Follicle-Stimulating Hormone Exacerbates Cardiovascular Disease in the Presence of Low or Castrate Testosterone Levels.

Low testosterone (T), common in aging men, associates with cardiovascular disease. We investigated whether follicle-stimulating hormone (FSH), which is affected by T, modulates the cardiovascular effects associated with low T or castration. FSHß-/-:low-density lipoprotein receptor (LDLR)-/- mice, untreated or castrated (orchiectomy, gonadotropin-releasing hormone agonist or antagonist), demonstrated significantly less atherogenesis compared with similarly treated LDLR-/- mice, but not following FSH delivery. Smaller plaque burden in LDLR-/- mice receiving gonadotropin-releasing hormone antagonists vs agonists were nullified in FSHß-/-:LDLR-/- mice. Atherosclerotic and necrotic plaque size and macrophage infiltration correlated with serum FSH/T. In patients with prostate cancer, FSH/T following androgen-deprivation therapy initiation predicted cardiovascular events. FSH facilitates cardiovascular disease when T is low or eliminated.

Protective effect of pharmacological castration on metabolic perturbations and cardiovascular disease in the hyperglycemic male ApoE-/-:Ins2+/Akita mouse model.

BACKGROUND: Unlike in other mouse models of atherogenesis, it has recently been suggested that orchiectomy plays a role in accelerating atherosclerosis and inhibiting the progression of cardiovascular disease in the ApoE-/-:Ins2+/Akita mouse model of hyperglycemia. Androgen-deprivation therapy (ADT) is a common treatment for prostate cancer, a population with high prevalence of cardiovascular disease and its risk factors. Our objectives were to test and further characterize the effects of pharmacological castration which is currently the acceptable modality to deliver ADT in the clinic. METHODS: Male ApoE-/-:Ins2+/Akita mice received one of three modes of ADT (gonadotropin-releasing hormone (GnRH)-antagonist (degarelix), GnRH-agonist (leuprolide), or bilateral orchiectomy) and were compared to corresponding untreated control mice (n = 9-13/group). Mice were followed for 5 months. Body weight, fasting blood glucose, glucose tolerance, serum C-peptide, leptin, and testosterone levels along with atherosclerotic aortic plaque size and characteristics were determined. In a separate experiment, the survival of mice, untreated and on ADT, was determined. RESULTS: Castration was achieved for all three modes of ADT. However, degarelix-treated mice gained significantly less weight, had lower serum leptin levels and systolic blood pressure compared to orchiectomy and leuprolide-treated mice. ADT improved dysglycemia and atherosclerotic burden. GnRH-antagonist significantly improved survival compared to GnRH-agonist but not compared to orchiectomy. CONCLUSIONS: Further characterization of the ApoE-/-:Ins2+/Akita mouse model confirms that pharmacological ADT ameliorated metabolic syndrome and cardiovascular complications. Improved dysglycemia and atherosclerosis associated with increased survival which was longest after degarelix followed by orchiectomy.

Endometriosis-associated Ovarian Cancer is a Subset With a More Favorable Outcome and Distinct Clinical-pathologic Characteristics.

There is a controversy about whether endometriosis-associated ovarian cancer (EAOC) might represent a different entity from the corresponding ovarian cancer occurring de novo, in the absence of endometriosis. This study investigated the clinical-pathologic characteristics and outcome of EAOC compared with other ovarian carcinomas that are not associated with endometriosis (non-EAOC) in a large cohort. Seven hundred two patients meeting the inclusion criteria were further subclassified as group I when patients had ovarian carcinoma associated with or arising within endometriosis (EAOC) and group II when patients had non-EAOC. Age, gross features, histologic type, International Federation of Gynecology and Obstetrics stage, and disease-free survival (DFS) were compared between the groups. One hundred sixty-eight (23.9%) patients had EAOC, whereas 534 (76.1%) patients had non-EAOC. EAOCs were mostly endometrioid and clear cell type. Patients with EAOC were younger, present early, and had a lower rate of recurrence when compared with patients with non-EAOC, P<0.001. Patients with EAOC had longer DFS time, 51.9 mo (95% confidence interval, 44.9-58.8) versus 30.5 mo (95% confidence interval, 27.7-33.3) in non-EAOC patients. The 5 yr Kaplan-Meier estimate of DFS rate was 70% in 166 patients of group I and was 39.3% in 532 patients of group II, P<0.001. On multivariate analysis, International Federation of Gynecology and Obstetrics staging, histologic type, and treatment were the only significant factors affecting the hazards of recurrence. Patients with tumors associated with endometriosis are usually, younger, present early, have lower rate of recurrence, longer DFS, and their tumors are of lower grade and are more likely endometrioid or clear cell carcinoma.

Anti-GRP78 autoantibodies induce endothelial cell activation and accelerate the development of atherosclerotic lesions.

The 78-kDa glucose-regulated protein (GRP78) is an ER molecular chaperone that aids in protein folding and secretion. However, pathological conditions that cause ER stress can promote the relocalization of GRP78 to the cell surface (csGRP78), where it acts as a signaling receptor to promote cancer progression. csGRP78 also possesses antigenic properties, leading to the production of anti-GRP78 autoantibodies, which contribute to tumor growth. In contrast, the presence and role of anti-GRP78 autoantibodies in atherosclerosis is unknown. Here, we show that atherosclerotic-prone ApoE-/- mice develop circulating anti-GRP78 autoantibodies that bind to csGRP78 on lesion-resident endothelial cells. Moreover, GRP78-immunized ApoE-/- mice exhibit a marked increase in circulating anti-GRP78 autoantibody titers that correlated with accelerated lesion growth. Mechanistically, engagement of anti-GRP78 autoantibodies with csGRP78 on human endothelial cells activated NF-κB, thereby inducing the expression of ICAM-1 and VCAM-1, a process blocked by NF-κB inhibitors. Disrupting the autoantibody/csGRP78 complex with enoxaparin, a low-molecular-weight heparin, reduced the expression of adhesion molecules and attenuated lesion growth. In conclusion, anti-GRP78 autoantibodies play a crucial role in atherosclerosis development, and disruption of the interaction between anti-GRP78 autoantibodies and csGRP78 represents a therapeutic strategy.

Comprehensive Clinicopathologic and Updated Immunohistochemical Characterization of Primary Ovarian Mucinous Carcinoma.

The distinction of primary mucinous ovarian carcinoma (PMOC) from other primaries or secondaries is essential for selecting therapeutic options and prognostication. We aimed to characterize the immunohistochemical profile of 36 PMOCs using an extended immunohistochemical panel, with clinicopathologic features and outcome. PAX8 was negative in 30 (83.3%), and SATB2 was negative in 32/35. HNF1B, AMACR, and napsin-A were detected in 33 (91.7%), 35 (97.2%), and 0 (0%), respectively. MMR proteins and ARID1A were retained in 100%; PTEN was lost in 4 (11.1%). P53 was aberrant in 10 (27.8%); none overexpressed p16. HER2 was positive in 6/35 (17.1%). Most PMOCs had a favorable outcome. However, recurrence is usually fatal. The typical tumor profile was CK7+, CK20+/-, CDX2+/-, PAX8-, ER-, PgR-, and SATB2-. HER2 positivity suggests a possible target for therapy in advanced disease.

MiR-301a regulates E-cadherin expression and is predictive of prostate cancer recurrence.

BACKGROUND: MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression post-transcriptionally. Dysregulation of miRNA has been implicated in the development and progression of prostate cancer. Through next generation miRNA sequencing, we recently identified a panel of five miRNAs associated with prostate cancer recurrence and metastasis. Of the five miRNAs, miR-301a had the strongest association with prostate cancer recurrence. Overexpression of miR-301a in prostate cancer cells, PC3, and LNCaP resulted in increased growth both in vitro and in xenografted tumors. We therefore sought to examine its role in prostate carcinogenesis in greater detail. METHODS: We examined the effect of miR-301a expression on biochemical recurrence and metastasis among 585 men treated with radical prostatectomy for prostate cancer. We examined the mechanism of growth deregulation by miR-301a in prostate cancer cells using analysis of the miRome of prostate cancer cell lines, quantitative PCR, and Western blotting. RESULTS: High levels of miR-301a (above the median) were associated with an increased risk of biochemical recurrence (adjusted hazard ratio [aHR] 1.42, 95% confidence interval (CI) 1.06-1.90, P = 0.002) but not of metastasis (aHR 0.84, 95%CI 0.41-1.70, P = 0.6) after adjustment for known prognostic factors. RNA transcriptome sequencing analysis of miR-301a overexpressing prostate cancer cell lines identified the tumor suppressor p63 as a potential direct miR-301a target. Transcriptome sequencing, qPCR and Western blotting showed that miR-301a induced epithelial-mesenchymal transition (EMT) in prostate cancer cells through a pathway initiated by p63 inhibition. Luciferase assay verified p63 as a direct target of miR-301a. Loss of p63 resulted in miR-205 downregulation, releasing Zeb1 and Zeb2 from inhibition, culminating in Zeb1/Zeb2 suppression of E-cadherin. This pathway of growth alteration mediated by miR-301a upregulation was shown to be valid in prostate cancer cell lines and patient-derived tumors. CONCLUSIONS: These data indicate that miR-301a functions as an oncogene in prostate cancer by directly targeting the p63 tumor suppressor leading to loss of E-cadherin and EMT. Hence, miR-301a may serve as a novel biomarker in prostate cancer as well as a therapeutic target for prostate cancer management. Prostate 76:869-884, 2016. © 2016 Wiley Periodicals, Inc.

Identification and Validation of a Five MicroRNA Signature Predictive of Prostate Cancer Recurrence and Metastasis: A Cohort Study.

BACKGROUND: MicroRNA (miRNA) have been shown to be important in regulating gene expression in prostate cancer. We used next generation miRNA sequencing to conduct a whole miRNome analysis to identify miRNAs associated with prostate cancer metastasis. METHODS: We conducted discovery and validation analyses of miRNAs among a total of 546 men who underwent surgery for prostate cancer using the development of metastasis as an endpoint. Genome wide analysis was conducted among the discovery group (n=31) to identify new miRNAs associated with prostate cancer metastasis. Selected miRNAs were then analyzed using qPCR on prostatectomy specimens from an independent cohort (n=515) to determine whether their expression could predict the development of metastasis after surgery. To examine the biology underlying these associations, we created prostate cancer cell lines which overexpressed miR-301a for in vitro and in vivo functional assays. RESULTS: We identified 33 miRNAs associated with prostate cancer metastasis and selected a panel comprising miRs-301a, 652, 454, 223 and 139 which strongly predicted metastasis (AUC=95.3%, 95%C.I.:84%-99%). Among the validation cohort, the 15-year metastasis-free survival was 77.5% (95% C.I.:63.9%-86.4%) for patients with a high miRNA panel score and 98.8% (95% C.I.:94.9%-99.7%, p<0.0001 for difference) for those with a low score. After adjusting for grade, stage, and PSA, the hazard ratio for metastasis was 4.3 (95% C.I.: 1.7-11.1, p=0.002) for patients with a high miRNA panel score, compared to those with a low score. Prostate cancer cell lines overexpressing miR-301a had in significantly higher tumor growth and metastasis in a xenograft mouse model. CONCLUSIONS: A panel of miRNAs is associated with prostate cancer metastasis. These could be used as potential new prognostic factors in the surgical management of prostate cancer.