scholarly journals Androgen actions via androgen receptor promote PTEN inactivation induced uterine cancer

2015 ◽  
Vol 22 (5) ◽  
pp. 687-701 ◽  
Author(s):  
Jaesung (Peter) Choi ◽  
Reena Desai ◽  
Yu Zheng ◽  
Mu Yao ◽  
Qihan Dong ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Uterine Cancer ◽  
Serum Testosterone ◽  
Cowden Syndrome ◽  
Corpora Lutea ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Uterine Growth ◽  
Uterine Cancers ◽  
Reproductive Cancers

Haploinsufficient inactivating phosphatase and tensin homolog (Pten) mutations cause Cowden syndrome, an autosomal dominant risk genotype for hormone dependent reproductive cancers. As androgen actions mediated via the androgen receptor (AR) supports uterine growth and may modify uterine cancer risk, we hypothesized that a functional AR may increase PTEN inactivation induced uterine cancer. To test the hypothesis, we compared the PTEN knockout (PTENKO) induced uterine pathology in heterozygous PTENKO and combined heterozygous PTEN and complete AR knockout (PTENARKO) female mice. PTENKO induced uterine pathology was significantly reduced by AR inactivation with severe macroscopic uterine pathology present in 21% of PTENARKO vs 46% of PTENKO at a median age of 45 weeks. This could be due to reduced stroma ERα expression in PTENARKO compared to PTENKO uterus, while AR inactivation did not modify PTEN or P-AKT levels. Unexpectedly, while progesterone (P4) is assumed protective in uterine cancers, serum P4was significantly higher in PTENKO females compared to WT, ARKO, and PTENARKO females consistent with more corpora lutea in PTENKO ovaries. Serum testosterone and ovarian estradiol were similar between all females. Hence, our results demonstrated AR inactivation mediated protection against PTENKO induced uterine pathology and suggests a potential role for antiandrogens in uterine cancer prevention and treatment.

scholarly journals Glandular epithelial AR inactivation enhances PTEN deletion-induced uterine pathology

2016 ◽  
Vol 23 (5) ◽  
pp. 377-390 ◽  
Author(s):  
Jaesung (Peter) Choi ◽  
Yu Zheng ◽  
David J Handelsman ◽  
Ulla Simanainen
Keyword(s):  
Estrogen Receptor Alpha ◽  
Uterine Cancer ◽  
Intraepithelial Neoplasia ◽  
Glandular Epithelium ◽  
Wild Type ◽  
Double Knockout ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Pten Deletion ◽  
Uterine Growth

Phosphatase and tensin homolog (PTEN) deletion induces uterine pathology, whereas androgen actions via androgen receptor (AR) support uterine growth and therefore may modify uterine cancer risk. We hypothesized that the androgen actions mediated via uterine glandular epithelial AR could modify PTEN deletion-induced uterine pathology. To test our hypothesis, we developed uterine glandular epithelium-specific PTEN and/or AR knockout mouse models comparing the uterine pathology among wild-type (WT), glandular epithelium-specific AR inactivation (ugeARKO), PTEN deletion (ugePTENKO), and the combined PTEN and AR knockout (ugePTENARKO) female mice. The double knockout restricted to glandular epithelium showed that AR inactivation enhanced PTEN deletion-induced uterine pathology with development of intraepithelial neoplasia by 20 weeks of age. In ugePTENARKO, 6/10 (60%) developed intraepithelial neoplasia, whereas 3/10 (30%) developed only glandular hyperplasia in ugePTENKO uterus. No uterine pathology was observed in WT (n=8) and ugeARKO (n=7) uteri. Uterine weight was significantly (P=0.002) increased in ugePTENARKO (374±97 mg (mean±s.e.)) compared with WT (97±6 mg), ugeARKO (94±12 mg), and ugePTENKO (205±33 mg). Estrogen receptor alpha (ERα) and P-AKT expression was modified by uterine pathology but did not differ between ugePTENKO and ugePTENARKO, suggesting that its expressions are not directly affected by androgens. However, progesterone receptor (PR) expression was reduced in ugePTENARKO compared to ugePTENKO uterus, suggesting that PR expression could be regulated by glandular epithelial AR inactivation. In conclusion, glandular epithelial AR inactivation (with persistent stromal AR action) enhanced PTEN deletion-induced uterine pathology possibly by downregulating PR expression in the uterus.

scholarly journals Screening for germline phosphatase and tensin homolog-mutations in suspected Cowden syndrome and Cowden syndrome-like families among uterine cancer patients

2015 ◽  
Vol 9 (4) ◽  
pp. 1782-1786 ◽  
Author(s):  
GERASIMOS TZORTZATOS ◽  
CHRISTOS ARAVIDIS ◽  
ANNIKA LINDBLOM ◽  
MIRIAM MINTS ◽  
EMMA THAM
Keyword(s):  
Cancer Patients ◽  
Uterine Cancer ◽  
Cowden Syndrome ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog

scholarly journals Subfertile Female Androgen Receptor Knockout Mice Exhibit Defects in Neuroendocrine Signaling, Intraovarian Function, and Uterine Development But Not Uterine Function

Endocrinology ◽  
2009 ◽  
Vol 150 (7) ◽  
pp. 3274-3282 ◽  
Author(s):  
K. A. Walters ◽  
K. J. McTavish ◽  
M. G. Seneviratne ◽  
M. Jimenez ◽  
A. C. McMahon ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Knockout Mice ◽  
Growth And Development ◽  
Direct Evidence ◽  
Female Fertility ◽  
Corpora Lutea ◽  
Wild Type ◽  
Uterine Growth ◽  
Uterine Function ◽  
Uterine Development

Female androgen receptor (AR) knockout mice (AR−/−) generated by an in-frame Ar exon 3 deletion are subfertile, but the mechanism is not clearly defined. To distinguish between extra- and intraovarian defects, reciprocal ovarian transplants were undertaken. Ovariectomized AR−/− hosts with wild-type (AR+/+) ovary transplants displayed abnormal estrus cycles, with longer cycles (50%, P < 0.05), and 66% were infertile (P < 0.05), whereas AR+/+ hosts with either AR−/− or surgical control AR+/+ ovary transplants displayed normal estrus cycles and fertility. These data imply a neuroendocrine defect, which is further supported by increased FSH (P <0.05) and estradiol (P <0.05), and greater LH suppressibility by estradiol in AR−/− females at estrus (P <0.05). Additional intraovarian defects were observed by the finding that both experimental transplant groups exhibited significantly reduced pups per litter (P < 0.05) and corpora lutea numbers (P < 0.05) compared with surgical controls. All groups exhibited normal uterine and lactation functions. AR−/− uteri were morphologically different from AR+/+ with an increase in horn length (P < 0.01) but a reduction in uterine diameter (P < 0.05), total uterine area (P < 0.05), endometrial area (P < 0.05), and myometrial area (P < 0.01) at diestrus, indicating a role for AR in uterine growth and development. Both experimental transplant groups displayed a significant reduction in uterine diameter (P < 0.01) compared with transplanted wild-type controls, indicating a role for both AR-mediated intraovarian and intrauterine influences on uterine physiology. In conclusion, these data provide direct evidence that extraovarian neuroendocrine, but not uterine effects, as well as local intraovarian AR-mediated actions are important in maintaining female fertility, and a disruption of AR signaling leads to altered uterine development.

scholarly journals Cowden Syndrome: report of a case and brief review of literature

2013 ◽  
Vol 88 (6 suppl 1) ◽  
pp. 52-52 ◽  
Author(s):  
Ana Carolina Souza Porto ◽  
Elisabeth Roider ◽  
Thomas Ruzicka
Keyword(s):  
Cell Cycle Progression ◽  
Cowden Syndrome ◽  
Pten Gene ◽  
Benign Tumors ◽  
Cutaneous Lesions ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Increased Risk ◽  
History Of ◽  
Risk Of Cancer

We present the case of a female patient with facial cutaneous lesions, a cobblestone-like pattern of the oral mucosa, and verruciform lesions on the hand since her youth. She reported a history of breast cancer, endometrial cancer, melanoma and multiple benign tumors and cysts. PTEN gene analysis was performed and confirmed Cowden Syndrome, a rare genodermatosis with an autosomal dominant pattern of inheritance, characterized by multiple hamartomas. The phosphatase and tensin homolog (PTEN) gene negatively regulates cell proliferation and cell cycle progression. Loss of PTEN function contributes to an increased risk of cancer. We emphasize the importance of early detection and accurate management of Cowden Syndrome.

scholarly journals The Skin in Cowden Syndrome

2021 ◽  
Vol 8 ◽  
Author(s):  
Agnes Lim ◽  
Joanne Ngeow
Keyword(s):  
Targeted Therapies ◽  
Autosomal Dominant ◽  
Malignant Tumors ◽  
Skin Lesions ◽  
Cowden Syndrome ◽  
Differential Diagnoses ◽  
Phosphatase And Tensin Homolog ◽  
Autosomal Dominant Condition ◽  
Tensin Homolog ◽  
Dominant Condition

Cowden syndrome (CS) is an autosomal dominant condition caused by mutations in the phosphatase and tensin homolog (PTEN) gene, and is characterized by multiple hamartomas and a predisposition to malignant tumors. Characteristic skin lesions include trichilemmomas, acral keratosis, mucocutaneous neuromas, oral papillomas, and penile macules, and are often the first clues to the underlying diagnosis. Here, we discuss the mucocutaneous manifestations of CS, differential diagnoses of genetic causes of each cutaneous finding, genetic analyses for patients with skin manifestations, management of patients with CS, and potential new targeted therapies for CS.

scholarly journals Testicular pain as a presentation of Cowden syndrome

2011 ◽  
Vol 93 (5) ◽  
pp. e51-e52 ◽  
Author(s):  
Hussain M Alnajjar ◽  
Arun Sahai ◽  
Andrew Keane ◽  
Stephen Gordon
Keyword(s):  
Cowden Syndrome ◽  
Limited Information ◽  
Nodular Goitre ◽  
Phosphatase And Tensin Homolog ◽  
Testicular Pain ◽  
Left Testicle ◽  
Tensin Homolog ◽  
History Of ◽  
Multiple Hamartoma Syndrome

This case report outlines a rare case in Cowden syndrome and PTEN (phosphatase and tensin homolog) gene mutation and how it may initially present to the urologist. Also known as multiple hamartoma syndrome, Cowden syndrome is a rare disorder associated with the development of several types of malignancy. A thorough search of the literature reveals limited information regarding its presentation to the urologist. We report the case of a 47-year-old gentleman with a two-week history of worsening pain and swelling in his left testicle. Testicular ultrasound revealed multiple hyperechoic areas bilaterally suggestive of multiple lipomas. He was also found to have macrocephaly, freckling of his glans and foreskin and an enlarged nodular goitre and the geneticist diagnosed Cowden syndrome. The disease is discussed and guidance is given on its management and follow up.

PTEN-Related Overgrowth Syndromes

2019 ◽  
pp. 163-186
Author(s):  
Lamis Yehia ◽  
Joanne Ngeow ◽  
Charis Eng
Keyword(s):  
Autosomal Dominant ◽  
Vascular Malformations ◽  
Treatment Strategies ◽  
Suppressor Gene ◽  
Cowden Syndrome ◽  
Loss Of Function ◽  
Autosomal Dominant Disorder ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Cell Growth And Proliferation

Individuals carrying germline mutations in the tumor suppressor gene phosphatase and tensin homolog (PTEN) may present with diverse clinical phenotypes, grouped under the term of PTEN hamartoma tumor syndrome (PHTS). This chapter will focus on two PHTS conditions: Bannayan-Riley-Ruvalcaba syndrome and Cowden syndrome. The first condition is an autosomal dominant disorder characterized by macrocephaly, intestinal hamartomatous polyposis, vascular malformations, lipomas, hemangiomas, and genital freckling. Other features include developmental delay, hypotonia, and scoliosis. Cowden syndrome is also an autosomal dominant disorder, mainly characterized by multiple hamartomas and high risk of breast, thyroid, and other cancers. PTEN encodes the main inhibitor of the PI3K-AKT pathway, regulating cell growth and proliferation, and protein synthesis. Therefore, germline loss-of-function mutations in this gene lead to excessive growth, particularly affecting connective tissues. Detection of PTEN mutations is critical for clinical management and treatment strategies.

scholarly journals A Pediatric Case of Cowden Syndrome with Graves’ Disease

2017 ◽  
Vol 2017 ◽  
pp. 1-4
Author(s):  
Cláudia Patraquim ◽  
Vera Fernandes ◽  
Sofia Martins ◽  
Ana Antunes ◽  
Olinda Marques ◽  
...  
Keyword(s):  
Treatment Options ◽  
Antithyroid Drug ◽  
Human Tumor ◽  
Suppressor Gene ◽  
Cowden Syndrome ◽  
Graves Disease ◽  
Multisystem Disorder ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Coarse Facies

Cowden syndrome (CS) is a rare dominantly inherited multisystem disorder, characterized by an extraordinary malignant potential. In 80% of cases, the human tumor suppressor gene phosphatase and tensin homolog (PTEN) is mutated. We present a case of a 17-year-old boy with genetically confirmed CS and Graves’ disease (GD). At the age of 15, he presented with intention tremor, palpitations, and marked anxiety. On examination, he had macrocephaly, coarse facies, slight prognathism, facial trichilemmomas, abdominal keratoses, leg hemangioma, and a diffusely enlarged thyroid gland. He started antithyroid drug (ATD) therapy with methimazole and, after a 2-year treatment period without achieving a remission status, a total thyroidectomy was performed. Diagnosis and management of CS should be multidisciplinary. Thyroid disease is frequent, but its management has yet to be fully defined. The authors present a case report of a pediatric patient with CS and GD and discuss treatment options.

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