB) by adenoviral infection. Cells were treated with progesterone or vehicle alone, and RNA was isolated. Affymetrix microarrays were performed and transcriptional control …
Progesterone Inhibits Human Endometrial Cancer Cell Growth And Invasiveness: Down-Regulation Of Cellular Adhesion Molecules Through Progesterone B Receptors, Donghai Dai, D. Wolf, E. Litman, M. White, Kimberly Leslie
Progesterone Inhibits Human Endometrial Cancer Cell Growth And Invasiveness: Down-Regulation Of Cellular Adhesion Molecules Through Progesterone B Receptors, Donghai Dai, D. Wolf, E. Litman, M. White, Kimberly Leslie
Kimberly K. Leslie
Progesterone is a critical steroid hormone that controls cell proliferation and differentiation in the female reproductive tract. Progesterone acts through two nuclear receptor isoforms, progesterone receptors A and B (PRA and PRB, respectively), each with unique cellular effects. Loss of PRB has recently been linked to the development of poorly differentiated endometrial tumors, a lethal form of cancer. To study the molecular effects of progesterone, progesterone receptors were introduced into Hec50co endometrial cancer cells by adenoviral vectors encoding either PRA or PRB. Progesterone induced the cyclin-dependent kinase inhibitors p21 and p27, thereby significantly reducing the percentage of proliferating cells. Cancer …
Oral Contraceptives And Skin Cancer: Is There A Link?, Kimberly Leslie, E. Espey
Oral Contraceptives And Skin Cancer: Is There A Link?, Kimberly Leslie, E. Espey
Kimberly K. Leslie
The skin expresses estrogen, progesterone, and androgen receptors. In the presence of steroid hormones, such as those contained in oral contraceptives, the skin likely responds to hormonal signals that control the cell cycle, apoptosis, DNA replication, and other cellular functions. Some estrogen-responsive pathways have the potential to promote tumor development, including the augmentation of epidermal growth factor signaling, the expression of proto-oncogenes, and inhibition of apoptosis. The question of whether oral contraceptives increase the risk for the development of skin cancer, particularly melanoma, is still an area of concern. This paper reviews the available evidence, the bulk of which suggests …
Breast Cancer And Pregnancy, Kimberly Leslie, C. Lange
Breast Cancer And Pregnancy, Kimberly Leslie, C. Lange
Kimberly K. Leslie
This article addresses a challenging diagnostic and treatment dilemma encountered in the care of pregnant women-breast cancer. The treatment of a breast cancer is significantly affected by an ongoing pregnancy and may result in an increased risk for a poor outcome in the mother. The definition, incidence, mechanism, diagnosis, and treatment of breast cancer associated with pregnancy and the normal physiologic and endocrine changes in the breast during pregnancy that contribute to the difficulty encountered by practitioners in diagnosing and treating the disorder are reviewed. The risks associated with pregnancy after breast cancer treatment and the effect of pregnancy on …
Hormones And Receptors In Endometrial Cancer, David Bender, Thomas Buekers, Kimberly Leslie
Hormones And Receptors In Endometrial Cancer, David Bender, Thomas Buekers, Kimberly Leslie
Kimberly K. Leslie
The uterine endometrium is exquisitely sensitive to hormones, in particular estrogen and progesterone and to a lesser extent androgens and glucocorticoids. These hormones tightly regulate the complex functioning of the female reproductive tract and are intimately involved in controlling the growth, development, and remodeling of reproductive tissues as well as the cyclic changes that occur during the menstrual cycle. Steroids function by binding to nuclear receptor proteins that act as transcription factors to modulate the expression of genes, though many non-genomic effects for steroids have also been described. An imbalance of the hormones leads to cancer. In particular, endometrial carcinogenesis …