Erfelijke borstkanker
Epigenetica & borstkanker
5 à 10 % ---------------------------< 2 % Vrouwen die drager zijn van het borstkankergen BRCA 1 of 2 hebben 55 tot 85% kans om voor hun 80ste borstkanker te krijgen. De kans op eierstokkanker bedraagt 40-60 % (bij het BRCA1) en 15-20 % (bij BCRA2).
Gabriël Devriendt
Borstkankergenen en de risico's Vrouwen die drager zijn van de borstkankergenen BRCA-1, BRCA-2 of beide, lopen minder risico om daadwerkelijk borstkanker te krijgen dan tot nu toe werd aangenomen. Dat schrijft de epidemioloog Colin Begg in het Journal of the National Cancer Institute. De te hoge risico's zijn het gevolg van de methodologisch zwakke opzet van de studies waarin de kans op borstkanker bij dragerschap van de genen zijn berekend. Deze familiestudies gaan namelijk uit van groepen borstkankerpatiënten die al dan niet drager zijn. Ze gaan volgens Begg voorbij aan het feit dat naast het dragerschap nog allerlei andere, onbekende risicofactoren een rol kunnen spelen bij het ontstaan van borstkanker. In vergelijking met de algemene populatie zijn deze onbekende risicofactoren bij borstkankerpatiënten oververtegenwoordigd. Hierdoor worden ze in feite opgeteld bij de risico's die horen bij de genen. Op basis van deze informatie worden immers belangrijke beslissingen genomen over bijvoorbeeld preventieve amputatie van de borsten. De belangrijkste conclusie die Burke en Austin aan het artikel van Begg verbinden, is dat het enthousiasme over de voorspellende genetica enigszins moet worden getemperd. 'Door alleen maar naar de genetische achtergrond van ziekte te kijken, missen we kansen op het ontwikkelen van echt effectieve preventieve strategieën', aldus de commentatoren.
Oorzaak en gevolg ?
Unborn Babies Soaked in Chemicals, Survey Finds July 14, 2005 — By Maggie Fox, Reuters
WASHINGTON — Unborn U.S. babies are soaking in a stew of chemicals, including mercury, gasoline byproducts and pesticides, according to a report to be released Thursday. Although the effects on the babies are not clear, the survey prompted several members of Congress to press for legislation that would strengthen controls on chemicals in the environment. The report by the Environmental Working Group is based on tests of 10 samples of umbilical cord blood taken by the American Red Cross. They found an average of 287 contaminants in the blood, including mercury, fire retardants, pesticides and the Teflon chemical PFOA. "These 10 newborn babies ... were born polluted," said New York Rep. Louise Slaughter, who planned to publicize the findings at a news conference Thursday. "If ever we had proof that our nation's pollution laws aren't working, it's reading the list of industrial chemicals in the bodies of babies who have not yet lived outside the womb," Slaughter, a Democrat, said. Cord blood reflects what the mother passes to the baby through the placenta.
Phtalaten en hyperoestrogenisme
"Of the 287 chemicals we detected in umbilical cord blood, we know that 180 cause cancer in humans or animals, 217 are toxic to the brain and nervous system, and 208 cause birth defects or abnormal development in animal tests," the report said. Blood tests did not show how the chemicals got into the mothers' bodies.
1
HYPERESTROGENISM Adrenals
Estrogenic Imbalance Hyperestrogenism Premenstrual syndrome Mastopathia Breast benign lesion Cervical lesion Endometrial cancer Breast cancer Mood disorders
Ovaries
Androgens Aromatase
Estrogens
Transport SHBG
16aOH-E genotoxic n 3,4 quinone 4OH-E tio oxydation genotoxic hyla 2OH-E et m nMethylation tio ta fa l u -s 4-MethoxyE tion a id n 2-MethoxyE o ur anticancer uc gl
ESTROGEN DETOXIFICATION PHASE I: CYTOCHROME-OXYDASE
Estrogenic Effects
Deconjugation
Estrogen Detoxication Estrogens
Estrogens Xenoestrogens
+ 2-Hydroxylase
2OH-Estrogens
Non Estrogenic
4-Hydroxylase
4OH-Estrogens
Estrogenic Genotoxic
16a-Hydroxylase
16aOH-Estrogens
Very Estrogenic Genotoxic
2-Hydroxylase
16a-Hydroxylase
2OH-Estrogens
16aOH-Estrogens
Non Estrogenic
2OH
16aOH
Low risk of Hormono-dependent cancers
Very Estrogenic Genotoxic 2OH
16aOH
High risk of Hormono-dependent cancers
2
Effect of Menstrual Cycle on Urinary and Serum 2/16 Ratio: No Oral Contraceptives
Effect of Menstrual Cycle on Urinary and Serum 2/16 Ratio: Oral Contraceptive Use (Caucasian)
Epigenetische mechanismen
3 NIVEAUS: • RNA Æ RNA geassocieerde regeling
• Nucleosomen Æ Modificaties van histon-eiwitten
• DNA Æ DNA methylatie
Regulatie ER expressie in borstkanker
J Nutr. 2000 Dec;130(12):2927-31.
Indole-3-carbinol is a negative regulator of estrogen receptor-alpha signaling in human tumor cells.
Oestrogenen en hun receptor spelen een belangrijke rol bij het ontstaan en de progressie van borstkanker. De aanwezigheid van ER in borstkanker is een voorspellende merker voor respons op hormonale behandeling. MAAR: • 1 op 3 borsttumoren vertonen geen ER expressie bij diagnose • Een fractie van de borsttumoren die initieel ER-positief zijn, verliezen ER expressie tijdens tumorprogressie.
Meng Q, Yuan F, Goldberg ID, Rosen EM, Auborn K, Fan S. Department of Radiation Oncology and. Department of Otolaryngology, Long Island Jewish Medical Center, New Hyde Park, NY 11040, USA. Estrogen, via its binding to the estrogen receptor (ER), plays an important role in breast cancer cell proliferation and tumor development. Indole-3-carbinol (I3C), a compound occurring naturally in cruciferous vegetables, exhibits a potent antitumor activity via its regulation of estrogen activity and metabolism. This study was designed to determine the effect of I3C on the potential to inhibit the ERalpha. Using a reporter gene driven by the estrogen receptor, I3C (10-125 micromol/L) significantly
Genetische veranderingen (deleties, mutaties) blijken geen belangrijke rol te spelen voor het verlies van ER expressie.
repressed the 17ss-estradiol (E2)-activated ER-alpha signaling in a dose-dependent manner. I3C and breast cancer susceptibility gene 1 (BRCA1) synergistically inhibited transcriptional activity of ER-alpha. Moreover, I3C down-regulated the expression of the estrogen-responsive genes, pS2 and cathepsin-D,
Andere (epigenetische) mechanismen verantwoordelijk voor ER inactivering?
and up-regulated BRCA1. The inhibitory effects of I3C did not contribute to its cytotoxic effects because these activities were observed at less than toxic concentrations. These results further suggest that antitumor activities of I3C are associated not only with its regulation of estrogen activity and metabolism, but also its modulation of ER transcription activity.
3
ER transcriptie en de behandeling van borstkanker
DNA hypermethylatie van de ER genpromotor
BIJ DIAGNOSE (1/3 borstcarcinomen) TIJDENS TUMORPROGRESSIE
Histon deacetylering
ER EXPRESSIE Oestrogeen onafhankelijke groei
Hormoontherapie
Methylatie Een sleutelstap in de oestrogeenontgifting Oestrogenen
2-hydroxylase
2OH-oestrogenen
4-hydroxylase
4OH-oestrogenen
METHYLATIE
Foliumzuur
SAM SAH
Vitamine B12
Homocysteïnecyclus
Vitamine B2 Vitamine B6 Betaïne
2Methoxy-oestron
4Methoxy-oestron
Anti-carcinogeen Anti-angiogeen
Non-oestrogeen
Choline
Methylatie bestaat uit biochemische sleutelreacties die een heel belangrijke rol spelen in vele biologische processen. Het verloop ervan hangt af van een correcte voedingsomgeving.
4
Homocysteïnemetabolisme bij de mens
Adv Cancer Res. 1998;72:141-96
Alterations in DNA methylation: a fundamental aspect of neoplasia. Baylin SB, Herman JG, Graff JR, Vertino PM, Issa JP. Johns Hopkins Comprehensive Cancer Center, Baltimore, Maryland, USA.
Neoplastic cells simultaneously harbor widespread genomic hypomethylation, more regional areas of hypermethylation, and increased DNA-methyltransferase (DNA-MTase) activity. Each component of this "methylation imbalance" may fundamentally contribute to tumor progression. The precise role of the hypomethylation is unclear, but this change may well be involved in the widespread chromosomal alterations in tumor cells. A main target of the regional hypermethylation are normally unmethylated CpG islands located in gene promoter regions. This hypermethylation correlates with transcriptional repression that can serve as an alternative to coding region mutations for inactivation of tumor suppressor genes, including p16, p15, VHL, and E-cad. Each gene can be partially reactivated by demethylation, and the selective advantage for loss of gene function is identical to that seen for loss by classic mutations. How abnormal methylation, in general, and hypermethylation, in particular, evolve during tumorigenesis are just beginning to be defined. Normally, unmethylated CpG islands appear protected from dense methylation affecting immediate flanking regions. In neoplastic cells, this protection is lost, possibly by chronic exposure to increased DNA-MTase activity and/or disruption of local protective mechanisms. Hypermethylation of some genes appears to occur only after onset of neoplastic evolution, whereas others, including the estrogen receptor, become hypermethylated in normal cells during aging. This latter change may predispose to neoplasia because tumors frequently are hypermethylated for these same genes. A model is proposed wherein tumor progression results from episodic clonal expansion of heterogeneous cell populations driven by continuous interaction between these methylation abnormalities and classic genetic changes.
NEUROTRANSMITTERS – IMMUNOTRANSMITTERS B3
Tyrosine
Tryptofaan O2 IJzer
Foliumzuur
Foliumzuur
L-Dopa
Apoptosis
5-HT
DNA topoisomerase
B6 Dopamine O2 Koper
Ascorbaat
DNA tyrokinase
Serotonine
Noradrenaline
Angiogenese
Duisternis
S-AdoMet
P 53
Melatonine Mg - B6 - B12 Foliumzuur
S-AdoMet Adrenaline
Glutathione inhibits experimental expression, and angiogenesis.
oral
carcinogenesis,
p53
²²
Schwartz JL, Shklar G Nutr Cancer 1996;26(2):229-36 Previous studies have shown that reduced glutathione (GSH) inhibits experimental oral carcinogenesis in the hamsterAt buccal understanding of molecular mechanisms the anticancer effect the pouchmodel. terminationToofgain thefurther experimental period, there were fewerintumors in of GSH, these studies examined levels of p53 protein expression. 7,12-Dimethylbenz[a]anthracene (DMBA) the DMBA-GSH than in the DMBA tumor control group, and the tumors was applied to the buccal pouches of 20 Syrian Golden hamsters (Mesocricetus auratus) in a 0.5% solution were smaller (tumor 315 3,04010mm3). in mineral oil thrice weekly for 14burden weeks. In 10vs. animals, mg/kg reduced glutathione (GSH) in 0.5 ml of mineral oil was administered by mouth thrice weekly on days alternate to the DMBA painting. An additional 20 animals served as DMBA-untreated and GSH controls. At the termination of the experimental period, there were fewer tumors in the DMBA-GSH than in the DMBA tumor control group, and the tumors were smaller (tumor burden 315 vs. 3,040 mm3). Histologically, the DMBA-GSH group showed a marked reduction in dysplasia, carcinoma in situ, and invasive epidermoid carcinoma sites. Immunohistochemically, by use of monoclonal antibodies for wild-type p53 (PAb 246), changes were observed in protein expression levels at dysplastic sites and within the malignant Staining for p53 protein waswith slightly in dysplasia The significant inhibition of oraltumors. carcinogenesis associated theincreased administration and cell carcinoma in the tumorthe control animals (painted compared with the tumor untreated ofsquamous GSH was correlated with increased levelswith ofDMBA) the wild-type p53 controls that were free of tumors. In the GSH and DMBA treatment group, p53 protein expression levels were suppressor gene, suggesting its possible use as a biomarker for GSH strongly increased in dysplastic and tumor sites. The significant inhibition of oral carcinogenesis associated chemoprevention. The inhibition of oral carcinogenesis by reduced GSH was with the administration of GSH was correlated with the increased levels of the wild-type p53also tumor related gene, to a very significant inhibition tumorfor angiogenesis, definedThe byinhibition factor VIII suppressor suggesting its possible use as a of biomarker GSH chemoprevention. of oral staining. by reduced GSH was also related to a very significant inhibition of tumor angiogenesis, carcinogenesis defined by factor VIII staining. Thus angiogenesis inhibition may be an additional mechanism for antioxidant chemoprevention, and this suggests another possible biomarker for antioxidant chemoprevention.
DNA REPRODUCTIE
5
ANGIOGENESE Ann N Y Acad Sci. 1997 Dec 29;833:112-28.
Avoidable causes of breast cancer: the known, unknown, and the suspected. Davis DL, Axelrod D, Osborne M, Telang N, Bradlow HL, Sittner E.
PREVASCULAIRE FASE INITIATON
Strang Cornell Cancer Research Laboratory, New York, New York 10021, USA.
P53
POSTVASCULAIRE FASE
PROMOTION
PROGRESSION
METASTASIS
INHIBITION
mutation frequency varies considerably in
breast cancer populations, which may reflect variation in exogenous exposures.
Rol van angiogenese in tumorale progressie
Chemotherapie Resistentie Mechanisme Inhibition of the multidrug resistance P-glycoprotein activity by green tea polyphenols.
AC Extra-cellulaire omgeving AC
AC
AC
AC AC
AC Pompe P-gp
AC
Jodoin J, Demeule M, Beliveau R. Biochim Biophys Acta 2002 Jan 30;1542(1-3):149-159 Many beneficial proprieties have been associated with polyphenols from green tea, such as chemopreventive, anticarcinogenic, antiatherogenic and antioxidant actions. In this study, we investigated the effects of green tea polyphenols (GTPs) and their principal catechins on the function of P-glycoprotein (P-gp), which is involved in the multidrug resistance phenotype of cancer cells.
AC AC AC
Afbraak van de stoffen van de chemotherapie
Intérieur de la cellule
Agents de chimiothérapie Noyau
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Green tea polyphenol epigallocatechin-3 gallate inhibits Her-2/neu signaling, proliferation, and transformed phenotype of breast cancer cells.
Matric Metalloproteases Invasive carcinoma
Pianetti S, Guo S, Kavanagh KT, Sonenshein GE. Cancer Res 2002 Feb 1;62(3):652-5 Department of Biochemistry, Boston University School of Medicine, 715 Albany Street, Boston,
Normal epithelium
MA 02118-2394, USA. Overexpression of the epidermal growth factor receptor family member Her-2/neu in breast
Distant metastasis
MMP activity
cancer is associated with poor prognosis. With evidence accumulating for a chemopreventive role of green tea polyphenols, the effects of epigallocatechin-3 gallate (EGCG) on Her-2/neuoverexpressing breast cancer cells were examined. EGCG inhibited mouse mammary tumor
Blood vessel
MMP activity
virus (MMTV)-Her-2/neu NF639 cell growth in culture and soft agar. EGCG reduced signaling via the phosphatidylinositol 3- kinase, Akt kinase to NF-kappaB pathway because of inhibition of basal Her-2/neu receptor tyrosine phosphorylation. EGCG similarly inhibited basal receptor
Stromal cells & matrix
phosphorylation in SMF and Ba/F3 2 + 4 cells, which suggests the potential beneficial use of EGCG in adjuvant therapy of tumors with Her-2/neu overexpression.
Diet and the cancer process Bioactive dietary constituents Alcohol Smoking
Smoking, chewing tobacco and betel Dietary carcinogens, heterocyclic, amines, PAHs
Genes
Workplace Procarcinogen
Phase I metabolising enzymes - P450s etc.
EXCRETION
Bioactive dietary constituents e.g. isothiocyanates
Ultimate carcinogen Genes
Phase II metabolising enzymes
EXCRETION DNA adducts Genes
Physical activity Energy intake
DNA repair
Obesity
Hormones
Dietary factors
Growth factors
Fibre
Onvermogen om te detoxificeren
NORMAL DNA Abnormal DNA and cell replication
2OH/16OH ↓ REDIFFERENTIATION
DNA damage
Verlaagde antioestrogene activiteit
Precancerous lesions / dysplasia
Immune system Growth factors
Tekort aan antioxidantia
APOPTOSIS (programmed cell death)
Volatile fatty acids DNA repair genes
Dietary factors
Zwakke galwerking Verhoogde werking v/ h aromataseenzym
Somatic alteration of oncogenes, tumour-suppressor genes and DNA-repair genes
Specific nutrients e.g. carotenoids, retinol Colonic bacteria
Borstkanker Nooit monocausaal!
Genes
Overbelaste HPA axis
Cancer
Hormones Smoking and other exposures
DNA damage
DNA repair genes
Metastasis
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