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Dive into the research topics where Keely May McNamara is active.

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Featured researches published by Keely May McNamara.


The Journal of Steroid Biochemistry and Molecular Biology | 2010

Measurement of sex steroids in murine blood and reproductive tissues by liquid chromatography–tandem mass spectrometry

Keely May McNamara; D.T. Harwood; Ulla Simanainen; Kirsty A. Walters; Mark Jimenez; David J. Handelsman

Accurate measurement of sex steroids is essential to evaluate mouse models for human reproductive development and disorders. The recent advent of liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays that match the sensitivity of steroid immunoassay could overcome problems arising from the limited specificity of steroid immunoassay. In this current study we validate a LC-MS/MS assay for the measurement of key sex steroids from murine serum and reproductive tissues. The assay gave excellent dilutional linearity (r(2)> or =0.98) and reproducibility (CV< or =10% of replicate samples) in serum and reproductive tissues with sensitive quantitation limits; testosterone (T; 2pg), dihydrotestosterone (DHT; 10pg), 5alpha-androstane-3alpha,17beta-diol (3alphaDiol; 40pg), 5alpha-androstane-3beta,17beta-diol (3betaDiol; 40pg), estradiol (E2; 0.5pg) and estrone (E1; 0.3pg). Using 0.1mL sample, T was the only consistently detectable steroid (detection limit 20pg/ml) in both male and female mouse serum. In the testis, T and DHT were quantifiable as were both diols at relatively high levels. Prostatic T levels were low and DHT was determined to be the most abundant androgen in this tissue. Uterine and ovarian levels of E2, E1 and T were measurable, with levels varying according to estrous cycle stage. Hence, we demonstrate that this LC-MS/MS method has the sensitivity, specificity and multi-analyte capability to offer accurate steroid profiling in mouse serum and reproductive tissues.


The Journal of Steroid Biochemistry and Molecular Biology | 2013

Androgen receptor in triple negative breast cancer

Keely May McNamara; Tomomi Yoda; Kiyoshi Takagi; Yasuhiro Miki; Takashi Suzuki; Hironobu Sasano

The clinical management of triple negative breast cancer (TNBC) is challenging due to the relatively aggressive biological behaviour and paucity of specific targeted therapy. A subset of TNBC patients has been reported to express androgen receptor (AR) in carcinoma cells and the manipulation of androgen signalling or AR targeted therapies have been proposed. However, the biological significance of AR in TNBC has remained relatively unknown. Therefore, this review aims to summarise the reported studies assessing the rates of AR positivity in TNBC patients and androgenic effects in TNBC cell lines. The rates of AR positivity among TNBC cases varied depending on the study population (0-53% of all TNBC patients). This difference among the reported studies may be largely due to the methodological differences of analysing AR. While the majority of cell line studies suggest that androgen increase proliferation and preliminary clinical studies suggest that AR antagonists improve the prognosis of AR positive TNBC patients, cell line transfection experiments and survival analyses of histological samples suggest that the presence of AR in tumour is either benign or predicts better survival. Therefore further translational investigations regarding the mechanisms of androgen action in TNBC are required to explain this discrepancy between clinical and basic studies.


Cancer Science | 2013

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

Keely May McNamara; Tomomi Yoda; Yasuhiro Miki; Niramol Chanplakorn; Sansanee Wongwaisayawan; Pimpin Incharoen; Youwanush Kongdan; Lin Wang; Kiyoshi Takagi; Takagi Mayu; Yasuhiro Nakamura; Takashi Suzuki; Noriko Nemoto; Minoru Miyashita; Kentaro Tamaki; Takanori Ishida; Noriaki Ohuchi; Hironobu Sasano

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.


Breast Cancer Research | 2013

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

Nirukshi Udayanga Gunasinghe Samarajeewa; Fangyuan Yang; Maria Docanto; Minako Sakurai; Keely May McNamara; Hironobu Sasano; Stephen B. Fox; Evan R. Simpson; Kristy A. Brown

IntroductionThe 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.MethodsHIF-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.ResultsResults 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.ConclusionsThis 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.


Endocrinology | 2008

Severe subfertility in mice with androgen receptor inactivation in sex accessory organs but not in testis.

Ulla Simanainen; Keely May McNamara; Rachel A. Davey; Jeffrey D. Zajac; David J. Handelsman

Androgen action on sex accessory organs influences rodent fertility, but the mechanisms remain unclear and investigation is difficult without the ability to restrict androgen action in specific tissues. We used Cre-LoxP technology to generate male mice with prostate epithelial-specific androgen receptor deficiency (denoted PEARKO). In addition to prostate, these males have reduced androgen action due to tissue-selective androgen receptor inactivation in seminal vesicle, epididymis, and vas deferens, whereas the testis is unaffected. We find that fertility of PEARKO males was severely reduced, compared with littermates with prominent defects in copulatory plug formation, which were smaller, softer, and more friable than controls. Despite normal testis sperm production, sperm numbers were reduced in caput but increased in cauda epididymis, suggesting alterations in sperm epididymal transit kinetics associated with increased rate of spontaneous acrosome reaction and abnormal flagellar morphology in PEARKO cauda epididymal sperm. Whereas the quantitative in vitro fertilizing ability of PEARKO epididymal sperm was normal, fewer fertilized oocytes were flushed from the oviducts of females after natural mating with PEARKO males. These data show that sperm formed in mice with impaired androgen action restricted to accessory glands and epididymis are quantitatively normal in number and in vitro fertilizing function but that severe in vivo subfertility reflects other functions related to sperm transport and survival in female reproductive tract that determine fertility in vivo.


European Journal of Endocrinology | 2015

Is there a role for segmental adrenal venous sampling and adrenal sparing surgery in patients with primary aldosteronism

Fumitoshi Satoh; Ryo Morimoto; Kazumasa Seiji; Nozomi Satani; Hideaki Ota; Yoshitsugu Iwakura; Yoshikiyo Ono; Masataka Kudo; Masahiro Nezu; Kei Omata; Yuta Tezuka; Yoshihide Kawasaki; Shigeto Ishidoya; Yoichi Arai; Kei Takase; Yasuhiro Nakamura; Keely May McNamara; Hironobu Sasano; Sadayoshi Ito

OBJECTIVE AND DESIGN Adrenal venous sampling (AVS) is critical to determine the subtype of primary aldosteronism (PA). Central AVS (C-AVS)--that is, the collection of effluents from bilateral adrenal central veins (CV)--sometimes does not allow differentiation between bilateral aldosterone-producing adenomas (APA) and idiopathic hyperaldosteronism. To establish the best treatment course, we have developed segmental AVS (S-AVS); that is, we collect effluents from the tributaries of CV to determine the intra-adrenal sources of aldosterone overproduction. We then evaluated the clinical utility of this novel approach in the diagnosis and treatment of PA. METHODS We performed C-AVS and/or S-AVS in 297 PA patients and assessed the accuracy of diagnosis based on the results of C-AVS (n=138, 46.5%) and S-AVS (n=159, 53.5%) by comparison with those of clinicopathological evaluation of resected specimens. RESULTS S-AVS demonstrated both elevated and attenuated secretion of aldosterone from APA and non-tumorous segments, respectively, in patients with bilateral APA and recurrent APA. These findings were completely confirmed by detailed histopathological examination after surgery. S-AVS, but not C-AVS, also served to identify APA located distal from the CV. CONCLUSIONS Compared to C-AVS, S-AVS served to identify APA in some patients, and its use should expand the pool of patients eligible for adrenal sparing surgery through the identification of unaffected segments, despite the fact that S-AVS requires more expertise and time. Especially, this new technique could enormously benefit patients with bilateral or recurrent APA because of the preservation of non-tumorous glandular tissue.


The Prostate | 2013

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

Yasuhiro Nakamura; Saulo J.A. Felizola; Yumi Kurotaki; Fumiyoshi Fujishima; Keely May McNamara; Takashi Suzuki; Yoichi Arai; Hironobu Sasano

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.


Molecular and Cellular Endocrinology | 2014

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

Saulo J.A. Felizola; Yasuhiro Nakamura; Fumitoshi Satoh; Ryo Morimoto; Kumi Kikuchi; Tomohiro Nakamura; Atsushi Hozawa; Lin Wang; Yoshiaki Onodera; Kazue Ise; Keely May McNamara; Sanae Midorikawa; Shinichi Suzuki; Hironobu Sasano

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.


Pathology International | 2014

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

Sachiko Konosu-Fukaya; Yasuhiro Nakamura; Fumiyoshi Fujishima; Atsuko Kasajima; Keely May McNamara; Yayoi Takahashi; Kensuke Joh; Hideo Saito; Naomasa Ioritani; Yoshihiro Ikeda; Yoichi Arai; Mika Watanabe; Hironobu Sasano

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.


Molecular and Cellular Endocrinology | 2013

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

Saulo J.A. Felizola; Yasuhiro Nakamura; Xiao Gang Hui; Fumitoshi Satoh; Ryo Morimoto; Keely May McNamara; Sanae Midorikawa; Shinichi Suzuki; William E. Rainey; Hironobu Sasano

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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