The CABLES1 cell cycle regulator participates in the adrenal–pituitary negative feedback, and its expression is reduced in corticotropinomas, pituitary tumors with a largely unexplained genetic basis. We investigated the presence of CABLES1 mutations/copy number variations (CNVs) and their associated clinical, histopathological and molecular features in patients with Cushing’s disease (CD). Samples from 146 pediatric (118 germline DNA only/28 germline and tumor DNA) and 35 adult (tumor DNA) CD patients were screened for CABLES1 mutations. CNVs were assessed in 116 pediatric CD patients (87 germline DNA only/29 germline and tumor DNA). Four potentially pathogenic missense variants in CABLES1 were identified, two in young adults (c.532G > A, p.E178K and c.718C > T, p.L240F) and two in children (c.935G > A, p.G312D and c.1388A > G, and p.D463G) with CD; no CNVs were found. The four variants affected residues within or close to the predicted cyclin-dependent kinase-3 (CDK3)-binding region of the CABLES1 protein and impaired its ability to block cell growth in a mouse corticotropinoma cell line (AtT20/D16v-F2). The four patients had macroadenomas. We provide evidence for a role of CABLES1 as a novel pituitary tumor-predisposing gene. Its function might link two of the main molecular mechanisms altered in corticotropinomas: the cyclin-dependent kinase/cyclin group of cell cycle regulators and the epidermal growth factor receptor signaling pathway. Further studies are needed to assess the prevalence of CABLES1 mutations among patients with other types of pituitary adenomas and to elucidate the pituitary-specific functions of this gene.
Laura C Hernández-Ramírez, Ryhem Gam, Nuria Valdés, Maya B Lodish, Nathan Pankratz, Aurelio Balsalobre, Yves Gauthier, Fabio R Faucz, Giampaolo Trivellin, Prashant Chittiboina, John Lane, Denise M Kay, Aggeliki Dimopoulos, Stephan Gaillard, Mario Neou, Jérôme Bertherat, Guillaume Assié, Chiara Villa, James L Mills, Jacques Drouin, and Constantine A Stratakis
Jan P Dumanski, Chiara Rasi, Peyman Björklund, Hanna Davies, Abir S Ali, Malin Grönberg, Staffan Welin, Halfdan Sorbye, Henning Grønbæk, Janet L Cunningham, Lars A Forsberg, Lars Lind, Erik Ingelsson, Peter Stålberg, Per Hellman, and Eva Tiensuu Janson
The genetics behind predisposition to small intestinal neuroendocrine tumors (SI-NETs) is largely unknown, but there is growing awareness of a familial form of the disease. We aimed to identify germline mutations involved in the carcinogenesis of SI-NETs. The strategy included next-generation sequencing of exome- and/or whole-genome of blood DNA, and in selected cases, tumor DNA, from 24 patients from 15 families with the history of SI-NETs. We identified seven candidate mutations in six genes that were further studied using 215 sporadic SI-NET patients. The result was compared with the frequency of the candidate mutations in three control cohorts with a total of 35,688 subjects. A heterozygous variant causing an amino acid substitution p.(Gly396Asp) in the MutY DNA glycosylase gene (MUTYH) was significantly enriched in SI-NET patients (minor allele frequencies 0.013 and 0.003 for patients and controls respectively) and resulted in odds ratio of 5.09 (95% confidence interval 1.56–14.74; P value = 0.0038). We also found a statistically significant difference in age at diagnosis between familial and sporadic SI-NETs. MUTYH is involved in the protection of DNA from mutations caused by oxidative stress. The inactivation of this gene leads to specific increase of G:C- > T:A transversions in DNA sequence and has been shown to cause various cancers in humans and experimental animals. Our results suggest that p.(Gly396Asp) in MUTYH, and potentially other mutations in additional members of the same DNA excision-repair pathway (such as the OGG1 gene) might be involved in driving the tumorigenesis leading to familial and sporadic SI-NETs.
Yuet-Kin Leung, Vinothini Govindarajah, Ana Cheong, Jennifer Veevers, Dan Song, Robin Gear, Xuegong Zhu, Jun Ying, Ady Kendler, Mario Medvedovic, Scott Belcher, and Shuk-Mei Ho
In utero exposure to bisphenol A (BPA) increases mammary cancer susceptibility in offspring. High-fat diet is widely believed to be a risk factor of breast cancer. The objective of this study was to determine whether maternal exposure to BPA in addition to high-butterfat (HBF) intake during pregnancy further influences carcinogen-induced mammary cancer risk in offspring, and its dose–response curve. In this study, we found that gestational HBF intake in addition to a low-dose BPA (25 µg/kg BW/day) exposure increased mammary tumor incidence in a 50-day-of-age chemical carcinogen administration model and altered mammary gland morphology in offspring in a non-monotonic manner, while shortening tumor-free survival time compared with the HBF-alone group. In utero HBF and BPA exposure elicited differential effects at the gene level in PND21 mammary glands through DNA methylation, compared with HBF intake in the absence of BPA. Top HBF + BPA-dysregulated genes (ALDH1B1, ASTL, CA7, CPLX4, KCNV2, MAGEE2 and TUBA3E) are associated with poor overall survival in The Cancer Genomic Atlas (TCGA) human breast cancer cohort (n = 1082). Furthermore, the prognostic power of the identified genes was further enhanced in the survival analysis of Caucasian patients with estrogen receptor-positive tumors. In conclusion, concurrent HBF dietary and a low-dose BPA exposure during pregnancy increases mammary tumor incidence in offspring, accompanied by alterations in mammary gland development and gene expression, and possibly through epigenetic reprogramming.
Siker Kimbung, Ching-yi Chang, Pär-Ola Bendahl, Laura Dubois, J Will Thompson, Donald P McDonnell, and Signe Borgquist
The impact of systemic 27-hydroxycholesterol (27HC) and intratumoral CYP27A1 expression on pathobiology and clinical response to statins in breast cancer needs clarification. 27HC is an oxysterol produced from cholesterol by the monooxygenase CYP27A1, which regulates intracellular cholesterol homeostasis. 27HC also acts as an endogenous selective estrogen receptor (ER) modulator capable of increasing breast cancer growth and metastasis. 27HC levels can be modulated by statins or direct inhibition of CYP27A1, thereby attenuating its pro-tumorigenic activities. Herein, the effect of statins on serum 27HC and tumor-specific CYP27A1 expression was evaluated in 42 breast cancer patients treated with atorvastatin within a phase II clinical trial. Further, the associations between CYP27A1 expression with other primary tumor pathological features and clinical outcomes were studied in two additional independent cohorts. Statin treatment effectively decreased serum 27HC and deregulated CYP27A1 expression in tumors. However, these changes were not associated with anti-proliferative responses to statin treatment. CYP27A1 was heterogeneously expressed among primary tumors, with high expression significantly associated with high tumor grade, ER negativity and basal-like subtype. High CYP27A1 expression was independently prognostic for longer recurrence-free and overall survival. Importantly, the beneficial effect of high CYP27A1 in ER-positive breast cancer seemed limited to women aged ≤50 years. These results establish a link between CYP27A1 and breast cancer pathobiology and prognosis and propose that the efficacy of statins in reducing serum lipids does not directly translate to anti-proliferative effects in tumors. Changes in other undetermined serum or tumor factors suggestively mediate the anti-proliferative effects of statins in breast cancer.
Jing Nie, Guang-long Huang, Sheng-Ze Deng, Yun Bao, Ya-Wei Liu, Zhan-Peng Feng, Chao-Hu Wang, Ming Chen, Song-Tao Qi, and Jun Pan
Craniopharyngiomas (CPs) are usually benign, non-metastasizing embryonic malformations originating from the sellar area. They are, however, locally invasive and generate adherent interfaces with the surrounding brain parenchyma. Previous studies have shown the tumor microenvironment is characterized by a local abundance of adenosine triphosphate (ATP), infiltration of leukocytes and elevated levels of pro-inflammatory cytokines that are thought to be responsible, at least in part, for the local invasion. Here, we examine whether ATP, via the P2X7R, participates in the regulation of cytokine expression in CPs. The expression of P2X7R and pro-inflammatory cytokines were measured at the RNA and protein levels both in tumor samples and in primary cultured tumor cells. Furthermore, cytokine modulation was measured after manipulating P2X7R in cultured tumor cells by siRNA-mediated knockdown, as well as pharmacologically by using selective agonists and antagonists. The following results were observed. A number of cytokines, in particular IL-6, IL-8 and MCP-1, were elevated in patient plasma, tumor tissue and cultured tumor cells. P2X7R was expressed in tumor tissue as well as in cultured tumor cells. RNA expression as measured in 48 resected tumors was positively correlated with the RNA levels of IL-6, IL-8 and MCP-1 in tumors. Furthermore, knockdown of P2X7R in primary tumor cultures reduced, and stimulation of P2XR7 by a specific agonist enhanced the expression of these cytokines. This latter stimulation involved a Ca2+-dependent mechanism and could be counteracted by the addition of an antagonist. In conclusion, the results suggest that P2X7R may promote IL-6, IL-8 and MCP-1 production and secretion and contribute to the invasion and adhesion of CPs to the surrounding tissue.
Massimo Bongiovanni, Caterina Rebecchini, Chiara Saglietti, Jean-Luc Bulliard, Laura Marino, Laurence de Leval, and Gerasimos P Sykiotis
Bethany Smith, Priyanka Agarwal, and Neil A Bhowmick
The high degree of conservation in microRNA from Caenorhabditis elegans to humans has enabled relatively rapid implementation of findings in model systems to the clinic. The convergence of the capacity for genomic screening being implemented in the prevailing precision medicine initiative and the capabilities of microRNA to address these changes holds significant promise. However, prostate, ovarian and breast cancers are heterogeneous and face issues of evolving therapeutic resistance. The transforming growth factor-beta (TGFβ) signaling axis plays an important role in the progression of these cancers by regulating microRNAs. Reciprocally, microRNAs regulate TGFβ actions during cancer progression. One must consider the expression of miRNA in the tumor microenvironment a source of biomarkers of disease progression and a viable target for therapeutic targeting. The differential expression pattern of microRNAs in health and disease, therapeutic response and resistance has resulted in its application as robust biomarkers. With two microRNA mimetics in ongoing restorative clinical trials, the paradigm for future clinical studies rests on the current observational trials to validate microRNA markers of disease progression. Some of today’s biomarkers can be translated to the next generation of microRNA-based therapies.
Marcia S Brose, Johannes Smit, Chia-Chi Lin, Fabian Pitoia, Marc Fellous, Yoriko DeSanctis, Martin Schlumberger, Masayuki Tori, and Iwao Sugitani
There are limited treatment options for patients with radioactive iodine refractory, progressive differentiated thyroid cancer. Although there is consensus that multikinase inhibitor therapy should be considered in patients with progressive disease with considerable tumor load or symptomatic disease, uncertainty exists on the optimal timing to treat with a multikinase inhibitor, especially for asymptomatic patients. RIFTOS MKI is an international, prospective, open-label, multicenter, noninterventional study with the primary objective to compare the time to symptomatic progression from study entry in asymptomatic patients with radioactive iodine refractory, progressive differentiated thyroid cancer for whom there is a decision to initiate multikinase inhibitors at study entry (cohort 1) with those for whom there is a decision to not initiate multikinase inhibitors at study entry (cohort 2). Secondary endpoints are overall survival and progression-free survival, which will be compared between cohorts 1 and 2. Additional secondary endpoints are postprogression survival from time of symptomatic progression, duration of and response to each systemic treatment regimen and dosing of sorafenib throughout the treatment period. Asymptomatic, multikinase inhibitor-naive patients aged ≥18 years with histologically/cytologically documented differentiated thyroid cancer that is radioactive iodine refractory are eligible. Patients may receive any therapy for differentiated thyroid cancer, including sorafenib or other multikinase inhibitors if indicated and decided on by the treating physician. In total, 700 patients are estimated to be enrolled from >20 countries. Final analysis will be performed once the last enrolled patient has been followed up with for 24 months (ClinicalTrials.gov identifier: Nbib2303444).
Andrew M K Law, Elgene Lim, Christopher J Ormandy, and David Gallego-Ortega
A cancer cell-centric view has long dominated the field of cancer biology. Research efforts have focussed on aberrant cancer cell signalling pathways and on changes to cancer cell DNA. Mounting evidence demonstrates that many cancer-associated cell types within the tumour stroma co-evolve and support tumour growth and development, greatly modifying cancer cell behaviour, facilitating invasion and metastasis and controlling dormancy and sensitivity to drug therapy. Thus, these stromal cells represent potential targets for cancer therapy. Among these cell types, immune cells have emerged as a promising target for therapy. The adaptive and the innate immune system play an important role in normal mammary development and breast cancer. The number of infiltrating adaptive immune system cells with tumour-rejecting capacity, primarily, T lymphocytes, is lower in breast cancer compared with other cancer types, but infiltration occurs in a large proportion of cases. There is strong evidence demonstrating the importance of the immunosuppressive role of the innate immune system during breast cancer progression. A consideration of components of both the innate and the adaptive immune system is essential for the design and development of immunotherapies in breast cancer. In this review, we focus on the importance of immunosuppressive myeloid-derived suppressor cells (MDSCs) as potential targets for breast cancer therapy.
K M Biernacka, R A Persad, A Bahl, D Gillatt, J M P Holly, and C M Perks
The incidence of many common cancers varies between different populations and appears to be affected by a Western lifestyle. Highly proliferative malignant cells require sufficient levels of nutrients for their anabolic activity. Therefore, targeting genes and pathways involved in metabolic pathways could yield future therapeutics. A common pathway implicated in energetic and nutritional requirements of a cell is the LKB1/AMPK pathway. Metformin is a widely studied anti-diabetic drug, which improves glycaemia in patients with type 2 diabetes by targeting this pathway. We investigated the effect of metformin on prostate cancer cell lines and evaluated its mechanism of action using DU145, LNCaP, PC3 and VCaP prostate cancer cell lines. Trypan blue dye-exclusion assay was used to assess levels of cell death. Western immunoblotting was used to determine the abundance of proteins. Insulin-like growth factor-binding protein-2 (IGFBP-2) and AMPK genes were silenced using siRNA. Effects on cell morphology were visualised using microscopy. IGFBP-2 gene expression was assessed using real-time RT-PCR. With DU145 and LNCaP cells metformin alone induced cell death, but this was reduced in hyperglycaemic conditions. Hyperglycaemia also reduced the sensitivity to Docetaxel, but this was countered by co-treatment with metformin. LKB1 was required for the activation of AMPK but was not essential to mediate the induction of cell death. An alternative pathway by which metformin exerted its action was through downregulation of IGFBP-2 in DU145 and LNCaP cells, independently of AMPK. This finding could have important implications in relation to therapeutic strategies in prostate cancer patients presenting with diabetes.