Publications by authors named "Keely M McNamara"

31 Publications

Histological and immunohistochemical characteristics and status studied by FISH in six incidentally detected cases of well-differentiated papillary mesothelioma of the peritoneum.

Indian J Pathol Microbiol 2021 Apr-Jun;64(2):277-281

Division of Pathology, Tohoku Medical and Pharmaceutical University, Sendai, Japan.

Well-differentiated papillary mesothelioma (WDPM) is an uncommon mesothelial neoplasm, which is generally regarded as benign or indolent in terms of its clinical behavior. However, details about WDPM have remained relatively unknown. Therefore, in this study, we examined six incidentally detected cases of WDPM of the peritoneum. All six cases were surgically excised, without any additional therapeutic measures. None of the cases showed recurrence. All six cases presented single lesions and the tumor sizes ranged from 2 to 10 mm. Histologically, all six cases exhibited papillary proliferation of cytologically bland mesothelial cells with a fibroconnective tissue core. One of the cases (Case 6) presented small invasive foci in the stalk. The tumor cells were immunohistochemically positive for mesothelial markers and negative for GLUT-1, p53, and CD146. The Ki-67 labeling index of the tumor cells was lower than 5% at the hot spots. All samples were BAP1-positive. None of the samples presented p16 homozygous deletion, as assessed by fluorescence in situ hybridization (FISH). None of the patients deceased due to WDPM. However, in Case 3, death occurred due to pancreatic cancer. The results of this study indicate the importance of analyzing immunohistochemical markers and p16 status to diagnose WDPM accurately.
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http://dx.doi.org/10.4103/IJPM.IJPM_111_20DOI Listing
April 2021

Androgen Receptor Is a Non-canonical Inhibitor of Wild-Type and Mutant Estrogen Receptors in Hormone Receptor-Positive Breast Cancers.

iScience 2019 Nov 23;21:341-358. Epub 2019 Oct 23.

Department of Medicine, College of Medicine, University of Tennessee Health Science Center, 19, S. Manassas, Room 120, Memphis, TN 38103, USA; West Cancer Center, Memphis, TN, USA. Electronic address:

Sustained treatment of estrogen receptor (ER)-positive breast cancer with ER-targeting drugs results in ER mutations and refractory unresponsive cancers. Androgen receptor (AR), which is expressed in 80%-95% of ER-positive breast cancers, could serve as an alternate therapeutic target. Although AR agonists were used in the past to treat breast cancer, their use is currently infrequent due to virilizing side effects. Discovery of tissue-selective AR modulators (SARMs) has renewed interest in using AR agonists to treat breast cancer. Using translational models, we show that AR agonist and SARM, but not antagonist, inhibit the proliferation and growth of ER-positive breast cancer cells, patient-derived tissues, and patient-derived xenografts (PDX). Ligand-activated AR inhibits wild-type and mutant ER activity by reprogramming the ER and FOXA1 cistrome and rendering tumor growth inhibition. These findings suggest that ligand-activated AR may function as a non-canonical inhibitor of ER and that AR agonists may offer a safe and effective treatment for ER-positive breast cancer.
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http://dx.doi.org/10.1016/j.isci.2019.10.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889594PMC
November 2019

Therapeutic advances in hormone-dependent cancers: focus on prostate, breast and ovarian cancers.

Endocr Connect 2019 Feb;8(2):R10-R26

University of Tennessee Health Science Center, Memphis, Tennessee, USA.

Hormonal cancers affect over 400,000 men and women and contribute collectively to over 100,000 deaths in the United States alone. Thanks to advances in the understanding of these cancers at the molecular level and to the discovery of several disease-modifying therapeutics, the last decade has seen a plateauing or even a decreasing trend in the number of deaths from these cancers. These advanced therapeutics not only effectively slow the growth of hormonal cancers, but also provide an insight on how these cancers become refractory and evolve as an altogether distinct subset. This review summarizes the current therapeutic trends in hormonal cancers, with focus on prostate, breast and ovarian cancers. The review discusses the clinical drugs being used now, promising molecules that are going through various stages of development and makes some predictions on how the therapeutic landscape will shift in the next decade.
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http://dx.doi.org/10.1530/EC-18-0425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365668PMC
February 2019

In breast cancer subtypes steroid sulfatase (STS) is associated with less aggressive tumour characteristics.

Br J Cancer 2018 05 22;118(9):1208-1216. Epub 2018 Mar 22.

Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

Background: The majority of breast cancer cases are steroid dependent neoplasms, with hormonal manipulation of either CYP19/aromatase or oestrogen receptor alpha axis being the most common therapy. Alternate pathways of steroid actions are documented, but their interconnections and correlations to BC subtypes and clinical outcome could be further explored.

Methods: We evaluated selected steroid receptors (Androgen Receptor, Oestrogen Receptor alpha and Beta, Glucocorticoid Receptor) and oestrogen pathways (steroid sulfatase (STS), 17β-hydroxysteroid dehydrogenase 2 (17βHSD2) and aromatase) in a cohort of 139 BC cases from Norway. Using logistic and cox regression analysis, we examined interactions between these and clinical outcomes such as distant metastasis, local relapse and survival.

Results: Our principal finding is an impact of STS expression on the risk for distant metastasis (p<0.001) and local relapses (p <0.001), HER2 subtype (p<0.015), and survival (p<0.001). The suggestion of a beneficial effect of alternative oestrogen synthesis pathways was strengthened by inverted, but non-significant findings for 17βHSD2.

Conclusions: Increased intratumoural metabolism of oestrogens through STS is associated with significantly lower incidence of relapse and/or distant metastasis and correspondingly improved prognosis. The enrichment of STS in the HER2 overexpressing subtype is intriguing, especially given the possible role of HER-2 over-expression in endocrine resistance.
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http://dx.doi.org/10.1038/s41416-018-0034-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943586PMC
May 2018

Possible roles for glucocorticoid signalling in breast cancer.

Mol Cell Endocrinol 2018 05 4;466:38-50. Epub 2017 Jul 4.

Department of Anatomical Pathology, School of Graduate Medicine, Tohoku University, Sendai, Japan.

Our understanding of breast cancer biology, and our ability to manipulate breast cancers have grown exponentially in the last 20 years. Much of that expansion has focused on the roles of steroids in driving these neoplasms. Initially this research focused on estrogens and progesterone receptors, and more recently on androgen actions in breast cancers. This review aims to make the case for glucocorticoids as the next essential steroid subclass that contributes significantly to our understanding of steroidogenic regulation of these neoplasms. Glucocorticoids have the potential to play multiple roles in the regulation of breast cancers including their control of cellular differentiation, apoptosis and proliferation. Beyond this they also act as a master integrator of organ homeostats in relation to such as circadian rhythms and stress responses. Therefore a better understanding of glucocorticoids and breast cancer could help to explain some of the epidemiological links between circadian disruption and/or stress and breast cancer development. Finally glucocorticoids are currently used during chemotherapeutic treatment in breast cancer therapy and yet results of various studies suggest that this may have an adverse impact on treatment success. This review aims to summarise the current evidence for glucocorticoids as actors in breast cancer and then suggest future essential approaches in order to determine the roles of glucocorticoids in this disease.
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http://dx.doi.org/10.1016/j.mce.2017.07.004DOI Listing
May 2018

Serotonin receptor 4 (5-hydroxytryptamine receptor Type 4) regulates expression of estrogen receptor beta and cell migration in hormone-naive prostate cancer.

Indian J Pathol Microbiol 2017 Jan-Mar;60(1):33-37

Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Background: Estrogens are considered to potentially play some roles in the development and progression of prostate cancer through estrogen receptor beta (ERβ). However, additional factors which could influence the clinical outcome of the patients through modulating these steroid signalings have also been proposed. Among these, increased expression of serotonin receptor especially that of 5-hydroxytryptamine receptor Type 4 (5-HTR4) has been recently proposed to be involved in autocrine/paracrine mechanisms of castration-resistant prostate cancer, but the presence and clinical significance of 5-HTR4 in hormone-naive prostate cancer (HNPC) and its interaction with hormonal signaling pathways have remained virtually unknown.

Materials And Methods: We evaluated the status of 5-HTR4 in 112 human HNPC cases (acinar adenocarcinoma) using immunohistochemistry and correlated the findings with clinicopathological features of individual patients and the status of androgen receptor (AR) and ERβ. To further elucidate its underlying mechanisms, androgen-dependent human prostate carcinoma cell line, LNCaP, expressing 5-HTR4, was treated by 5-HTR4 agonist.

Results: 5-HTR4 immunoreactivity was detected in 34% of prostate cancer cases examined (38/112) and was significantly correlated with the status of ERβ but not with that of AR and other clinicopathological factors of the patients. Results of in vitro studies demonstrated that 24 h incubation with 5-HTR4 agonist (10 nM) increased the expression level of ERβ messenger RNA compared to controls. 5-HTR4 agonist (100 nM) significantly inhibited LNCaP carcinoma cell migration (P < 0.05).

Conclusion: Results of our present study indicated that 5-HTR4 signaling upregulated ERβ expression in HNPCs and could impact on biological processes in HNPC.
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http://dx.doi.org/10.4103/0377-4929.200022DOI Listing
March 2017

Virilism and Ectopic Expression of HSD17B5 in Mature Cystic Teratoma.

Tohoku J Exp Med 2017 02;241(2):125-129

Department of Endocrinology and Diabetes, Japan Community Health care Organization Chukyo Hospital.

Mature cystic teratoma (MCT) is rarely involved in the overproduction of steroid hormones in contrast to sex cord stromal tumors. A 31-year-old woman visited our hospital with hirsutism, hoarseness, and hair loss from the scalp. Serum testosterone and free-testosterone levels were 7.3 ng/ml and 2.3 pg/ml, respectively, which were markedly in excess of the age adjusted female standard levels. Basal blood levels of steroid hormones and serum levels of 17-hydroxyprogesterone at 1 h after intravenous injection of adrenocorticotropic hormone demonstrated that 21-hydroxylase deficiency was not the underlying cause of her virilization. A subsequent chromosomal test with G-banding revealed a karyotype of 46XX. Magnetic resonance imaging revealed a mass in the left ovary, which was subsequently diagnosed as MCT. Detailed pathological analysis of the tumor indicated that it was comprised of skin components, sweat glands, with hair and fat texture, glandular epithelium and fibrous connective tissue, consistent with the characteristic composition of MCT. Immunohistochemical analysis demonstrated marked immunoreactivity of 17beta-hydroxysteroid dehydrogenase (HSD17B5), an enzyme that can convert androstenedione to testosterone. Following surgical removal of the tumor, testosterone and free testosterone levels were markedly decreased (0.3 ng/ml and 0.4 pg/ml, respectively) and other symptoms abated. In conclusion, this is the first report of an ovarian MCT associated with clinical virilization caused by the ectopic production of testosterone possibly because of an overexpression of intratumoral HSD17B5.
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http://dx.doi.org/10.1620/tjem.241.125DOI Listing
February 2017

Estrogen receptor β in Merkel cell carcinoma: its possible roles in pathogenesis.

Hum Pathol 2016 10 23;56:128-33. Epub 2016 Jun 23.

Department of Pathology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.

Sex steroids have been postulated to influence skin development and functions as well as its pathogenesis. MCC occurs in both sexes; however, the specific differences in pathogenesis among sexes have yet to be conclusively defined. The detailed status of sex steroid receptors (AR, PRA and PRB, and ERα, ERβ) are also unknown in MCC patients. We first immunolocalized sex steroid receptors and compared the results with immunolocalization of relevant transcription factors including SOX2, FOXA1, and Bcl-2 and Ki-67 in 18 cases of MCCs. AR, PRA, PRB, ERα, ERβ, Bcl-2, SOX2, and FOXA1 immunoreactivity was evaluated by using the modified H score method, and Ki-67 was quantified using labeling index. ERβ immunoreactivity was markedly present in all the cases of MCC examined, with relatively weak immunoreactivity of ERα, AR, PRA, and PRB. The status of ERβ immunoreactivity was also significantly correlated with Ki-67 labeling index and Bcl-2 score. These results demonstrated that ERβ could be associated with regulation of both cell proliferation and apoptosis in MCCs.
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http://dx.doi.org/10.1016/j.humpath.2016.06.005DOI Listing
October 2016

Androgen and breast cancer: an update.

Curr Opin Endocrinol Diabetes Obes 2016 06;23(3):249-56

Department of Anatomical Pathology, Tohoku University School of Graduate Medicine, 2-1 Seiryo-machi Aoba-Ku, Sendai, Japan.

Purpose Of Review: The review is targeted at describing the advances in our understanding of androgen actions in the breast over the last 18 months. Androgens are current 'hot topics' in breast cancer because of their potential as therapeutics in situations where we currently do not have good clinical options. This is true for both estrogen receptor alpha (ERα) negative and ERα positive cancers.

Recent Findings: The review has focused on examining associations between androgen receptor and patient prognosis and outcomes in different breast cancer subtypes. A logical extension of this is covering the timely topic of the use of androgen-directed therapy in these patients. The principle settings in which this is being considered is in ERα positive cancer with therapeutic resistance to ER-directed therapies and in ERα negative breast cancer that lack current standard targeted therapies. Finally interactions between mutations, and the potential role of androgen in the normal hierarchy of mammary cell differentiation and the relationship of this to cancer, are considered.

Summary: Androgens are firmly established as important factors across multiple breast cancer subtypes. The future challenge for basic researchers and important development for clinicians is going to be translating this understanding into effective therapeutics for the benefit of breast cancer patients.
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http://dx.doi.org/10.1097/MED.0000000000000251DOI Listing
June 2016

Prognostic significance of proline, glutamic acid, leucine rich protein 1 (PELP1) in triple-negative breast cancer: a retrospective study on 129 cases.

BMC Cancer 2015 Oct 15;15:699. Epub 2015 Oct 15.

Department of Pathology, Harbin Medical University-Daqing, No. 39 Xinyang Road, Hi-Tech Zone, Daqing, Heilongjiang, China.

Background: Triple-negative breast cancer (TNBC) is associated with an aggressive clinical course due to the lack of therapeutic targets. Therefore, identifying reliable prognostic biomarkers and novel therapeutic targets for patients with TNBC is required. Proline, glutamic acid, leucine rich protein 1 (PELP1) is a novel steroidal receptor co-regulator, functioning as an oncogene and its expression is maintained in estrogen receptor (ER) negative breast cancers. PELP1 has been proposed as a prognostic biomarker in hormone-related cancers, including luminal-type breast cancers, but its significance in TNBC has not been studied.

Methods: PELP1 immunoreactivity was evaluated using immunohistochemistry in 129 patients with TNBC. Results were correlated with clinicopathological variables including patient's age, tumor size, lymph node stage, tumor grade, clinical stage, histological type, Ki-67 LI, as well as clinical outcome of the patients, including disease-free survival (DFS) and overall survival (OS).

Results: PELP1 was localized predominantly in the nuclei of carcinoma cells in TNBC. With the exception of a positive correlation between PELP1 protein expression and lymph node stage (p = 0.027), no significant associations between PELP1 protein expression and other clinicopathological variables, including DFS and OS, were found. However, when PELP1 and Ki-67 LI were grouped together, we found that patients in the PELP1/Ki-67 double high group (n = 48) demonstrated significantly reduced DFS (p = 0.005, log rank test) and OS (p = 0.002, log rank test) than others (n = 81). Multivariable analysis supported PELP1/Ki-67 double high expression as an independent prognostic factor in patients with TNBC, with an adjusted hazard ratio of 2.020 for recurrence (95 % CL, 1.022-3.990; p = 0.043) and of 2.380 for death (95 % CL, 1.138-4.978; p = 0.021).

Conclusions: We found that evaluating both PELP1 and Ki-67 expression in TNBC could enhance the prognostic sensitivity of the two biomarkers. Therefore, we propose that PELP1/Ki-67 double high expression in tumors is an independent prognostic factor for predicting a poor outcome for patients with TNBC.
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http://dx.doi.org/10.1186/s12885-015-1694-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4608314PMC
October 2015

Androgen receptor, androgen-producing enzymes and their transcription factors in extramammary Paget disease.

Hum Pathol 2015 Nov 21;46(11):1662-9. Epub 2015 Jul 21.

Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, 980-8575 Japan.

Extramammary Paget disease (EMPD) has been known to frequently express androgen receptor (AR). Therefore, androgens could play roles in the biological behavior of Paget cells. 5α-Reductase (5α-red) types 1 and 2 and 17β-hydroxysteroid dehydrogenase type 5 (17β-HSD5) are pivotal in situ regulators of androgen production in androgen-responsive tissues including androgen-dependent neoplasms. Therefore, in this study, we immunolocalized AR, androgen-producing enzymes, and their transcription factors to assess the state of in situ androgen production and actions and its correlation of invasiveness in EMPD. We studied 51 cases of EMPD with known clinicopathological status. AR, 5α-red1, 17β-HSD5, and β-catenin immunoreactivity was evaluated by using the modified H-score method while cyclin D1, p53, forkhead box protein P1, and a proliferation marker, Ki-67, were quantified using labeling index. The mean scores of AR, 5α-red1, and 17β-HSD5 in invasive EMPD were all significantly higher than noninvasive EMPD (P < .0001). Ki-67 labeling index as well as the cyclin D1 score was also significantly higher in invasive than noninvasive lesions of EMPD. These results demonstrated that androgen receptor and androgen-producing enzymes were both associated with cell cycle regulation and subsequently the invasiveness of EMPD lesions and could also indicate those above as potential markers of invasive potentials in EMPD.
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http://dx.doi.org/10.1016/j.humpath.2015.07.007DOI Listing
November 2015

The Role of Androgen Under Normal and Pathological Conditions in Sebaceous Glands: The Possibility of Target Therapy.

Curr Mol Pharmacol 2016 ;9(4):311-319

Department of Pathology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575 Japan.

The androgen receptor plays a pivotal role in the sebaceous glands. Its primary function is to stimulate cell proliferation and differentiation in the sebaceous and its associate with acne. Previous studies have demonstrated expression of AR and steroidogenic enzymes in normal sebaceous glands and in all sebaceous disorders present evidence that androgen receptor may be a sensitive marker of sebaceous differentiation. It has been previously suggested that AR and steroidogenic enzymes immunohistochemistry may be useful particularly in identifying poorly sebaceous carcinoma. This review will provide an overview of the AR functions in the sebaceous glands and discussion of the therapeutic targets in acne and carcinoma.
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http://dx.doi.org/10.2174/1874467208666150710120217DOI Listing
October 2017

Hypoelectrolytic isoosmotic solution for infusion prevents saline-induced ultrastuructural artifacts of renal biopsy specimens.

Pathol Int 2015 Jul 29;65(7):374-8. Epub 2015 Apr 29.

Department of Pathology, Tohoku University, Sendai, Japan.

Artifacts in the process of specimen preparation are frequent in ultrastructural evaluation of renal biopsy. We hypothesized that the common practice of wrapping kidney biopsy specimens in saline-soaked gauze to prevent the drying of the specimens could be the major factor of artifacts. In this study, whole kidneys from two male Sprague-Dawley rats were used. Before fixation, fresh small cubes of kidney tissue were macerated in saline (Saline group) or hypoelectrolytic isoosmotic solution for infusion (HISI group) (Sorita T3 or SOLDEM 3A) for 10 or 30 min. Then, the specimens were processed by 1% OsO(4) in 0.1 M phosphate buffer (pH 7.4) and embedded by EPON 812 for ultramicroscopic analysis. In the Saline group, ultrastructural examination revealed swollen podocyte, swollen capillary protuberance of the mesangium into the glomerular capillary loop, tubular cells with swollen mitochondria and microvilli, and the smooth muscle cells in the arteriolar wall with marked vacuolar degeneration were detected after 10 min maceration in saline and these findings become more pronounced after 30 min maceration. However, in the HISI group, these artifacts were not identified or limited within 30 min. It is postulated that HISI solution could prevent the artifacts, and be used for soaking and wrapping instead of physiologic saline solution.
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http://dx.doi.org/10.1111/pin.12302DOI Listing
July 2015

Clinical significance of subtype classification in metastatic lymph nodes of breast cancer patients undergoing neoadjuvant chemotherapy.

Int J Biol Markers 2015 May 26;30(2):e174-83. Epub 2015 May 26.

1 Division of Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai, Miyagi - Japan.

Background: Neoadjuvant chemotherapy has been increasingly utilized in the treatment of breast cancer patients. However, there are no established surrogate markers predicting the response to subsequent adjuvant therapy and clinical outcome of patients. In particular, whether primary or lymph nodes metastasis should be evaluated for these analyses has remained unknown. Therefore, in this study, we first evaluated the differences in biomarkers between primary and metastatic cancer tissues in the patients undergoing neoadjuvant chemotherapy. We then correlated the findings with the clinical outcomes of these patients.

Methods: We examined 49 patients receiving neoadjuvant chemotherapy and subsequent surgery with lymph node metastasis. Estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2) and Ki-67 were all immunohistochemically evaluated in core needle biopsy samples from primary and metastatic tumors following chemotherapy.

Results: No statistically significant differences in these markers were detected between the primary tumor and metastatic lymph nodes following therapy, but the Ki-67 labeling index was significantly higher in metastatic lymph nodes than in primary tumor (p = 0.017). The patients associated with luminal A type carcinoma in their lymph nodes following chemotherapy demonstrated significantly better clinical outcomes (disease-free survival: p = 0.0045, overall survival: p = 0.0006) than those who were not.

Conclusion: These data indicate that subtype classification following chemotherapy, in the metastatic lymph nodes rather than primary tumor could predict long-term outcomes of patients undergoing neoadjuvant chemotherapy.
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http://dx.doi.org/10.5301/jbm.5000128DOI Listing
May 2015

Steroidogenic enzymes, their related transcription factors and nuclear receptors in human sebaceous glands under normal and pathological conditions.

J Steroid Biochem Mol Biol 2014 Oct 30;144 Pt B:268-79. Epub 2014 Jul 30.

Department of Pathology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.

The sebaceous gland is a major site of steroid synthesis in human skin, but details of the status of steroidogenic enzymes and their regulation in human sebaceous glands under normal and pathological conditions have rarely been reported. Therefore, in this study, we examined the status of steroidogenic enzymes, sex steroid receptors and transcription factors in human sebaceous glands under normal and pathological conditions to explore their possible roles in in situ steroid production in human skin. Immunohistochemical analysis was performed in a total of 59 human skin specimens, including 22 normal human sebaceous glands, 12 with sebaceous nevus, 12 with sebaceous gland hyperplasia, 3 with sebaceoma and 10 with sebaceous carcinoma. Immortalised human SZ95 sebocytes were treated with forskolin or vehicle for 3h, 6h, 12h or 24h, and the mRNA levels of steroidogenic enzymes were evaluated at each time point using quantitative RT-PCR (qPCR). The results of immunohistochemistry demonstrated the immunoreactivity of 3β-HSD1, CYP11A1, StAR, 17β-HSD5, CYP17A1, 5α-red1, PRB, AR and NGFI-B in normal human sebaceous gland, with lower levels of expression in pathological sebaceous glands. The results of the in vitro study also indicated that the expression levels of 3β-HSD1, CYP11A1, StAR, 5α-red1 and NGFI-B were elevated by forskolin. 3β-HSD1 and other steroidogenic enzymes were expressed in sebaceous glands resulting in in situ androgen and progesterone synthesis and their functions.
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http://dx.doi.org/10.1016/j.jsbmb.2014.07.010DOI Listing
October 2014

Complexities of androgen receptor signalling in breast cancer.

Endocr Relat Cancer 2014 Aug 20;21(4):T161-81. Epub 2014 Jun 20.

Department of PathologyTohoku University School of Medicine, Miyagi, Sendai, JapanDame Roma Mitchell Cancer Research LaboratoriesDiscipline of Medicine, The University of Adelaide and Hanson Institute, DX 650801, Adelaide, South Australia 5005, Australia

While the clinical benefit of androgen-based therapeutics in breast cancer has been known since the 1940s, we have only recently begun to fully understand the mechanisms of androgen action in breast cancer. Androgen signalling pathways can have either beneficial or deleterious effects in breast cancer depending on the breast cancer subtype and intracellular context. This review discusses our current knowledge of androgen signalling in breast cancer, including the relationship between serum androgens and breast cancer risk, the prognostic significance of androgen receptor (AR) expression in different breast cancer subtypes and the downstream molecular pathways mediating androgen action in breast cancer cells. Intracrine androgen metabolism has also been discussed and proposed as a potential mechanism that may explain some of the reported differences regarding dichotomous androgen actions in breast cancers. A better understanding of AR signalling in this disease is critical given the current resurgence in interest in utilising contemporary AR-directed therapies for breast cancer and the need for biomarkers that will accurately predict clinical response.
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http://dx.doi.org/10.1530/ERC-14-0243DOI Listing
August 2014

3βHSD and CYB5A double positive adrenocortical cells during adrenal development/aging.

Endocr Res 2015 15;40(1):8-13. Epub 2014 May 15.

Department of Pathology, Tohoku University Graduate School of Medicine , Sendai , Japan and.

Androstenedione is a common precursor of sex steroids produced and secreted in the human adrenal gland and produced by 3β-hydroxysteroid dehydrogenase (3βHSD), 17β-hydroxylase/17,20-lyase (CYP17) and cytochrome b5 (CYB5A). 3βHSD is expressed in the zona glomerulosa (ZG) and fasciculata (ZF), CYP17 in the ZF and zona reticularis (ZR) and CYB5A in the ZR, respectively. We previously demonstrated the presence of cortical parenchymal cells co-expressing 3βHSD and CYB5A with hybrid features of both ZF and ZR in human adrenal cortex and hypothesized that these cells may play an important role in androstenedione production in human adrenal gland. Age-related morphologic development of these hybrid cells has, however, not been studied. Therefore, in this study, 48 human adrenal specimens from various age groups were retrieved. Double-immunohistochemical analyses were used in order to study the correlation between this hybrid cell type and age. In both male and female adrenal cortex, the means of total adrenocortical area, the area positive for CYB5A and its ratio reached highest peak in the 21-40-year-old (y.o.) group. The greatest overlap between 3βHSD and CYB5A in both total and relative area was present in the 13-20 y.o. group. For all the markers mentioned above, statistically significant differences were detected among the different age groups examined (p < 0.05). These findings indicated that both area and ratio of 3βHSD and CYB5A double positive cells, which could represent the hybrid cells of ZF and ZR, are correlated with human adrenal development and could subsequently influence age-related serum androstenedione levels.
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http://dx.doi.org/10.3109/07435800.2014.895377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4242803PMC
September 2015

Androgenic pathways in the progression of triple-negative breast carcinoma: a comparison between aggressive and non-aggressive subtypes.

Breast Cancer Res Treat 2014 Jun 9;145(2):281-93. Epub 2014 Apr 9.

Department of Pathology, Tohoku University School of Medicine, Sendai, Japan,

One of the active intracellular pathways/networks in triple-negative breast carcinoma (TNBC) is that of the androgen receptor (AR). In this study, we examined AR and androgen-metabolising enzyme immunoreactivity in subcategories of TNBC to further elucidate the roles of androgenic pathways in TNBC. We utilised formalin-fixed paraffin-embedded breast cancer samples from ductal carcinoma in situ (DCIS) and invasive ductal carcinoma patient cohorts. We then used immunohistochemistry to classify these samples into basal-like and non-basal samples and to assess interactions between AR, androgen-metabolising enzymes and proliferation. To further substantiate our hypothesis and provide mechanistic insights, we also looked at the expression and regulation of these factors in publically available microarray data and in a panel of TNBC AR-positive cell lines. DCIS was associated with higher levels of AR and enzymes (p < 0.02), although a similar difference was not noticed in basal and non-basal samples. AR and enzymes were correlated in all states. In TNBC cell lines (MDA-MD-453, MFM-223 and SUM185-PE), we found that DHT treatment up-regulated 5αR1 and 17βHSD5 suggesting a mechanistic explanation for the correlations observed in the histological samples. Publicly available microarray data in TNBC cases suggested similar patterns to those observed in histological samples. In the majority of settings, including publically available microarray data, an inverse association between AR and proliferation was detected. These findings suggest that decreases in AR and androgen-metabolising enzymes may be involved in the increased biological aggressiveness in TNBC development.
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http://dx.doi.org/10.1007/s10549-014-2942-6DOI Listing
June 2014

Renal epithelioid angiomyolipoma with malignant features: Histological evaluation and novel immunohistochemical findings.

Pathol Int 2014 Mar;64(3):133-41

Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Renal epithelioid angiomyolipoma (EAML) is a potentially malignant tumor type whose characteristics and biomarkers predictive of malignant behavior have not been elucidated. Here, we report three cases of renal EAML with malignant features but without histories of tuberous sclerosis complex. Case 1 involved a 29-year-old man with a 12-cm solid mass in the right kidney who underwent radical right nephrectomy. Case 2 involved a 22-year-old woman with a retroperitoneal mass who underwent radical right nephrectomy and retroperitoneal tumorectomy. Local recurrence was detected 7 years post-surgery. Case 3 involved a 23-year-old man with a 14-cm solid mass in the left kidney who underwent radical left nephrectomy. Microscopically, the tumors in all cases demonstrated proliferation of epithelioid cells with atypia, mitotic activity, necrosis, hemorrhage, and vascular invasion. Epithelioid cells in all cases were immunohistochemically positive for melanocytic and myoid markers and weakly positive for E-cadherin and β-catenin. Immunohistochemistry revealed activation of the mammalian target of rapamycin pathway. Here, we report the morphological and immunohistochemical features of clinically or histologically malignant renal EAML.
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http://dx.doi.org/10.1111/pin.12142DOI Listing
March 2014

GATA6, SF1, NGFIB and DAX1 in the remodeled subcapsular zones in primary aldosteronism.

Endocr J 2014 15;61(4):393-401. Epub 2014 Feb 15.

Department of Pathology, Tohoku University Graduate School of Medicine, Sendai 980- 8575, Japan.

The majority of the cases diagnosed as primary aldosteronism (PA) are caused by aldosterone-producing adenoma (APA) or idiopathic hyperaldosteronism (IHA). Histopathologically, both IHA and adjacent adrenal glands of APA demonstrate remodeled subcapsular zone (RSZ) but these zones in two disorders are markedly different in terms of steroidogenesis. 3β-Hydroxysteroid dehydrogenase/Δ⁵-Δ⁴ isomerase (3β-HSD) expression has been known to be activated synergistically by GATA6 and SF1, and repressed by DAX1 through abolishing the activation. Nerve growth factor-induced clone B (NGFIB) is also known as one of the transcription factors to bind to and activate 3β-HSD promoter. The results of our immunohistochemical analysis demonstrated the expression levels of 3β-HSD in RSZ of IHA were higher than in RSZ of adjacent adrenals of APA, while those in the zona glomerulosa (ZG) of normal adrenal gland (NA) were in between these two RSZs. The expression levels of GATA6, SF1 and DAX1 did not prominently differ among these three types of adrenals, especially between in RSZs of IHA and APA cases, indicating the marked difference of 3β-HSD expression was unlikely to be explained by the levels of these three factors. However, the levels of NGFIB expression were significantly higher in RSZ of IHA than in RSZ of adjacent adrenals of APA and the ZG of NA (P<0.05), which may partly account for the expression levels of 3β-HSD among the three groups of adrenals. These results may imply NGFIB plays important roles in the marked differences in steroidogenic functions in the two distinct types of RSZ of PA cases.
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http://dx.doi.org/10.1507/endocrj.ej13-0103DOI Listing
December 2014

A patient with POEMS syndrome: the pathology of glomerular microangiopathy.

Tohoku J Exp Med 2013 11;231(3):229-34

Department of Pathology, Tohoku University Graduate School of Medicine.

POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes) is potentially fatal multisystem disorder but its renal complication has often been overlooked because renal involvement is not necessarily included in the diagnostic criteria of POEMS. This report documents the patient with POEMS syndrome with long-term renal histopathological changes evaluated by renal biopsy. A 32-year-old Japanese woman presented with symptoms consistent with POEMS syndrome associated with proteinuria and IgA-λ type monoclonal gammopathy. Initial renal biopsy for confirmation of diagnosis revealed the proliferation of glomerular capillary loops located in the expanded mesangial matrices associated with glomerular enlargement. Electron microscopy examination of the renal biopsy revealed the presence of double contoured glomerular basement membrane containing peculiar fibrillary structure. The patient was therefore initially diagnosed as membranoproliferative glomerulonephritis (MPGN)-like lesion without any significant immunoglobulins and complements deposition. The patient was subsequently admitted to hospital on five occasions due to renal dysfunction and anasarca for the next four years of her clinical course. The severity of anasarca was correlated mainly with serum titer of vascular endothelial growth factor (VEGF) during this period. Acute renal failure occurred at the last admission and the second biopsy was performed. An increased mesangial matrix and frequent global sclerosis of the glomeruli with arteriolosclerosis was noted in this second biopsy compared to the first one. These findings of renal biopsies suggest that the glomerular microangiopathy of POEMS syndrome may occur in the context of systemic capillary leak syndrome superimposed on chronic endothelial injury.
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http://dx.doi.org/10.1620/tjem.231.229DOI Listing
November 2013

Identification of androgen-responsive microRNAs and androgen-related genes in breast cancer.

Anticancer Res 2013 Nov;33(11):4811-9

2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575 Japan.

Background: Androgen receptors (ARs) are expressed in many breast cancer cells, but the mechanism of action of androgens is not as well-characterized as in other cell types. The study of microRNAs has recently provided with important insights into the biology of hormone-dependent cancer.

Materials And Methods: We attempted to identify microRNAs induced by dihydrotestosterone in an AR-positive cell line. We examined a possible correlation among microRNAs, target genes, and ARs in breast cancer tissues using immunohistochemistry and laser capture microscopy.

Results: Our analysis demonstrated that miR-363 and its possible target IQ motif and WD repeats-1 (IQWD1) are involved in a microRNA-mRNA pathway related to the mechanism of action of androgens. Our analyses showed that a high tumor level of IQWD1 in patients with breast cancer was significantly associated with adverse clinical outcomes.

Conclusion: Our findings indicated that the recruitment of IQWD1 to ARs may be a prerequisite for the growth stimulation by androgens through ARs in breast cancer cells.
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November 2013

Glutamate receptors and the regulation of steroidogenesis in the human adrenal gland: the metabotropic pathway.

Mol Cell Endocrinol 2014 Jan 27;382(1):170-177. Epub 2013 Sep 27.

Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Background: l-glutamate is a major excitatory neurotransmitter in the mammalian brain. Glutamate receptors have been reported in the rat adrenal cortex and in human aldosterone-producing adenomas (APA). However, details regarding the expression levels and functions of these receptors in human adrenocortical tissues remain unknown.

Methods: The mRNA levels of glutamate receptors were evaluated by qPCR in: 12 normal adrenal cortex (NAC), 11 APA, and 12 cortisol-producing adenoma (CPA) tissues. Protein localization was evaluated by immunohistochemistry for 15 NAC, 5 idiopathic hyperaldosteronism cases, 15 APA and 15 CPA. H295R cells were treated with angiotensin-II or forskolin alone or combined with the GRM2/3 agonist LY354740.

Results: The level of GRM3 mRNA was higher in APA than in CPA (P=0.0086) or NAC (P=0.0022). GRM1, IGLUR2, and IGLUR3 were also detected in adrenocortical tissues. When added to angiotensin-II/forskolin treatments, LY354740 decreased aldosterone and cortisol production in H295R cells.

Conclusions: GRM3 is considered to regulate steroidogenesis in adrenocortical tissues.
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http://dx.doi.org/10.1016/j.mce.2013.09.025DOI Listing
January 2014

Phase two steroid metabolism and its roles in breast and prostate cancer patients.

Front Endocrinol (Lausanne) 2013 Sep 4;4:116. Epub 2013 Sep 4.

Department of Pathology, Tohoku University School of Medicine, Miyagi , Sendai , Japan.

Breast and prostate cancer are diseases in which steroids and steroid metabolism could markedly influence clinical outcomes for patients. In both malignancies the modification of ketone and hydroxyl groups attached to the steroid backbone (phase one metabolism) has been examined in detail but the conjugation reactions (phase two metabolism) have not been extensively studied. Therefore, in this review we aim to summarize phase two metabolism in breast and prostate cancers from a number of perspectives, including the impact of variation in serum levels of conjugated steroids, tissue, and pathology specific expression of phase two enzymes, and consequences of genetic variations of these conjugation enzymes. In addition to this biological perspective, we will also address current pharmacological efforts to manipulate phase two metabolism as a potential therapy for hormone dependent cancers, including clinical trials of STS inhibitors and preclinical STS inhibitor development. While this review is not intended to cover any one particular area in great technical depth, it is intended as an introduction to and/or update on the importance of variance in phase two metabolic pathways in breast and prostate cancers.
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http://dx.doi.org/10.3389/fendo.2013.00116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3761226PMC
September 2013

HIF-1α stimulates aromatase expression driven by prostaglandin E2 in breast adipose stroma.

Breast Cancer Res 2013 Apr 8;15(2):R30. Epub 2013 Apr 8.

Introduction: The majority of postmenopausal breast cancers are estrogen-dependent. Tumor-derived factors, such as prostaglandin E2 (PGE2), stimulate CREB1 binding to cAMP response elements (CREs) on aromatase promoter II (PII), leading to the increased expression of aromatase and biosynthesis of estrogens within human breast adipose stromal cells (ASCs). Hypoxia inducible factor-1α (HIF-1α), a key mediator of cellular adaptation to low oxygen levels, is emerging as a novel prognostic marker in breast cancer. We have identified the presence of a consensus HIF-1α binding motif overlapping with the proximal CRE of aromatase PII. However, the regulation of aromatase expression by HIF-1α in breast cancer has not been characterized. This study aimed to characterize the role of HIF-1α in the activation of aromatase PII.

Methods: HIF-1α expression and localization were examined in human breast ASCs using quantitative PCR (QPCR), Western blotting, immunofluorescence and high content screening. QPCR and tritiated water-release assays were performed to assess the effect of HIF-1α on aromatase expression and activity. Reporter assays and chromatin immunoprecipitation (ChIP) were performed to assess the effect of HIF-1α on PII activity and binding. Treatments included PGE2 or DMOG ((dimethyloxalglycine), HIF-1α stabilizer). Double immunohistochemistry for HIF-1α and aromatase was performed on tissues obtained from breast cancer and cancer-free patients.

Results: Results indicate that PGE2 increases HIF-1α transcript and protein expression, nuclear localization and binding to aromatase PII in human breast ASCs. Results also demonstrate that HIF-1α significantly increases PII activity, and aromatase transcript expression and activity, in the presence of DMOG and/or PGE2, and that HIF-1α and CREB1 act co-operatively on PII. There is a significant increase in HIF-1α positive ASCs in breast cancer patients compared to cancer-free women, and a positive association between HIF-1α and aromatase expression.

Conclusions: This study is the first to identify HIF-1α as a modulator of PII-driven aromatase expression in human breast tumor-associated stroma and provides a novel mechanism for estrogen regulation in obesity-related, post-menopausal breast cancer. Together with our on-going studies on the role of AMP-activated protein kinase (AMPK) in the regulation of breast aromatase, this work provides another link between disregulated metabolism and breast cancer.
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http://dx.doi.org/10.1186/bcr3410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3672802PMC
April 2013

Androgenic pathway in triple negative invasive ductal tumors: its correlation with tumor cell proliferation.

Cancer Sci 2013 May 15;104(5):639-46. Epub 2013 Mar 15.

Department of Pathology, Tohoku University School of Medicine, Sendai, Japan.

Triple negative breast cancer (TNBC) is defined by estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 negativity. Patients with TNBC frequently undergo an aggressive clinical course due to the unavailability of specific targeted therapies. Androgen receptor (AR) was reported to be expressed in up to 60% of TNBC cases but there have been controversies as to the roles of androgen signaling through AR in TNBC. Therefore, in this study, we analyzed the status of AR in combination with androgen synthesizing enzymes (5α-reductase type 1 (5αR1) and 17β-hydroxysteroid dehydrogenase type 5 (17βHSD5)] in order to further understand androgenic actions in TNBC. Androgen receptor, 5αR1, and 17βHSD5 were immunolocalized in a cohort of 203 TNBC patients from Thailand and Japan. We then correlated the findings with clinicopathological characteristics (age, stage, tumor diameter, lymph node invasion, metastatic spread, Ki-67 labeling index, disease-free survival, and overall survival) of the patients. Univariate analysis revealed that AR+/enzyme+ cases were associated with a significantly lower Ki-67 labeling index than AR-/enzyme- samples. Multivariate analysis indicated the presence of significant positive correlations between AR and enzyme status in tumor cells, and between tumor diameter, lymph node invasion, and distant metastasis. Significant negative correlations were also detected between Ki-67 labeling index and AR status (P = 0.04) or 5αR1 (P < 0.001). Cox proportional hazards analysis showed that Ki-67 labeling index and stage were the only factors predicting disease-free and overall survival of the patients, although univariate Kaplan-Meier analysis revealed AR/5αR1 negativity suggested a more adverse clinical course up to 80 months after surgery. These results suggest that the presence of androgen synthesizing pathways in addition to AR expression in tumor cells could confer a better clinical outcome through suppression of cell proliferation.
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http://dx.doi.org/10.1111/cas.12121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657136PMC
May 2013

Estrogen-related receptor α in normal adrenal cortex and adrenocortical tumors: involvement in development and oncogenesis.

Mol Cell Endocrinol 2013 Jan 30;365(2):207-11. Epub 2012 Oct 30.

Tohoku University Graduate School of Medicine, Department of Pathology, Sendai, Japan.

Aims: The nuclear hormone receptor estrogen-related receptor α (ERRα) regulates the activation of mitochondrial genes in various human tissues, but its role in the adrenal gland and its disorders has not been defined. Therefore, we examined ERRα expression in both normal adrenal cortex (NAC) and adrenocortical tumor (ACT) in order to study the possible correlation of ERRα with adrenal development and tumor development.

Methods: Human adrenal specimens (non-pathological fetal n=7; non-pathological post-birth n=40; aldosterone producing adenoma (APA) n=11; cortisol producing adenoma (CPA) n=11; adrenocortical carcinoma (ACC) n=8) were immunohistochemically examined in this study. NAC (n=13) and ACT (n=28) frozen tissue specimens were also available for studying ERRα mRNA levels.

Key Findings: In fetal NAC tissues, ERRα labeling index (LI) in fetal zone (FZ) was significantly higher that that in neocortex (NC), and the differences among age groups for overall mean LI was statistically significant when analyzed according to individual cortical layers. ERRα LI was also significantly higher in ACC than in other types of ACT. ERRα mRNA was detected in NAC and all types of ACT.

Significance: Results of our present study suggest a possible role of ERRα in adrenal development and ACC.
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http://dx.doi.org/10.1016/j.mce.2012.10.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4097865PMC
January 2013

Cyclin D1 (CCND1) expression is involved in estrogen receptor beta (ERβ) in human prostate cancer.

Prostate 2013 May 11;73(6):590-5. Epub 2012 Oct 11.

Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Background: Estrogen receptor beta (ERβ) has been demonstrated to be expressed in prostate carcinoma cells and estrogen signals through ERβ to act as a tumor suppressor in prostate cancer patients. ERβ is thought to regulate the cell cycle of prostate carcinoma cells by controlling the expression of cell cycle regulators including cyclin D1 (CCND1). This interaction is of particular interest as CCND1 has been implicated in the development of prostate cancer.

Methods: We evaluated ERβ and CCND1 immunoreactivity in human prostate cancer (n = 112, surgical specimens), and correlated the findings with clinicopathological features of the patients. Subsequent in vitro experiments using PC-3 prostate carcinoma cells were also performed to examine whether estradiol (E2) could change the expression level of CCND1 mRNA.

Results: CCND1 immunoreactivity was detected in 78/112 cases (70%), and was significantly correlated with incidence of perineural invasion and ERβ immunoreactivity (P < 0.05). Forty-eight hours incubation with E2 (10 nM) increased the expression level of CCND1 mRNA as well as c-jun (JUN) and c-fos (FOS) in PC-3 cells, and PHTPP (ERβ antagonist) suppressed E2 -induced expression of those mRNAs.

Conclusions: These findings suggest that CCND1 expression is possibly regulated by estrogens via ERβ and that this signaling pathway may influence prostate cancer development.
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http://dx.doi.org/10.1002/pros.22599DOI Listing
May 2013

Prostate epithelial AR inactivation leads to increased intraprostatic androgen synthesis.

Prostate 2013 Feb 13;73(3):316-27. Epub 2012 Sep 13.

Andrology, ANZAC Research Institute, University of Sydney, Sydney, Australia.

Background: Regulation of steroid synthesis within the prostate is not well understood. In this study, we examined androgen synthesis and metabolism in the mouse prostate.

Methods: Using LC-MSMS steroid assays, immunohistochemistry and real-time PCR we examined the role of prostate epithelial AR in regulating 5αR expression and subsequent androgen metabolism by analyzing natural differences in epithelial AR expression between lobes as well as in the prostate epithelial AR knockout (PEARKO) mouse model. Subsequently, the role of intraprostatic androgen metabolism and epithelial AR in the generation and progression of prostate epithelial pathology was examined using long-term exogenous testosterone (T) + estradiol (E2) exposure.

Results: Epithelial AR and 5αR2 expression as well as intraprostatic DHT followed the same lobe-specific pattern being lower in anterior than the other lobes (n = 6-8, P < 0.05). Lobe-specific 5αR2 expression was similar in PEARKO and wild-type (WT) prostate. However, PEARKO prostate had higher intraprostatic DHT content with significantly increased 5αR2 expression localized in abnormal epithelium. T + E2 treatment induced epithelial pathology was more common in PEARKO prostate compared to WT (20% vs. 2%), and was associated with increased 5αR2 expression (n = 6, P < 0.001).

Conclusions: We suggest that androgen synthesis via 5αR2 expression is driven by its own product (DHT) acting on adjacent stromal cells in a paracrine loop leading to increased in situ androgen levels in the PEARKO prostate. This may form part of a feed-forward loop that promotes the development of epithelial pathology.
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http://dx.doi.org/10.1002/pros.22570DOI Listing
February 2013