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Shikha Saini, Lakshmi Sripada, Kiara Tulla, Guilin Qiao, Nicholas Kunda, Ajay V Maker and Bellur S Prabhakar

ATC is an aggressive disease with limited therapeutic options due to drug resistance. TRAIL is an attractive anti-cancer therapy that can trigger apoptosis in a cancer cell-selective manner. However, TRAIL resistance is a major clinical obstacle for its use as a therapeutic drug. Previously, we demonstrated that MADD is a cancer cell pro-survival factor that can modulate TRAIL resistance. However, its role, if any, in overcoming TRAIL resistance in ATC is unknown. First, we characterized ATC cell lines as either TRAIL resistant, TRAIL sensitive or moderately TRAIL sensitive and evaluated MADD expression/cellular localization. We determined the effect of MADD siRNA on cellular growth and investigated its effect on TRAIL treatment. We assessed the effect of combination treatment (MADD siRNA and TRAIL) on mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) levels. The effect of combination treatment on tumor growth was assessed in vivo. We found increased levels of MADD in ATC cells relative to Nthy-ori 3-1. MADD protein localizes in the cytosol (endoplasmic reticulum and Golgi body) and membrane. MADD knockdown resulted in spontaneous cell death that was synergistically enhanced when combined with TRAIL treatment in otherwise resistant ATC cells. Combination treatment resulted in a significant reduction in MMP and enhanced generation of ROS indicating the putative mechanism of action. In an orthotopic mouse model of TRAIL-resistant ATC, treatment with MADD siRNA alone reduced tumor growth that, when combined with TRAIL, resulted in significant tumor regressions. We demonstrated the potential clinical utility of MADD knockdown in sensitizing cells to TRAIL-induced apoptosis in ATC.

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Marijn A Vermeulen, Carolien H M van Deurzen, Shusma C Doebar, Wendy W J de Leng, John W M Martens, Paul J van Diest and Cathy B Moelans

Ductal carcinoma in situ (DCIS) of the male breast is very rare and has hardly been studied molecularly. In males, we compared methylation status of 25 breast cancer-related genes in pure DCIS (n = 18) and invasive breast carcinoma (IBC) with adjacent DCIS (DCIS-AIC) (n = 44) using methylation-specific multiplex ligation-dependent probe amplification. Results were compared to female breast cancer (BC). There were no significant differences in methylation features between male pure DCIS, DCIS-AIC and IBC after correction for multiple comparisons. In paired analysis of IBC and adjacent DCIS, CADM1 showed a significantly higher absolute methylation percentage in DCIS (P = 0.002). In cluster analysis, two clusters stood out with respectively infrequent and frequent methylation (GATA5, KLLN, PAX6, PAX5, CDH13, MSH6 and WT1 were frequently methylated). Compared to female DCIS, methylation was in general much less common in male DCIS, especially for VHL, ESR1, CDKN2A, CD44, CHFR, BRCA2, RB1 and STK11. In contrast, THBS1 and GATA5 were more frequently methylated in male DCIS. In conclusion, there is frequent methylation of GATA5, KLLN, PAX6, PAX5, CDH13, MSH6 and WT1 in male DCIS. Since there was little change in the methylation status for the studied genes from pure male DCIS to DCIS-AIC and IBC, methylation of these seven genes is more likely to occur early in male breast carcinogenesis. Based on the current markers male DCIS seems to be an epigenetically more advanced precursor of male BC, although in comparison to its female counterpart it appears that fewer loci harbor methylation, pointing to differences between male and female breast carcinogenesis with regard to the studied loci.

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S Latteyer, S Christoph, S Theurer, G S Hönes, K W Schmid, D Führer and L C Moeller

Thyroid hormones are important for physiology and homeostasis. In addition to nuclear thyroid hormone receptors, the plasma membrane protein integrin αvβ3 has been recognized as a receptor for both thyroxine (T4) and triiodothyronine (T3). Here, we studied whether thyroid hormone promotes growth of murine lung cancer via αvβ3 in vivo. Murine Lewis lung carcinoma cells (3LL), stably transfected with luciferase, were injected into mouse lungs. Tumor growth in untreated mice was compared to hypothyroid mice and hypothyroid mice treated with T3 or T4 with or without the αvβ3 inhibitor 3,5,3′,5′-tetraiodothyroacetic acid (Tetrac). Tumor progression was determined by serial in vivo imaging of bioluminescence emitted from the tumor. Tumor weight was recorded at the end of the experiment. Neoangiogenesis was determined by immunohistochemistry for CD31. Tumor growth was reduced in hypothyroidism and increased by T4 treatment. Strikingly, only T4 but not T3 treatment promoted tumor growth. This T4 effect was abrogated by the αvβ3 inhibitor Tetrac. Tumor weight and neoangiogenesis were also significantly increased only in T4-treated mice. The T4 effect on tumor weight and neoangiogenesis was abolished by Tetrac. In vitro, T4 did not stimulate 3LL cell proliferation or signaling pathway activation. We conclude that T4 promotes lung cancer growth in this orthotopic mouse model. The tumor-promoting effect is mediated via the plasma membrane integrin αvβ3 and increased neoangiogenesis rather than direct stimulation of 3LL cells. These data suggest that such effects of levothyroxine may need to be considered in cancer patients on T4 substitution.

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Suzan Stelloo, Andries M Bergman and Wilbert Zwart

The androgen receptor (AR) is commonly known as a key transcription factor in prostate cancer development, progression and therapy resistance. Genome-wide chromatin association studies revealed that transcriptional regulation by AR mainly depends on binding to distal regulatory enhancer elements that control gene expression through chromatin looping to gene promoters. Changes in the chromatin epigenetic landscape and DNA sequence can locally alter AR-DNA-binding capacity and consequently impact transcriptional output and disease outcome. The vast majority of reports describing AR chromatin interactions have been limited to cell lines, identifying numerous other factors and interacting transcription factors that impact AR chromatin interactions. Do these factors also impact AR cistromics – the genome-wide chromatin-binding landscape of AR – in vivo? Recent technological advances now enable researchers to identify AR chromatin-binding sites and their target genes in human specimens. In this review, we provide an overview of the different factors that influence AR chromatin binding in prostate cancer specimens, which is complemented with knowledge from cell line studies. Finally, we discuss novel perspectives on studying AR cistromics in clinical samples.

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Grant D Foglesong, Nicholas J Queen, Wei Huang, Kyle J Widstrom and Lei Cao

Obesity is becoming a global epidemic and is a risk factor for breast cancer. Environmental enrichment (EE), a model recapitulating an active lifestyle, leads to leanness, resistance to diet-induced obesity (DIO) and cancer. One mechanism is the activation of the hypothalamic–sympathoneural–adipocyte (HSA) axis. This results in the release of norepinephrine onto adipose tissue inducing a drop of leptin. This study aimed to test the effects of EE on breast cancer onset and progression while considering the effect of leptin by utilizing the transgenic MMTV-PyMT model as well as several models of varied leptin signaling. EE was highly effective at reducing weight gain, regardless of the presence of leptin. However, the effects of EE on tumor progression were dependent on leptin signaling. EE decreased leptin and reduced mammary tumor growth rate in MMTV-PyMT spontaneous and DIO transplantation models; in contrast, the absence of leptin in ob/ob mice resulted in increased tumor growth likely due to elevated norepinephrine levels. Our results suggest that the microenvironment is critical in breast tumorigenesis and that the drop in leptin is an important peripheral mediator of the EE anti-breast cancer effects, offsetting the potential pro-tumorigenic effects of norepinephrine responding to a complex environment.

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Feng Wu, Fuxingzi Li, Xiao Lin, Feng Xu, Rong-Rong Cui, Jia-Yu Zhong, Ting Zhu, Su-Kang Shan, Xiao-Bo Liao, Ling-Qing Yuan and Zhao-Hui Mo

Tumour-derived exosomes under hypoxic conditions contain informative miRNAs involved in the interaction of cancer and para-carcinoma cells, thus contributing to tissue remodelling of the tumour microenvironment (TME). Exosomes isolated from hypoxic papillary thyroid cancer cells, BCPAP cells and KTC-1 cells enhanced the angiogenesis of human umbilical vein endothelial cells (HUVECs) compared with exosomes isolated from normal thyroid follicular cell line (Nthy-ori-3-1), normoxic BCPAP or KTC-1 cells both in vitro and in vivo. miR-21-5p was significantly upregulated in exosomes from papillary thyroid cancer BCPAP cells under hypoxic conditions, while the exosomes isolated from hypoxic BCPAP cells with knockdown of miR-21-5p attenuated the promoting effect of angiogenesis. In addition, our experiment revealed that miR-21-5p directly targeted and suppressed TGFBI and COL4A1, thereby increasing endothelial tube formation. Furthermore, elevated levels of exosomal miR-21-5p are found in the sera of papillary thyroid cancer patients, which promote the angiogenesis of HUVECs. Taken together, our study reveals the cell interaction between hypoxic papillary thyroid cancer cells and endothelial cells, elucidating a new mechanism by which hypoxic papillary thyroid cancer cells increase angiogenesis via exosomal miR-21-5p/TGFBI and miR-21-5p/COL4A1 regulatory pathway.

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Joakim Crona, Angela Lamarca, Suman Ghosal, Staffan Welin, Britt Skogseid and Karel Pacak

Pheochromocytoma and paraganglioma (PPGL) can be divided into at least four molecular subgroups. Whether such categorizations are independent factors for prognosis or metastatic disease is unknown. We performed a systematic review and individual patient meta-analysis aiming to estimate if driver mutation status can predict metastatic disease and survival. Driver mutations were used to categorize patients according to three different molecular systems: two subgroups (SDHB mutated or wild type), three subgroups (pseudohypoxia, kinase signaling or Wnt/unknown) and four subgroups (tricarboxylic acid cycle, VHL/EPAS1, kinase signaling or Wnt/unknown). Twenty-one studies and 703 patients were analyzed. Multivariate models for association with metastasis showed correlation with SDHB mutation (OR 5.68 (95% CI 1.79–18.06)) as well as norepinephrine (OR 3.01 (95% CI 1.02–8.79)) and dopamine (OR 6.39 (95% CI 1.62–25.24)) but not to PPGL location. Other molecular systems were not associated with metastasis. In multivariate models for association with survival, age (HR 1.04 (95% CI 1.02–1.06)) and metastases (HR 6.13 (95% CI 2.86–13.13)) but neither paraganglioma nor SDHB mutation remained significant. Other molecular subgroups did not correlate with survival. We conclude that molecular categorization accordingly to SDHB provided independent information on the risk of metastasis. Driver mutations status did not correlate independently with survival. These data may ultimately be used to guide current and future risk stratification of PPGL.

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Rayzel C Fernandes, Theresa E Hickey, Wayne D Tilley and Luke A Selth

The androgen receptor (AR) is a ligand-activated transcription factor that drives prostate cancer. Since therapies that target the AR are the mainstay treatment for men with metastatic disease, it is essential to understand the molecular mechanisms underlying oncogenic AR signaling in the prostate. miRNAs are small, non-coding regulators of gene expression that play a key role in prostate cancer and are increasingly recognized as targets or modulators of the AR signaling axis. In this review, we examine the regulation of AR signaling by miRNAs and vice versa and discuss how this interplay influences prostate cancer growth, metastasis and resistance to therapy. Finally, we explore the potential clinical applications of miRNAs implicated in the regulation of AR signaling in this prevalent hormone-driven disease.

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María Andrea Camilletti, Alejandra Abeledo-Machado, Pablo A Perez, Erika Y Faraoni, Fernanda De Fino, Susana B Rulli, Jimena Ferraris, Daniel Pisera, Silvina Gutierrez, Peter Thomas and Graciela Díaz-Torga

Membrane progesterone receptors are known to mediate rapid nongenomic progesterone effects in different cell types. Recent evidence revealed that mPRα is highly expressed in the rat pituitary, being primarily localized in lactotrophs, acting as an intermediary of P4-inhibitory actions on prolactin secretion. The role of mPRs in prolactinoma development remains unclear. We hypothesize that mPR agonists represent a novel tool for hyperprolactinemia treatment. To this end, pituitary expression of mPRs was studied in three animal models of prolactinoma. Expression of mPRs and nuclear receptor was significantly decreased in tumoral pituitaries compared to normal ones. However, the relative proportion of mPRα and mPRβ was highly increased in prolactinomas. Interestingly, the selective mPR agonist (Org OD 02-0) significantly inhibited PRL release in both normal and tumoral pituitary explants, displaying a more pronounced effect in tumoral tissues. As P4 also regulates PRL secretion indirectly, by acting on dopaminergic neurons, we studied mPR involvement in this effect. We found that the hypothalamus has a high expression of mPRs. Interestingly, both P4 and OrgOD 02-0 increased dopamine release in hypothalamus explants. Moreover, in an in vivo treatment, that allows both, pituitary and hypothalamus actions, the mPR agonist strongly reduced the hyperprolactinemia in transgenic females carrying prolactinoma. Finally, we also found and interesting gender difference: males express higher levels of pituitary mPRα/β, a sex that does not develop prolactinoma in these mice models. Taken together, these findings suggest mPRs activation could represent a novel tool for hyperprolactinemic patients, especially those that present resistance to dopaminergic drugs.

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Pedro Weslley Rosario and Gabriela Franco Mourão

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is an encapsulated or clearly delimited, noninvasive neoplasm with a follicular growth pattern and nuclear features of papillary thyroid carcinoma (PTC). It is considered a ‘pre-malignant’ lesion of the RAS-like group. Ultrasonography (US), cytology and molecular tests are useful to suspect thyroid nodules that correspond to NIFTP but there is wide overlap of the results with the encapsulated follicular variant of PTC (E-FVPTC). In these nodules that possibly or likely correspond to NIFTP, if surgery is indicated, lobectomy is favored over total thyroidectomy. The diagnosis of NIFTP is made after complete resection of the lesion by observing well-defined criteria. In the case of patients who received the diagnosis of FVPTC and whose pathology report does not show findings of malignancy (lymph node metastasis, extrathyroidal invasion, vascular/capsular invasion), if the tumor was encapsulated or well delimited, the slides can be revised by an experienced pathologist to determine whether the diagnostic criteria of NIFTP are met, but special attention must be paid to the adequate representativeness of the capsule and tumor. Since NIFTP is not ‘malignant’, tumor staging is not necessary and patients are not submitted to thyroid cancer protocols or guidelines. We believe that patients with NIFTP without associated malignancy and without nodules detected by US of the remnant lobe (if submitted to lobectomy) can be managed like those with follicular adenoma.