Zinc transporters in prostate cancer

Prostate cancer is a major health concern as it has the second highest incidence rate among cancers in men. Despite progress in tumor diagnostics and therapeutic approaches, prognosis for men with advanced disease remains poor. In this review we provide insight into the changes of the intermediary metabolism in normal prostate and prostate cancer. In contrast to normal cells, prostate cancer cells are reprogrammed for optimal energy-efficiency with a functional Krebs cycle and minimal apoptosis rates. A key element in this relationship is the uniquely high zinc level of normal prostate epithelial cells. Zinc is transported by the SLC30 and SLC39 families of zinc transporters. However, in prostate cancer the intracellular zinc content is remarkably reduced and expression levels of certain zinc transporters are altered. Here, we summarize the role of different zinc transporters in the development of prostate cancer.

Solute carriers (SLCs) in cancer

During tumor progression cells acquire an altered metabolism, either as a cause or as a consequence of an increased need of energy and nutrients. All four major classes of macromolecules are affected: carbohydrates, proteins, lipids and nucleic acids. As a result of the changed needs, solute carriers (SLCs) which are the major transporters of these molecules are differently expressed. This renders them important targets in the treatment of cancer. Blocking or activating SLCs is one possible therapeutic strategy. For example, some SLCs are upregulated in tumor cells due to the increased demand for energy and nutritional needs. Thus, blocking them and turning off the delivery of fuel or nutrients could be one way to interfere with tumor progression. Specific drug delivery to cancer cells via transporters is another approach. Some SLCs are also interesting as chemosensitizing targets because blocking or activating them may result in an altered response to chemotherapy. In this review we summarize the roles of SLCs in cancer therapy and specifically their potential as direct or indirect targets, as drug carriers or as chemosensitizing targets.

Estrogen receptor β expression and androgen receptor phosphorylation correlate with a poor clinical outcome in hormone-naive prostate cancer and are elevated in castration-resistant disease

Patients with advanced prostate cancer (PC) are usually treated with androgen withdrawal. While this therapy is initially effective, nearly all PCs become refractory to it. As hormone receptors play a crucial role in this process, we constructed a tissue microarray consisting of PC samples from 107 hormone-naïve (HN) and 101 castration-resistant (CR) PC patients and analyzed the androgen receptor (AR) gene copy number and the protein expression profiles of AR, Serin210-phosphorylated AR (pAR(210)), estrogen receptor (ER)β, ERα and the proliferation marker Ki67. The amplification of the AR gene was virtually restricted to CR PC and was significantly associated with increased AR protein expression (P<0.0001) and higher tumor cell proliferation (P=0.001). Strong AR expression was observed in a subgroup of HN PC patients with an adverse prognosis. In contrast, the absence of AR expression in CR PC was significantly associated with a poor overall survival. While pAR(210) was predominantly found in CR PC patients (P<0.0001), pAR(210) positivity was observed in a subgroup of HN PC patients with a poor survival (P<0.05). Epithelial ERα expression was restricted to CR PC cells (9%). ERβ protein expression was found in 38% of both HN and CR PCs, but was elevated in matched CR PC specimens. Similar to pAR(210), the presence of ERβ in HN patients was significantly associated with an adverse prognosis (P<0.005). Our results strongly suggest a major role for pAR(210) and ERβ in HN PC. The expression of these markers might be directly involved in CR tumor growth.

Development and preliminary validation of the cancer family impact scale for colorectal cancer

This study aimed to develop and validate The Cancer Family Impact Scale (CFIS), an instrument for use in studies investigating relationships among family factors and colorectal cancer (CRC) screening when family history is a risk factor. We used existing data to develop the measure from 1,285 participants (637 families) across the United States who were in the Johns Hopkins Colon Cancer Genetic Testing study. Participants were 94% white with an average age of 50.1 years, and 60% were women. None had a personal CRC history, and eighty percent had 1 FDR with CRC and 20% had more than one FDR with CRC. The study had three aims: (1) to identify the latent factors underlying the CFIS via exploratory factor analysis (EFA); (2) to confirm the findings of the EFA via confirmatory factor analysis (CFA); and (3) to assess the reliability of the scale via Cronbach's alpha. Exploratory analyses were performed on a split half of the sample, and the final model was confirmed on the other half. The EFA suggested the CFIS was an 18-item measure with 5 latent constructs: (1) NEGATIVE: negative effects of cancer on the family; (2) POSITIVE: positive effects of cancer on the family; (3) COMMUNICATE: how families communicate about cancer; (4) FLOW: how information about cancer is conveyed in families; and (5) NORM: how individuals react to family norms about cancer. CFA on the holdout sample showed the CFIS to have a reasonably good fit (Chi-square = 389.977, df = 122, RMSEA= 0.058 (.052-.065), CFI=.902, TLI=.877, GF1=.939). The overall reliability of the scale was α=0.65. The reliability of the subscales was: (1) NEGATIVE α = 0.682; (2) POSITIVE α = 0.686; (3) COMMUNICATE α = 0.723; (4) FLOW α = 0.467; and (5) NORM α = 0.732. ^ We concluded the CFIS to be a good measure with most fit levels over 0.90. The CFIS could be used to compare theoretically driven hypotheses about the pathways through which family factors could influence health behavior among unaffected individuals at risk due to family history, and also aid in the development and evaluation of cancer prevention interventions including a family component. ^

THE IMPACT OF FAMILY HISTORY ON MEDULLARY THYROID CANCER IN MEN2A PATIENTS

The American Thyroid Association recently classified all MEN2A-associated codons into increasing risk levels A-C and stated that some patients may delay prophylactic thyroidectomy if certain criteria are met. One criterion is a less aggressive family history of MTC but whether families with the same mutated codon have variable MTC aggressiveness is not well described. We developed several novel measures of MTC aggressiveness and compared families with the same mutated codon to determine if there is significant inter-familial variability. Pedigrees of families with MEN2A were reviewed for codon mutated and proportion of RET mutation carriers with MTC. Individuals with MTC were classified as having local or distant MTC and whether they had progressive MTC. MTC status and age were assessed at diagnosis and most advanced MTC stage. For those without MTC, age was recorded at prophylactic thyroidectomy or last follow-up if the patient did not have a thyroidectomy. For each pedigree, the mean age of members without MTC, with MTC, and the proportion of RET mutation carriers with local or distant and progressive MTC were calculated. We assessed differences in these variables using ANOVA and the Fisher’s exact test. Sufficient data for analysis were available for families with mutated codons 609 (92 patients from 13 families), 618 (41 patients from 7 families), and 634 (152 patients from 13 families). The only significant differences found were the mean age of patients without MTC between families with codon 609 and 618 mutations even after accounting for prophylactic thyroidectomy (p=0.006 and 0.001, respectively), and in the mean age of MTC diagnosis between families with codon 618 and 634 mutations even after accounting for symptomatic presentation (p=0.023 and 0.014, respectively). However, these differences may be explained by generational differences in ascertainment of RET carriers and the availability of genetic testing when the proband initially presented.

Understanding multiple endocrine neoplasia type 1.

Mode of access: Internet.

Endocrine therapy in general practice,

"Published in response to requests for the printing of a series f lectures given before a variety of medical organizations during the last two years."--Pref.

Endocrine therapy in general practice /

Includes bibliographical references and index.

Ductless and other glands; a popular account of their nature and functions,

Mode of access: Internet.

Adrenomedullin and calcitonin gene-related peptide receptors in endocrine-related cancers:opportunities and challenges

Adrenomedullin (AM), adrenomedullin 2 (AM2/intermedin) and calcitonin gene-related peptide (CGRP) are members of the calcitonin family of peptides. They can act as growth or survival factors for a number of tumours, including those that are endocrine-related. One mechanism through which this occurs is stimulating angiogenesis and lymphangiogenesis. AM is expressed by numerous tumour types and for some cancers, plasma AM levels can be correlated with the severity of the disease. In cancer models, lowering AM content or blocking AM receptors can reduce tumour mass. AM receptors are complexes formed between a seven transmembrane protein, calcitonin receptor-like receptor and one of the two accessory proteins, receptor activity-modifying proteins (RAMPs) 2 or 3 to give the AM1 and AM2 receptors respectively. AM also has affinity at the CGRP receptor, which uses RAMP1. Unfortunately, due to a lack of selective pharmacological tools or antibodies to distinguish AM and CGRP receptors, the precise receptors and signal transduction pathways used by the peptides are often uncertain. Two other membrane proteins, RDC1 and L1/G10D (the 'ADMR'), are not currently considered to be genuine CGRP or AM receptors. In order to properly evaluate whether AM or CGRP receptor inhibition has a role in cancer therapy, it is important to identify which receptors mediate the effects of these peptides. To effectively distinguish AM1 and AM2 receptors, selective receptor antagonists need to be developed. The development of specific CGRP receptor antagonists suggests that this is now feasible.

HNF1B variants associate with promoter methylation and regulate gene networks activated in prostate and ovarian cancer

Two independent regions within HNF1B are consistently identified in prostate and ovarian cancer genome-wide association studies (GWAS); their functional roles are unclear. We link prostate cancer (PC) risk SNPs rs11649743 and rs3760511 with elevated HNF1B gene expression and allele-specific epigenetic silencing, and outline a mechanism by which common risk variants could effect functional changes that increase disease risk: functional assays suggest that HNF1B is a pro-differentiation factor that suppresses epithelial-to-mesenchymal transition (EMT) in unmethylated, healthy tissues. This tumor-suppressor activity is lost when HNF1B is silenced by promoter methylation in the progression to PC. Epigenetic inactivation of HNF1B in ovarian cancer also associates with known risk SNPs, with a similar impact on EMT. This represents one of the first comprehensive studies into the pleiotropic role of a GWAS-associated transcription factor across distinct cancer types, and is the first to describe a conserved role for a multi-cancer genetic risk factor.

Functional characterisation of putative Cis-Regulatory Risk Loci for breast cancer

Dissertação de Mestrado, Qualidade em Análises - Erasmus Mundus, Faculdade de Ciências e Tecnologia, Universidade do Algarve, 2015