Molecular analysis of the vaginal response to estrogens in the ovariectomized rat and postmenopausal woman

<p>Abstract</p> <p>Background</p> <p>Vaginal atrophy (VA) is the thinning of the vaginal epithelial lining, typically the result of lowered estrogen levels during menopause. Some of the consequences of VA include increased susceptibility to bacterial infection, pain during sexual intercourse, and vaginal burning or itching. Although estrogen treatment is highly effective, alternative therapies are also desired for women who are not candidates for post-menopausal hormone therapy (HT). The ovariectomized (OVX) rat is widely accepted as an appropriate animal model for many estrogen-dependent responses in humans; however, since reproductive biology can vary significantly between mammalian systems, this study examined how well the OVX rat recapitulates human biology.</p> <p>Methods</p> <p>We analyzed 19 vaginal biopsies from human subjects pre and post 3-month 17β-estradiol treated by expression profiling. Data were compared to transcriptional profiling generated from vaginal samples obtained from ovariectomized rats treated with 17β-estradiol for 6 hrs, 3 days or 5 days. The level of differential expression between pre- vs. post- estrogen treatment was calculated for each of the human and OVX rat datasets. Probe sets corresponding to orthologous rat and human genes were mapped to each other using NCBI Homologene.</p> <p>Results</p> <p>A positive correlation was observed between the rat and human responses to estrogen. Genes belonging to several biological pathways and GO categories were similarly differentially expressed in rat and human. A large number of the coordinately regulated biological processes are already known to be involved in human VA, such as inflammation, epithelial development, and EGF pathway activation.</p> <p>Conclusion</p> <p>At the transcriptional level, there is evidence of significant overlap of the effects of estrogen treatment between the OVX rat and human VA samples.</p

PenQuest Volume 2, Number 1

Table of Contents for this Volume: Untitled by Janet Collins Untitled by Judy Gozdur Last Hour of Light by Susan Reed Untitled by Judy Godzur Untitled by Rick Wagner Untitled by Carol Groover Untitled by R. Wagner Only in the Portico by Linda Banicki Untitled by Helen Hagadorn Private Place, Pubic Place by David Reed Untitled by Tammy Hutchinson Untitled by Tammy Hutchinson Madison Knights by Susan Reed Untitled by Sissy Crabtree The Price by Sandra Coleman Untitled by Ann Harrington Invasion of Privacy by Mark Touchton Untitled by Bruce Warner Untitled by Tom Schifanella Untitled by Tammy Hutchinson Bloodwork by Laura Jo Last Untitled by David Whitsett Burial Instructions by Bill Slaughter Untitled by S. Trevett PenQuest Interview: Joe Haldeman by David Reed Her Name Came from the Sea by Richard L. Ewart Untitled by V. Williams In the Woodshed by R. E. Mallery Untitled by Modesta Matthews Untitled by David Olson Illumination by E. Allen Tilley Untitled by Joseph Avanzini Everywoman by Laura Jo Last Untitled by Beth Goeckel Believe Me by Donna Kaluzniak Untitled by Judy Gozdur Untitled by Judy Gozdur Unicorn by David Reed Untitled by Susan Reed untitled by Paul Cramer Unititled by Lucinda Halsema The Violin by Richard L. Ewart Untitled by Maria Barry Untitled by Roger Whitt Jr. Haiku by Lori Nasrallah Rhymer’s Revolt by R. E. Mallery Untitled by Valerie William

Clinical and Preclinical Advances in Gastroenteropancreatic Neuroendocrine Tumor Therapy

The molecular events leading to gastroenteropancreatic neuroendocrine tumor (GEP-NET) formation are largely unknown. Over the past decades, systemic chemotherapies have been replaced by therapies directed at particular molecular targets such as the somatostatin receptors, mTOR complexes or proangiogenic molecules. These approaches have demonstrated some success in subtypes of this heterogeneous tumor group, but responses are still widely varied. This review highlights the clinical trials ongoing for neuroendocrine tumors (NETs) and includes emerging immunotherapy, which holds great promise for NETs based on successes in other tumor types. Current avenues of preclinical research, including Notch and PI3K/AKT, will lead to additional targeted therapies based on genome-wide studies that have cast a wide net in the search for driver mutations. Future preclinical and clinical investigations are required to identify those mutations predictive of therapeutic response or disease progression. Results of current clinical trials outlined here will better inform patient management with respect to agent selection, timing, duration and combination therapy in the treatment of NETs

Breast Cancer Stem Cells

Breast cancer stem cells (BCSC) have been implicated in tumor initiation, progression, metastasis, recurrence, and resistance to therapy. The origins of BCSCs remain controversial due to tumor heterogeneity and the presence of such small side populations for study, but nonetheless, cell surface markers and their correlation with BCSC functionality continue to be identified. BCSCs are driven by persistent activation of developmental pathways, such as Notch, Wnt, Hippo, and Hedgehog and new treatment strategies that are aimed at these pathways are in preclinical and clinical development

The Cell Death Inhibitor ARC Is Induced in a Tissue-Specific Manner by Deletion of the Tumor Suppressor Gene Men1, but Not Required for Tumor Development and Growth.

Multiple endocrine neoplasia type 1 (MEN1) is a genetic disorder characterized by tissue-specific tumors in the endocrine pancreas, parathyroid, and pituitary glands. Although tumor development in these tissues is dependent upon genetic inactivation of the tumor suppressor Men1, loss of both alleles of this gene is not sufficient to induce these cancers. Men1 encodes menin, a nuclear protein that influences transcription. A previous ChIP on chip analysis suggested that menin binds promoter sequences of nol3, encoding ARC, which is a cell death inhibitor that has been implicated in cancer pathogenesis. We hypothesized that ARC functions as a co-factor with Men1 loss to induce the tissue-restricted distribution of tumors seen in MEN1. Using mouse models that recapitulate this syndrome, we found that biallelic deletion of Men1 results in selective induction of ARC expression in tissues that develop tumors. Specifically, loss of Men1 in all cells of the pancreas resulted in marked increases in ARC mRNA and protein in the endocrine, but not exocrine, pancreas. Similarly, ARC expression increased in the parathyroid with inactivation of Men1 in that tissue. To test if ARC contributes to MEN1 tumor development in the endocrine pancreas, we generated mice that lacked none, one, or both copies of ARC in the context of Men1 deletion. Studies in a cohort of 126 mice demonstrated that, although mice lacking Men1 developed insulinomas as expected, elimination of ARC in this context did not significantly alter tumor load. Cellular rates of proliferation and death in these tumors were also not perturbed in the absence of ARC. These results indicate that ARC is upregulated by loss Men1 in the tissue-restricted distribution of MEN1 tumors, but that ARC is not required for tumor development in this syndrome

Generalized deletion of ARC in Pdx1-Cre; Men1 f/f mice does not significantly change islet tumor load.

<p>A) Body weights (both genders). B) Fasting plasma insulin concentrations (both genders). C) Fasting blood glucose concentrations (both genders). D) and E) Fasting insulin and glucose measurements in females. F) and G) Fasting insulin and glucose measurements in males. * P < 0.05 Pdx1-Cre; Men1 f/f; ARC -/- versus Pdx1-Cre; Men1 f/f; ARC +/+.</p

Deletion of <i>Men1</i> in the parathyroid hormone-secreting cells increases ARC mRNA expression.

<p>A) Parathyroid tissue (inside blue circle) from 12 m old PTH-Cre; Men1 f/f mouse subsequently subjected to laser microdissection. B) qRT-PCR for ARC in parathyroid tissue from the indicated genotypes. N = 3 mice per genotype. **** P < 0.0001 versus PTH-Cre. C) qRT-PCR for ARC in liver tissue from the indicated genotypes. Each bar in panel C represents mRNA samples isolated from a single mouse.</p

Deletion of <i>Men1</i> in all pancreatic cells increases ARC mRNA levels preferentially in islets.

<p>A) Endocrine (Endo) and exocrine (Exo) pancreatic tissue from 12 m old mice before (top) and after (bottom) laser capture microdissection. B) qRT-PCR for ARC in mouse pancreatic endocrine tissue from the indicated genotypes. C) qRT-PCR for ARC in mouse pancreatic exocrine tissue from the indicated genotypes. N = 3 mice per genotype. ** P < 0.01 versus Pdx1-Cre. *** P < 0.001 versus Pdx1-Cre, ^## P < 0.01 versus Men1 f/f, ^#### P < 0.0001 versus Men1 f/f.</p