A source on BRCA1 Selenium and DCA

AMPK a Target for Treatment

Sat, 31 Oct 2009 02:28:58 +0100

AMPK in Health and Disease

Gregory R. Steinberg and Bruce E. Kemp

Protein Chemistry and Metabolism, St. Vincent's Institute of Medical Research, University of Melbourne, Fitzroy, Victoria, Australia

http://physrev.physiology.org/cgi/content/abstract/89/3/1025

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T3 Throws the Switch for AMPK

Sat, 31 Oct 2009 02:16:42 +0100

Thyroid Hormone Activates Adenosine 5'-Monophosphate-Activated Protein Kinase via Intracellular Calcium Mobilization and Activation of Calcium/Calmodulin-Dependent Protein Kinase Kinase-β

http://mend.endojournals.org/cgi/content/abstract/22/4/893

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Elevated total homocysteine concentrations in pregnant women ~ Folate gene polymorphisms, Cobalamin

Wed, 21 Jan 2009 23:57:04 +0100

http://www.nature.com/ejcn/journal/v62/n8/abs/1602810a.html

Association between decreased vitamin levels and MTHFR, MTR and MTRR gene polymorphisms as determinants for elevated total homocysteine concentrations in pregnant women.

Barbosa P, Stabler SP, Machado AL, Braga RC, Hirata RD, Hirata MH, Sampaio-Neto LF, Allen RH, Guerra-Shinohara EM.

Departamento de Análises Clínicas e Toxicológicas, Faculdade de Ciências Farmacêuticas da Universidade de São Paulo, São Paulo, SP, Brazil.

OBJECTIVES: To examine the association between methylenetetrahydrofolate reductase (MTHFR) (C677T and A1298C), methionine synthase (MTR) A2756G and methionine synthase reductase (MTRR) A66G gene polymorphisms and total homocysteine (tHcy), methylmalonic acid (MMA) and S-adenosylmethionine/S-adenosylhomocysteine (SAM/SAH) levels; and to evaluate the potential interactions with folate or cobalamin (Cbl) status.

SUBJECTS/METHODS: Two hundred seventy-five healthy women at labor who delivered full-term normal babies. Cbl, folate, tHcy, MMA, SAM and SAH were measured in serum specimens. The genotypes for polymorphisms were determined by PCR-restriction fragment length polymorphism (RFLP).

RESULTS: Serum folate, MTHFR 677T allele and MTR 2756AA genotypes were the predictors of tHcy levels in pregnant women. Serum Cbl and creatinine were the predictors of SAM/SAH ratio and MMA levels, respectively. The gene polymorphisms were not determinants for MMA levels and SAM/SAH ratios.

Low levels of serum folate were associated with elevated tHcy in pregnant women, independently of the gene polymorphisms.

In pregnant women carrying MTHFR 677T allele, or MTHFR 1298AA or MTRR 66AA genotypes, lower Cbl levels were associated with higher levels of tHcy. Lower SAM/SAH ratio was found in MTHFR 677CC or MTRR A2756AA genotypes carriers when Cbl levels were lower than 142 pmol/l.

CONCLUSIONS: Serum folate and MTHFR C677T and MTR A2576G gene polymorphisms were the determinants for tHcy levels. The interaction between low levels of serum Cbl and MTHFR (C677T or A1298C) or MTRR A66G gene polymorphisms was associated with increased tHcy.

PMID: 17522601 [PubMed - indexed for MEDLINE]

http://www.nature.com/ejcn/journal/v62/n8/abs/1602810a.html

European Journal of Clinical Nutrition (2008) 62, 1010–1021;
doi:10.1038/sj.ejcn.1602810;
published online 23 May 2007

Keywords: cobalamin, folate, polymorphisms, homocysteine, methylmalonic acid, pregnant women

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BRCA1 and BRCA2 mutation carriers Methionine Dependent Phenotype

Wed, 21 Jan 2009 23:09:49 +0100

http://cebp.aacrjournals.org/cgi/content/abstract/17/10/2565

Methionine-dependence phenotype in the de novo pathway in BRCA1 and BRCA2 mutation carriers with and without breast cancer.

Beetstra S Suthers G, Dhillon V, Salisbury C, Turner J, Altree M, McKinnon R, Fenech M

Commonwealth Scientific and Industrial Research Organisation Human Nutrition, South Australia 5000, Australia. sasja.beetstra__siro.au

Methionine-dependence phenotype (MDP) refers to the reduced ability of cells to proliferate when methionine is restricted and/or replaced by its immediate precursor homocysteine. MDP is a characteristic of human tumors in vivo, human tumor cell lines, and normal somatic tissue in some individuals. It was hypothesized that MDP is a risk factor for developing breast cancer in BRCA (BRCA1 and BRCA2) germline mutation carriers.

To test the hypothesis, human peripheral blood lymphocytes of BRCA carriers with and without breast cancer and healthy non-carrier relatives (controls) were cultured for 9 days in medium containing either 0.1 mmol/L L-methionine or 0.2 mmol/L D,L-homocysteine, with the ratio of viable cell growth in both types of medium after 9 days used to calculate the methionine-dependence index (MDI), a measure of MDP. We also tested whether MDP was associated with common polymorphisms in methionine metabolism.

Viable cell growth, MDI, and polymorphism frequency in MTRR (A66G and C524T) and MTHFR (A1298C and A1793G) did not differ among the study groups; however, MDI tended to be higher in BRCA carriers with breast cancer than those without and was significantly increased in MTHFR 677T allele carriers relative to wild-type carriers (P=0.017). The presence of MTR A2756G mutant allele and MTHFR C677T mutant allele in carriers was associated with increased breast cancer risk [odds ration, 3.2 (P=0.16; 95% confidence interval, 0.76-13.9) and 3.9 (P=0.09; 95% confidence interval, 0.93-16.3), respectively].

The results of this study support the hypothesis that defects in methionine metabolism may be associated with breast cancer risk in BRCA carriers.

PMID: 18842997 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/18842997

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ER alpha (Estrogen Receptors) and ERR alpha

Mon, 10 Mar 2008 20:01:35 +0100

Estrogen Induces Estrogen-related Receptor Gene Expression and Chromatin Structural Changes in Estrogen Receptor (ER)-positive and ER-negative Breast Cancer Cells*

http://www.jbc.org/cgi/content/abstract/M705937200v1

J. Biol. Chem., Vol. 283, Issue 11, 6752-6763, March 14, 2008

Peng Hu, H. Karimi Kinyamu, Liangli Wang, Jessica Martin, Trevor K. Archer, and Christina Teng¹

From the Gene Regulation Section, Laboratory of Reproductive and Developmental Toxicology and Chromatin and Gene Expression Section, Laboratory of Molecular Carcinogenesis, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709

Estrogen-related receptor (ERR) alpha, a member of the nuclear receptorsuperfamily, is closely related to the estrogen receptors (ER alpha and ERR alpha).

The ERR alpha gene is estrogen-responsive in severalmouse tissues and cell lines, and a multiple hormone-responseelement (MHRE) in the promoter is an important regulatory regionfor estrogen-induced ERR alpha gene expression.

ERR alpha was recently shownto be a negative prognostic factor for breast cancer survival,with its expression being highest in cancer cells lacking functionalER. The contribution of ERR alpha in breast cancer progression remainsunknown but may have important clinical implications. In thisstudy, we investigated ERR alpha gene expression and chromatin structuralchanges under the influence of 17?-estradiol in both ER-positiveMCF-7 and ER-negative SKBR3 breast cancer cells.

We mapped thenucleosome positions of the ERR alpha promoter around the MHRE regionand found that the MHRE resides within a single nucleosome.

Local chromatin structure of the MHRE exhibited increased restrictionenzyme hypersensitivity and enhanced histone H3 and H4 acetylationupon estrogen treatment. Interestingly, estrogen-induced chromatinstructural changes could be repressed by estrogen antagonistICI 182 780 in MCF-7 cells yet were enhanced in SKBR3 cells.

We demonstrated, using chromatin immunoprecipitation assays,that 17 beta-estradiol induces ERR alpha gene expression in MCF-7cells through active recruitment of co-activators and releaseof co-repressors when ERR and AP1 bind and ER alpha is tethered tothe MHRE. We also found that this estrogen effect requires theMAPK signaling pathway in both cell lines.Link

Comments

BRCA 1 tests Patent ruling EU

Fri, 12 Oct 2007 09:25:10 +0200

http://bmj.com/cgi/content/short/335/7623/740-a?etoc

Scientists welcome ruling on patent on breast cancer gene

but will it still cost an arm and a leg ?

Comments

Tamoxifen may help with HCV as well ?

Sat, 18 Aug 2007 11:31:51 +0200

http://www.jbc.org/cgi/content/abstract/M704418200v1?papetoc

Anti-hepatitis C virus activity of tamoxifen reveals the functional association of estrogen receptor with viral RNA polymerase NS5B

J. Biol. Chem, 10.1074/jbc.M704418200

[[...We found that tamoxifen (TAM) suppressed HCV genome replication...]]

Comments

Polish work ..Obesity-Insulin.. E.Kowalska

Sun, 13 May 2007 09:56:30 +0200

Evaluation of the effect of obesity on selected haemostatic and fibrinolytic parameters in peri- and postmenopausal women

Polac I, Stetkiewicz T, Stachowiak G, Jedrzejczyk S, Pertynski T, Pakalski A, Kowalska E.
Klinika Ginekologii i Chorob Menopauzy Instytutu Centrum Zdrowia Matki Polki w Lodzi.

Localization of adipose tissue influence on obesity-dependent diseases. In obese people many abnormalities are observed connected with coagulation factors and fibrinolysis. We studied 47 peri- and postmenopausal female patients, who were operated on for benign changes within the pelvis minor. The patients were divided according to BMI (group I--BMI <25 kg/m2, group II--BMI > 29 kg/m2). In obese women lower SHBG concentration, higher insulin and glucose fasting blood levels, higher LDL, higher total fatty tissue content, higher fibrinogen level and elevated PAI-1 activity were found. A positive correlation between area under insulin curve and PAI-1 activity and a negative correlation between fasting insulin levels and tPA were also observed.

Based on the studies performed it can be said that:

1. Fatty tissue content in postmenopausal women exerts an influence on PAI-1 activity.
2. Obesity influences coagulation and fibrinolysis system in peri- and postmenopausal women.
3. Carbohydrate metabolism disturbances have influence on PAI-1 activity in peri- and postmenopausal women.

PMID: 12474565 [PubMed - indexed for MEDLINE]

Pol Merkur Lekarski. 2002 Sep;13(75):182-4

Comments

A source on BRCA1 and Selenium

Sun, 13 May 2007 09:33:00 +0200

[I edited the date of first posting to bring this one to the top of the blog ~ originally 2nd January 2006]
can be edited under 'advanced properties' time stamp

Comments

Mitochondrial target of apoptosis

Sun, 13 May 2007 09:13:14 +0200

Metabolic Targeting as an Anticancer Strategy: Dawn of a New Era?

James G. Pan1* and Tak W. Mak2*

1Campbell Family Institute for Breast Cancer Research, University Health Network TMDT East Tower, MaRs Centre, 101 College Street, 5-705, Toronto, ON M5G 1L7, Canada.
2Campbell Family Institute for Breast Cancer Research, University Health Network and Departments of Medical Biophysics and Immunology, University of Toronto, 620 University Avenue, Suite 706, Toronto, ON, M5G 2C1, Canada.

http://dx.doi.org/10.1126/stke.3812007pe14

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p53 and more

Fri, 11 May 2007 20:38:54 +0200

http://www.signaling-gateway.org/update/updates/200705/nrm2168.html

Gain-of-function mutations in the tumor suppressor p53 promote oncogenesis by interfering with DNA repair.

[[...The authors argue that "a novel gain-of-function of common p53 cancer mutants in disrupting critical DNA DSB damage responses will have significant implications on the therapeutic interventions for human cancers that express p53 cancer mutants."...]]

Comments

Folate deficiency and BRCA1/2 mutations

Sat, 08 Jul 2006 13:21:20 +0200

http://carcin.oxfordjournals.org/cgi/content/short/bgi226v1

Lymphocytes of BRCA1 and BRCA2 germ-line mutation carriers, with or without breast cancer, are not abnormally sensitive to the chromosome damaging effect of moderate folate deficiency

Sasja Beetstra 1, 2, Carolyn Salisbury 1, Julie Turner 1, Meryl Altree 3, Ross McKinnon 2, Graeme Suthers 3, 4 and Michael Fenech 1, *

1 CSIRO Human Nutrition, PO Box 10041, Gouger Street, Adelaide BC 5000, SA, Australia, 2 Sansom Research Institute, The University of South Australia, Adelaide 5000, SA, Australia, 3 Familial Cancer Unit, SA Clinical Genetics Service, Children's, Youth and Women's Health Service, North Adelaide 5006, SA, Australia 4 Department of Pediatrics, University of Adelaide, Adelaide 5003, SA, Australia

Mutations in BRCA1 and BRCA2 genes may cause defective DNA repair and increase the risk for breast cancer. Folate deficiency is associated with increased breast cancer risk and induces chromosome abnormalities. We hypothesized that BRCA1 and BRCA2 germline mutation carriers are more sensitive to the genome damaging effect of folate deficiency compared with healthy non-carrier controls and that this sensitivity is further increased in those carriers who develop breast cancer. We tested these hypotheses in lymphocytes cultured in a medium containing 12 or 120 nM folic acid (FA) for 9 days and measured proliferative capacity and chromosomal instability using the cytokinesis-block micronucleus assay. BRCA1 and BRCA2 mutation carriers with or without breast cancer were not abnormally sensitive to FA deficiency-induced chromosome instability; however, BRCA2 mutation carriers had significantly reduced cell proliferation. FA deficiency reduced cell proliferation and increased micronucleus formation significantly, accounting for 45–59% and 70–75% of the variance in these parameters compared with 0.3–8.5% and 0.2–0.3% contributed by BRCA1 or BRCA2 mutation carrier status, respectively. The results of this study suggest that moderate folate deficiency has a stronger effect on chromosomal instability than BRCA1 or BRCA2 mutations found in breast cancer families.

~ so folate deficiency might be more risky than having a BRCA 1 or BRCA 2 mutation?
Bob

Edit:- but see
http://jn.nutrition.org/cgi/content/full/130/2/129
Folate and Carcinogenesis: An Integrated Scheme
and ~
http://tealady-health.blog.co.uk/2006/09/09/thiamin_transporters~1110229

edit trackback
http://www.blog.co.uk/htsrv/trackback3.php/1139057/68531

http://www.blog.co.uk/htsrv/trackback3.php/1146252/f6a5b

Comments

Breast Cancer (Prodigy)

Tue, 21 Mar 2006 21:30:48 +0100

http://www.prodigy.nhs.uk/ProdigyKnowledge/Guidance/GuidanceView.aspx?GuidanceId=37367&TypeId=1

Breast cancer - managing women with a family history

Patient Information Leaflet (PIL) @ ~
http://www.prodigy.nhs.uk/ProdigyKnowledge/PatientInformation/PatientInformationView.aspx?GuidanceId=37367

Comments

Some respite on testing...

Tue, 21 Mar 2006 18:54:41 +0100

http://www.dh.gov.uk/PublicationsAndStatistics/PressReleases/fs/en

Restrictions on genetic testing and insurance extended to 2011

as of last year ~
Published: Monday 14 March 2005Reference number: 2005/0112

Comments

BRCA1 and BRCA2 Clinical management

Mon, 27 Feb 2006 12:36:02 +0100

Clinical management of BRCA1 and BRCA2 mutation carriers

http://www.nature.com/ncponc/journal/v3/n1/full/ncponc0384.html

Abramson Cancer Center, University of Pennsylvania, 14 Penn Tower, 3400 Spruce Street, Philadelphia, PA 19014, USA

Susan M Domchek*, Katrina Armstrong and Barbara L Weber

[[More than a decade has passed since the cancer predisposition genes BRCA1 and BRCA2 were identified. Collectively, these genes appear to be responsible for cancer predisposition in virtually all families with hereditary breast/ovarian cancer, and a smaller subset of families with hereditary site-specific breast cancer. Fortunately, effective strategies have been developed to reduce the risk of breast and ovarian cancer in women with BRCA1/2 mutations, making genetic testing for these mutations an important part of the management of women with a strong family history of these diseases. Here we review the current evidence for risk reduction strategies and outline future research directions....]]

Nature Clinical Practice Oncology (2006) 3, 2-3
doi:10.1038/ncponc0384

Bob

Comments

Selenium database

Wed, 22 Feb 2006 18:13:10 +0100

http://www.charite.de/selenoprotein/deutsch/index1.html

Veranstaltungen und Auszeichnungen
Selenium 2006 International Symposium
25th - 30th July 2006,
Madison, Wisconsin USA

Infos Poster

Selenoprotein Genomics
Se Incorporation into Selenoproteins
Characterization of Selenoproteins and their Function
Enzymes and Metabolites in Se Metabolism
Selenoprotein Knockout Models
Selenium - Virus Interactions
Human Se Metabolism and Requirements
Se and Cancer Chemoprevention
Se Metabolism and Speciation in Plants
Se in Domestic Animals
Bacterial Selenoenzymes and Unique Se Metabolism
Se in the Environment
Se and Reactive Oxygen and Nitrogen Species

Bob

Comments

BRCA1 and p53 interactions

Mon, 20 Feb 2006 13:02:11 +0100

Functional and physical interactions between BRCA1 and p53 in transcriptional regulation of the IGF-IR gene.

Abramovitch S, Werner H.

Department of Clinical Biochemistry, Sackler School of Medicine, Tel Aviv University, Israel.

The insulin-like growth factor-I receptor (IGF-IR) mediates the biological actions of the IGFs, and is critical for normal mammary gland development as well as for malignant transformation.

Transcription of the IGF-IR gene is under inhibitory control by a number of transcription factors with tumor suppressor activity, including BRCA1 and p53. To assess the potential functional interactions between BRCA1 and p53 in transcriptional control of the IGF-IR gene, co-transfections were performed on MCF-7 breast cancer cells using an IGF-IR promoter luciferase reporter construct together with expression vectors encoding BRCA1 and wild-type and mutant p53.

Similar experiments were performed in the colorectal cancer cell line HCT116 (+/+), which expresses a wild-type p53 gene, and its HCT116 (-/-) derivative, which lacks p53. BRCA1 was able to suppress IGF-IR promoter activity both in the absence and presence of p53. However, BRCA1 had no effect in mutant p53-expressing cells. Co-immunoprecipitation experiments showed that BRCA1 and p53 physically interact.

In summary, our data suggest that the transcriptional activity of BRCA1 depends on the cellular status of p53. Inability of mutant tumor suppressors to repress IGF-IR gene expression may result in increased IGF-IR levels and IGF binding, leading to a reduction in apoptosis and enhanced survival capacity of malignant cells.

Horm Metab Res. 2003 Nov-Dec;35(11-12):758-62
PMID: 14710355 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14710355&query_hl=42&itool=pubmed_DocSum

Comments

Crystal structure of the BRCT repeat region from BRCA1.

Sat, 11 Feb 2006 23:11:47 +0100

http://www.rcsb.org/pdb/pubmed.do?structureId=1JNX

Crystal structure of the BRCT repeat region from the breast cancer-associated protein BRCA1.

Amino Acid Sequence, BRCA1 Protein, Breast Neoplasms, Crystallography, X-Ray, Genes, Tumor Suppressor, Humans, Hydrolysis, Molecular Sequence Data, Mutation, Peptide Mapping, Protein Conformation, Repetitive Sequences, Amino Acid, Research Support, Non-U.S. Gov't, Sequence Homology, Amino Acid

Comments

both Ends (N&C terminals) of BRCA1 needed

Sat, 11 Feb 2006 14:19:25 +0100

http://www.jbc.org/cgi/content/abstract/C500475200v1?etoc

Direct stimulation of transcription initiation by BRCA1 requires both its amino and carboxy-termini

Andrew A. Horwitz, Satish Sankaran, and Jeffrey D. Parvin

Published experiments suggest that BRCA1 interaction with RNAPII and regulation of a number of target genes may be central to its role as a tumor suppressor. Previous in vivo and in vitro work has implicated the carboxy-terminus of BRCA1 in transcriptional stimulation, but the mechanism of action remains unknown, and whether the full-length protein stimulates transcription is controversial. BRCA1 interacts with a number of enhancer-binding transcriptional activators, suggesting that these factors recruit BRCA1 to promoters, where it stimulates RNA synthesis. To investigate whether BRCA1 has intrinsic transcriptional activity, we established a fully purified transcription assay. We demonstrate here that BRCA1 stimulates transcription initiation across a range of promoters. Both the amino and carboxy-termini of BRCA1 are required for this activity, but the BRCA1 binding partner, BARD1, is not. Our data support a model whereby BRCA1 stabilizes productive pre-initiation complexes and thus stimulates transcription.

Comments

Phenyl Isothiocyanate and Curcumin ~ Prostate cancer

Sat, 11 Feb 2006 14:09:37 +0100

http://cancerres.aacrjournals.org/cgi/content/abstract/66/2/613

Combined Inhibitory Effects of Curcumin and Phenethyl Isothiocyanate on the Growth of Human PC-3 Prostate Xenografts in Immunodeficient Mice

Tin Oo Khor1,2, Young-Sam Keum1,2, Wen Lin1,2, Jung-Hwan Kim1,2, Rong Hu1,2, Guoxiang Shen1,2, Changjiang Xu1,2, Avanthika Gopalakrishnan1,2, Bandaru Reddy1,3, Xi Zheng1,3, Allan H. Conney1,3 and Ah-Ng Tony Kong1,2

Earlier studies using prostate cancer cells in culture showed that phenethyl isothiocyanate (PEITC) and curcumin have significant chemopreventive and possibly chemotherapeutic effects. However, their in vivo effects are still lacking. Hence, this study was undertaken to determine the possible in vivo efficacy of prostate cancer-prevention as well as cancer-therapeutic treatment by PEITC and curcumin alone or in combination. We evaluated the effects on tumor growth in vivo, using NCr immunodeficient (nu/nu) mice bearing s.c. xenografts of PC-3 human prostate cancer cells. Molecular biomarkers representing proliferation and apoptosis were determined. Continued i.p. injection of curcumin or PEITC (6 and 5 µmol; thrice a week for 28 days), beginning a day before tumor implantation significantly retarded the growth of PC-3 xenografts. Combination of i.p. administration of PEITC (2.5 µmol) and curcumin (3 µmol) showed stronger growth-inhibitory effects. Next, we evaluated the cancer-therapeutic potential of curcumin and PEITC in mice with well-established tumors, and the results showed that PEITC or curcumin alone had little effect, whereas combination of curcumin and PEITC significantly reduced the growth of PC-3 xenografts. Immunohistochemistry staining and Western blot analysis revealed that the inhibition of Akt and nuclear factor-B signaling pathways could contribute to the inhibition of cell proliferation and induction of apoptosis. Taken together, our results show that PEITC and curcumin alone or in combination possess significant cancer-preventive activities in the PC-3 prostate tumor xenografts. Furthermore, we found that combination of PEITC and curcumin could be effective in the cancer-therapeutic treatment of prostate cancers. (Cancer Res 2006; 66(2): 613-21)

Comments

BRCA1 and BRCA2 risks and prevention

Fri, 10 Feb 2006 09:20:40 +0100

http://www.jco.org/cgi/content/full/18/suppl_1/93s#TBL10225

Chemoprevention Options for BRCA1 and BRCA2 Mutation Carriers

By Rosalind A. Eeles, Trevor J. Powles

From the Institute of Cancer Research, The Royal Marsden National Health Service (NHS) Trust, Sutton, Surrey, United Kingdom.

BRCA1 and BRCA2 breast cancer predisposition gene mutation carriers are at markedly increased risk of breast and other cancers. The consideration of chemopreventative options will depend on the cancer site and age-specific penetrance curve. Most chemoprevention studies to date have investigated the role of endocrine intervention in women at increased risk of breast cancer, and study results are conflicting. At the present time, there is uncertainty regarding whether endocrine intervention, particularly with tamoxifen, is as effective in BRCA1 and BRCA2 mutation carriers as in other women who are at increased risk of breast cancer because of hormonal factors or genes with moderately conferred cancer risks. Furthermore, if chemoprevention were needed for at least 10 years to produce an effect, new chemoprevention agents will need to be developed for women in their 30s, as the breast cancer risk curves are steepest between 40 and 50 years of age. Consideration is now being given to types of chemoprevention in this younger age group. There is also an increased risk of other cancers (in particular ovarian cancer and, in men, prostate cancer), and considerations regarding chemoprevention will have to encompass cancer at these sites.

Comments

Estrogen Receptor alpha and p53

Fri, 10 Feb 2006 08:55:20 +0100

http://www.jbc.org/cgi/content/abstract/C600001200v1?etoc

Estrogen receptor- binds p53 tumor suppressor protein directly and represses its function

Wensheng Liu, Santhi D. Konduri, Sanjay Bansal, Bijaya K. Nayak, Sigrid A. Rajasekaran, Sankunny M. Karuppayil, Ayyappan K. Rajasekaran, and Gokul M. Das

Pharmacology & Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263

Estrogen receptor- (ER) promotes cell proliferation of breast cancer cells whereas tumor suppressor protein p53 impedes proliferation of cells with genomic damage. Whether there is a direct link between these two antagonistic pathways has remained unclear. Here we report that ER binds directly to p53 and negatively regulates its function. The activation function-2 (AF-2) domain of ER and the C-terminal regulatory domain of p53 are necessary for the interaction. Knocking down p53 and ER by small interfering RNA (siRNA) elicits opposite effects on p53-target gene expression and cell cycle progression. Remarkably, ionizing radiation that causes genomic damage disrupts the interaction between ER and p53. Ionizing radiation together with ERa knock down results in an additive effect on transcription of endogenous p53-target gene p21 (CDKN1) in human breast cancer cells. Our findings reveal a novel mechanism for regulating p53 and suggest that suppressing p53 function is an important component in the pro-proliferative role of ER.

Comments

The Brassicas have it..!

Thu, 09 Feb 2006 05:56:06 +0100

British Journal of Cancer (2006) 94, 407-426.
doi:10.1038/sj.bjc.6602935 Published online 24 January 2006

http://www.nature.com/bjc/journal/v94/n3/full/6602935a.html

BRCA1 and BRCA2 as molecular targets for phytochemicals indole-3-carbinol and genistein in breast and prostate cancer cells

S Fan(1), Q Meng(1), K Auborn(2), T Carter(2) and E M Rosen(1)

Indole-3-carbinol (I3C) and genistein are naturally occurring chemicals derived from cruciferous vegetables and soy, respectively, with potential cancer prevention activity for hormone-responsive tumours (e.g., breast and prostate cancers). Previously, we showed that I3C induces BRCA1 expression and that both I3C and BRCA1 inhibit oestrogen (E2)-stimulated oestrogen receptor (ER-alpha) activity in human breast cancer cells. We now report that both I3C and genistein induce the expression of both breast cancer susceptibility genes (BRCA1 and BRCA2) in breast (MCF-7 and T47D) and prostate (DU-145 and LNCaP) cancer cell types, in a time- and dose-dependent fashion
.........

PMID: 16434996 [PubMed - as supplied by publisher]

Indole-3-carbinol
Tryptophan with the glycine removed, leaving only a CH2OH group in its place at the -3- position
http://www.thorne.com/altmedrev/.fulltext/10/4/337.pdf

'Brassicas' have the 'equipment'

Bob

Comments

IGF-1 ~ Growth Factor

Fri, 13 Jan 2006 01:28:07 +0100

Insulin-like growth factor 1 (IGF-1): a growth hormone

Prof Z. Laron

http://mp.bmjjournals.com/cgi/content/full/54/5/311

Abstract
Aim—To contribute to the debate about whether growth hormone (GH) and insulin-like growth factor 1 (IGF-1) act independently on the growth process.
Methods—To describe growth in human and animal models of isolated IGF-1 deficiency (IGHD), such as in Laron syndrome (LS; primary IGF-1 deficiency and GH resistance) and IGF-1 gene or GH receptor gene knockout (KO) mice.
Results—Since the description of LS in 1966, 51 patients were followed, many since infancy. Newborns with LS are shorter (42–47 cm) than healthy babies (49–52 cm), suggesting that IGF-1 has some influence on intrauterine growth. Newborn mice with IGF-1 gene KO are 30% smaller. The postnatal growth rate of patients with LS is very slow, the distance from the lowest normal centile increasing progressively. If untreated, the final height is 100–136 cm for female and 109–138 cm for male patients. They have acromicia, organomicria including the brain, heart, gonads, genitalia, and retardation of skeletal maturation. The availability of biosynthetic IGF-1 since 1988 has enabled it to be administered to children with LS. It accelerated linear growth rates to 8–9 cm in the first year of treatment, compared with 10–12 cm/year during GH treatment of IGHD. The growth rate in following years was 5–6.5 cm/year.
Conclusion—IGF-1 is an important growth hormone, mediating the protein anabolic and linear growth promoting effect of pituitary GH. It has a GH independent growth stimulating effect, which with respect to cartilage cells is possibly optimised by the synergistic action with GH.
Key Words: insulin-like growth factor I • growth hormones • Laron syndrome • growth
Z Laron
Endocrinology and Diabetes Research Unit, WHO Collaborating Center for the Study of Diabetes in Youth, Schneider Children's Medical Center, Tel Aviv University, 14 Kaplan Street, Petah Tikva 49202, Tel Aviv, Israel
Correspondence: Professor Laron laronz@clalit.org.il
Accepted for publication April 24, 2001
Clin Pathol: Mol Pathol 2001; 54:311-316
© 2001 Journal of Clinical Pathology
http://mp.bmjjournals.com/cgi/content/full/54/5/311

http://mp.bmjjournals.com/cgi/external_ref?access_num=11577173&link_type=PUBMED

[[.....IGF-1 and IGF-2 were identified in 1957 by Salmon and Daughaday8 and designated "sulphation factor" by their ability to stimulate 35-sulphate incorporation into rat cartilage. Froesch et al described the non-suppressible insulin-like activity (NSILA) of two soluble serum components (NSILA I and II).9 In 1972, the labels sulphation factor and NSILA were replaced by the term "somatomedin", denoting a substance under control and mediating the effects of GH.10 In 1976, Rinderknecht and Humbel11 isolated two active substances from human serum, which owing to their structural resemblance to proinsulin were renamed "insulin-like growth factor 1 and 2" (IGF-1 and 2). IGF-1 is the mediator of the anabolic and mitogenic activity of GH....]]

[[.....The IGFs are members of a family of insulin related peptides that include relaxin and several peptides isolated from lower invertebrates.13 IGF-1 is a small peptide consisting of 70 amino acids with a molecular weight of 7649 Da....]]

Comments

IGF-1 Neuroprotection UCP3

Thu, 12 Jan 2006 22:28:25 +0100

http://www.diva-portal.org/diva/getDocument?urn_nbn_se_su_diva-121-1__fulltext.pdf

Abstract
Diabetic neuropathy is believed to arise due to oxidative stress following
hyperglycemic situations. Uncoupling proteins (UCPs) constitute a subgroup
of mitochondrial transporter proteins with putative antioxidant properties. By
dissipating the proton gradient over the mitochondrial inner membrane, these
proteins reduce the mitochondrial inner membrane potential (MMP), and
thereby, the mitochondrial production of reactive oxygen species (ROS) is
decreased. In this thesis I have examined the regulation of UCP2, UCP3, and
UCP4 by the neuroprotective hormone insulin-like growth factor type 1 (IGF-
1). I have also investigated the possible involvement of UCP3 in IGF-1-
mediated neuroprotection following high glucose treatments. All studies were
performed using human neuroblastoma SH-SY5Y cells as an in vitro cell
model. The major findings were as follows:
i. Native SH-SY5Y cells expressed UCP2, UCP3, and UCP4.
ii. UCP3 was upregulated by IGF-1 via activation of the IGF-1 receptor. IGF-
1 increased UCP3 mRNA and protein levels primarily via activation of the
“classical” anti-apoptotic phosphatidyl inositol 3 (PI3)-kinase signaling
pathway, as shown by incubation with specific inhibitors of the PI3-kinase
and mitogen activated protein (MAP) kinase signaling pathways.
iii. UCP2 and UCP4 protein levels were only marginally or not at all
regulated by IGF-1. These UCPs are probably not involved in IGF-1-
mediated neuroprotection.
iv. High glucose concentrations reduced the UCP3 protein levels in highly
differentiated SH-SY5Y cells. Concomitantly, the MMP and the levels of
ROS and glutathione increased, whereas the number of neurites per cell
was reduced. This supports an antioxidant and neuroprotective role of
UCP3
v. IGF-1 prevented the glucose-induced reduction in UCP3 protein levels. In
parallel, the effects on MMP, levels of ROS and glutathione, and number
of neurites per cell were abolished or significantly reduced. These data
suggest that UCP3 is involved in IGF-1-mediated neuroprotection.

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TSH and LEPTIN variation in Obesity (Premenopausal)

Wed, 04 Jan 2006 04:41:04 +0100

SPONTANEOUS DIURNAL TSH SECRETION IS ENHANCED IN PROPORTION TO CIRCULATING LEPTIN IN OBESE PREMENOPAUSAL WOMEN

http://jcem.endojournals.org/cgi/content/short/jc.2005-0003v1

Context. Recent evidence implicates leptin as an important modulator of thyroid axis activity.

Objective. To study spontaneous 24 h TSH secretion and 24 h circulating leptin concentrations in obese and lean women.

Design. Prospective parallel study (2004).

Setting. Clinical Research Center LUMC.

Participants. 12 healthy obese premenopausal women (BMI 33.2 ± 0.9 kg/m2) and 11 lean controls (BMI 21.4 ± 0.5 kg/m2) were studied in the follicular phase of their menstrual cycle.

Intervention(s). None.

Main Outcome Measure(s). Spontaneous 24 h TSH concentrations (10 min time intervals) and secretion, calculated using waveform-independent deconvolution technique (Pulse). 24 h circulating leptin concentrations (20 min time intervals).

Results. Mean TSH concentration (obese 1.9 ± 0.2 vs. lean 1.1 ± 0.1 mU/L, P = 0.009) and secretion rate (obese 43.4 ± 5.5 vs. in lean 26.1 ± 2.2 mU/liter distribution volume. 24 h, P = 0.011) were substantially enhanced in obesity, whereas the fasting free thyroxine concentrations were similar (free T4 in obese 15.4 ± 1.5 vs. in lean 16.4 ± 1.5 pmol/L, P = 0.147). TSH secretion was positively related to 24 h leptin concentrations (R2 = 0.31, P = 0.007).

Conclusions. TSH release is enhanced in the face of normal plasma free thyroxine concentrations in obese premenopausal women and hyperleptinemia may well be involved in this neuroendocrine alteration.

Key words: Hormone Rhythms • Body Fat Distribution • Obesity • Circadian

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Endocrine System - Selenium

Wed, 04 Jan 2006 04:23:39 +0100

http://edrv.endojournals.org/cgi/content/abstract/26/7/944

Selenium, the Thyroid, and the Endocrine System

Recent identification of new selenocysteine-containing proteins has revealed relationships between the two trace elements selenium (Se) and iodine and the hormone network. Several selenoproteins participate in the protection of thyrocytes from damage by H(2)O(2) produced for thyroid hormone biosynthesis. Iodothyronine deiodinases are selenoproteins contributing to systemic or local thyroid hormone homeostasis. The Se content in endocrine tissues (thyroid, adrenals, pituitary, testes, ovary) is higher than in many other organs. Nutritional Se depletion results in retention, whereas Se repletion is followed by a rapid accumulation of Se in endocrine tissues, reproductive organs, and the brain. Selenoproteins such as thioredoxin reductases constitute the link between the Se metabolism and the regulation of transcription by redox sensitive ligand-modulated nuclear hormone receptors. Hormones and growth factors regulate the expression of selenoproteins and, conversely, Se supply modulates hormone actions. Selenoproteins are involved in bone metabolism as well as functions of the endocrine pancreas and adrenal glands. Furthermore, spermatogenesis depends on adequate Se supply, whereas Se excess may impair ovarian function. Comparative analysis of the genomes of several life forms reveals that higher mammals contain a limited number of identical genes encoding newly detected selenocysteine-containing proteins.

PMID: 16174820 [PubMed - in process]

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Critical Illness and Thyroid

Tue, 03 Jan 2006 06:33:05 +0100

Serum 3,3',5'-Triiodothyronine (rT3) and 3,5,3'-Triiodothyronine/rT3 Are Prognostic Markers in Critically Ill Patients and Are Associated with Postmortem Tissue Deiodinase Activities

http://jcem.endojournals.org/cgi/content/abstract/90/8/4559

Robin P. Peeters, Pieter J. Wouters, Hans van Toor, Ellen Kaptein, Theo J. Visser and Greet Van den Berghe

Introduction and Methods: Critical illness is associated with reduced TSH and thyroid hormone secretion, and with changes in peripheral thyroid hormone metabolism, resulting in low serum T3 and high rT3. In 451 critically ill patients who received intensive care for more than 5 d, serum thyroid parameters were determined on d 1, 5, 15, and last day (LD). All patients had been randomized for intensive or conventional insulin treatment. Seventy-one patients died, and postmortem liver and skeletal muscle biopsies were obtained from 50 of them for analysis of deiodinase (D1–3) activities.

Results: Insulin treatment did not affect thyroid parameters. On d 1, rT3 was higher and T3/rT3 was lower in nonsurvivors as compared with survivors (P = 0.001). Odds ratio for survival of the highest vs. the lowest quartile was 0.3 for rT3 and 2.9 for T3/rT3. TSH, T4, and T3 were lower in nonsurvivors from d 5 until LD (P less than 0.001). TSH, T4, T3, and T3/rT3 increased over time in survivors, but decreased or remained unaltered in nonsurvivors. Liver D1 activity was positively correlated with LD serum T3/rT3 (R = 0.83, P less than 0.001) and negatively correlated with rT3 (R = –0.69, P less than 0.001). Both liver and skeletal muscle D3 activity were positively correlated with LD serum rT3 (R = 0.32, P = 0.02 and R = 0.31, P = 0.03).

Conclusion: In critically ill patients who required more than 5 d of intensive care, rT3 and T3/rT3 were already prognostic for survival on d 1. On d 5, T4, T3, but also TSH levels are higher in patients who will survive. Serum rT3 and T3/rT3 were correlated with postmortem tissue deiodinase activities.

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Endocrine system and Selenium

Tue, 03 Jan 2006 06:06:28 +0100

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&list_uids=16174820&dopt=Abstract

PMID: 16174820 [PubMed - in process]

Edit:-
Serum Selenium tested 78mcg/L (range 70 - 130)

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