Breast cancer is the second leading cause of cancer-related death in women. Mutations in the tumor suppressor gene BRCA-1 confer a high risk of breast tumor development. However, in sporadic breast cancers, which represent 90-95% of breast cancer cases, BRCA-1 expression is downregulated in the absence of mutations in the BRCA-1 gene. This suggests that epigenetic effectors may contribute to disruption of BRCA-1 expression and the onset of mammary tumors.Prototypical environmental contaminants found in industrial pollution, tobacco smoke, and cooked foods include benzo[a]pyrene (B[a]P) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which have been shown to alter mammary gland development, act as endocrine disruptors and tumor promoters. Population studies detected accumulation of TCDD in women's adipose tissue and breast milk. Moreover, sporadic breast tissue exhibited statistically significant higher levels of PAH-DNA adducts. Based on this information, we examined the effect of B[a]P on the tumor suppressor BRCA-1and observed that exposure to B[a]P led to repression of BRCA-1 transcription through a p53-dependent mechanism. We have also demonstrated that 17β-estradiol (E2) stimulated the recruitment of ERα and AP-1 family members to a region of the BRCA-1 promoter flanking an AP-1-like site. However, accumulation of p53 prevented E2-mediated BRCA-1 transcription and recruitment of ERα, potentially providing one mechanism of B[a]P-mediated repression.In addition, the effects of B[a]P and TCDD are mediated through binding of the liganded aromatic hydrocarbon receptor (AhR) to dioxin or xenobiotic-responsive elements (XRE). We have evidence that suggests B[a]P and TCDD may modulate repression of E2-stimulated BRCA-1 expression through 1) binding of the liganded AhR to XREs on the BRCA-1 promoter and 2) preventing promoter occupancy by p300 and SRC-1.Taken together, the data presented here suggest that the transcriptional regulation of BRCA-1 is complex and involves modulation of the recruitment of ERα, AhR, p53, and their cofactors. An important implication of these findings is a greater understanding of the role of ERα, AhR, and p53 in regulation of BRCA-1 which could lead to the development of therapeutic strategies that target these interactions to enhance upregulation of BRCA-1 expression in sporadic breast tumors.

Epigenetic mechanisms may contribute to reduced expression of the tumor suppressor gene BRCA-1 in sporadic breast cancers. Through environmental exposure and diet, humans are exposed to xenobiotics and food compounds that bind the aromatic hydrocarbon receptor (AhR). AhR-ligands include the dioxin-like and tumor promoter 2,3,7,8 tetrachlorobenzo-p-dioxin (TCDD). The activated AhR regulates transcription through binding to xenobiotic response elements (XRE=GCGTG) and interactions with transcription cofactors. Previously, we reported on the presence of several XRE in the proximal BRCA-1 promoter, and that the expression of endogenous AhR was required for silencing of BRCA-1 expression by TCDD. Here, we document that in estrogen receptor-alpha-positive and BRCA-1 wild-type MCF-7 breast cancer cells, the treatment with TCDD attenuated 17-beta estradiol (E2)-dependent stimulation of BRCA-1 protein and induced hypermethylation of a CpG island spanning the BRCA-1 transcriptional start site of exon-1a. Additionally, we found that TCDD enhanced the association of the AhR, DNA methyl transferases (DNMT)1, DNMT3a, and DNMT3b; methyl binding protein (MBD)2; and tri-methylated H3K9 (H3K9me3) with the BRCA-1 promoter. Conversely, the phytoalexin resveratrol, selected as a prototype dietary AhR antagonist, antagonized at physiologically relevant doses the TCDD-induced repression of BRCA-1 protein, BRCA-1 promoter methylation, and the recruitment of the AhR, MBD2, H3K9me3, and DNMTs (1, 3a, and 3b). Taken together, these observations provide evidence for a mechanistic role for AhR-agonists in establishment of BRCA-1 promoter hypermethylation and the basis for the development of prevention strategies based on AhR antagonists.

Zugl.: Berlin, Freie Univ., Diss., 2008

Für die hier beschriebene Studie wurde ein Fragebogen erstellt, welcher von 80 Trägerinnen und Trägern einer pathogenen Mutation in den Genen BRCA1 oder BRCA2 ausgefüllt wurde. Die Befragung sollte untersuchen, ob den Befragten das Risiko ihrer Verwandten, ebenso Mutationsträger zu sein, bewusst war. Weiterhin sollte ermittelt werden, ob sie die jeweiligen Risikopersonen darüber informierten. Es zeigte sich, dass den meisten Befragten dieses Risiko bekannt war. Einigen Personen schienen jedoch nicht genau zu wissen, welche Verwandten als „Risikopersonen“ zählen. Insbesondere war nicht allen Befragten die Möglichkeit bewusst, dass auch Männer die Mutation tragen und an ihre Kinder weitergeben sowie selbst an Brustkrebs erkranken können. Weiterhin gaben mehr als ein Viertel der Befragten an, dass sie mindestens ein Familienmitglied, obwohl es ihnen als Risikoperson bekannt war, nicht informierten. Als häufigste Grund hierfür wurde mangelnder Kontakt genannt. Vor dem Hintergrund der Angaben der Befragten sowie der aktuellen Forschungslage werden in der vorliegenden Arbeit Möglichkeiten diskutiert, wie die Anzahl der informierten Angehörigen verbessert werden könnte. / A questionnaire was sent to carriers of BRCA1/2 mutations to survey whether they knew about the risk of their relatives to be carriers as well and whether they informed those relatives about that risk. Among the 80 participants, most were aware of the risk of their relatives. However, the risk of male relatives to be mutation carriers seemed to have been undererstimated and more than one in four participants stated they did not inform every relative they knew to be at risk. The most frequently stated reason for not informing at-risk relatives was lack of contact.

The deregulation of the MYC oncoprotein family plays a major role in tumorigenesis and tumour maintenance of many human tumours. Because of their structure and nuclear localisation, they are defined as undruggable targets which makes it difficult to find direct therapeutic approaches. An alternative approach for targeting MYC-driven tumours is the identification and targeting of partner proteins which score as essential in a synthetic lethality screen. Neuroblastoma, an aggressive entity of MYCN-driven tumours coming along with a bad prognosis, are dependent on the tumour suppressor protein BRCA1 as synthetic lethal data showed. BRCA1 is recruited to promoter regions in a MYCN-dependent manner. The aim of this study was to characterise the role of BRCA1 in neuroblastoma with molecular biological methods. BRCA1 prevents the accumulation of RNA Polymerase II (RNAPII) at the promoter region. Its absence results in the formation of DNA/RNA-hybrids, so called R-loops, and DNA damage. To prevent the accumulation of RNAPII, the cell uses DCP1A, a decapping factor known for its cytoplasmatic and nuclear role in mRNA decay. It is the priming factor in the removal of the protective 5’CAP of mRNA, which leads to degradation by exonucleases. BRCA1 is necessary for the chromatin recruitment of DCP1A and its proximity to RNAPII. Cells showed upon acute activation of MYCN a higher dependency on DCP1A. Its activity prevents the deregulation of transcription and leads to proper coordination of transcription and replication. The deregulation of transcription in the absence of DCP1A results in replication fork stalling and leads to activation of the Ataxia telangiectasia and Rad3 related (ATR) kinase. The result is a disturbed cell proliferation to the point of increased apoptosis. The activation of the ATR kinase pathway in the situation where DCP1A is knocked down and MYCN is activated, makes those cells more vulnerable for the treatment with ATR inhibitors. In summary, the tumour suppressor protein BRCA1 and the decapping factor DCP1A, mainly known for its function in the cytoplasm, have a new nuclear role in a MYCN-dependent context. This study shows their essentiality in the coordination of transcription and replication which leads to an unrestrained growth of tumour cells if uncontrolled. / Die MYC Onkoproteine spielen in einer Vielzahl humaner Tumore eine entscheidende Rolle und sind in fast allen Fällen dereguliert. Aufgrund ihrer Struktur und Lokalisation im Zellkern gelten sie für die Arzneimittelentwicklung als therapeutisch schwer angreifbar. Der Ansatz der synthetischen Lethalität ist es, Partnerproteine zu finden, die gerade für MYC-getriebene Tumore essenziell sind und diese zu inhibieren. Neuroblastome, die in einer besonders aggressiven Entität durch eine MYCN-Amplifikation getrieben sind und damit mit einer schlechten Prognose einhergehen, sind abhängig vom Tumorsupressor BRCA1, wie Daten zur synthetischen Lethalität zeigten. BRCA1 wird in Abhängigkeit von MYCN zu Promotoren rekrutiert. Diese Arbeit diente daher der Charakterisierung der Funktionalität von BRCA1 im Neuroblastom. BRCA1 verhindert die Akkumulation von RNA Polymerase II (RNAPII) in der Promoterregion. Ist BRCA1 nicht präsent, führt dies zur Bildung von DNA/RNA-Hybriden, sogenannten R-loops, und zu DNA Schäden. Um die Akkumulation von RNAPII zu verhindern, nutzt die Zelle DCP1A, einen Decapping Faktor, der sowohl im Cytoplasma als auch im Nukleus eine Rolle im mRNA Abbau spielt. DCP1A entfernt den schützenden 5’CAP der mRNA, wodurch diese von Exonukleasen abgebaut wird. BRCA1 ist notwendig für die Chromatin Bindung von DCP1A und die Rekrutierung zu RNAPII. Zellen mit einer akuten Aktivierung des MYCN Onkoproteins zeigen eine erhöhte Abhängigkeit von DCP1A. DCP1A verhindert eine Deregulation der Transkription, um Transkription mit Replikation erfolgreich zu koordinieren. Andernfalls führt dies beim Verlust von DCP1A zur Blockierung von Replikationsgabeln und der Aktivierung der Ataxia telangiectasia and Rad3 related (ATR) Kinase führt. In der Folge ist das Zellwachstum gestört und Zellen gehen vermehrt in Apoptose. Die Aktivierung des ATR Signalweges beim Verlust von DCP1A und MYCN Aktivierung verhindert vorerst den Zelltod, wodurch diese Zellen jedoch sensitiver auf die Inhibition von ATR reagieren. Zusammenfassend lässt sich sagen, dass BRCA1 als Tumorsupressor und DCP1A als Decapping Faktor, hauptsächlich beschrieben als cytoplasmatisches Protein, eine entscheidende nukleäre Rolle in der Situation einer akuten Aktivierung von MYCN spielen. Dort sind sie essenziell um Transkription mit Replikation zu koordinieren und damit zu einem ungebremsten Wachstum der Tumorzellen beizutragen.

In general population 1 of 72 women develop ovarian cancer and to 1 of 95 women this disease is lethal. A great number of clinical trials have shown that the course of the disease is not dependent only on the classical prognostic indicators such as histological tumor type, tumor differentiation, stage of the disease or treatment modalities. More than two decades ago the first publications on heredity factors indicated similarity among the patients diagnosed ovarian malignancies and their first degree relatives. The first genetic autosomal dominant inheritance was determined in the high-risk cancer tumor suppressor BRCA1/2 genes. In spite of the abundant number of trials studying the BRCA1/2 genes role in breast and ovarian carcinogenesis still it is not sufficiently clear the influence of these genes for the disease prognosis. The aim of our conducted trial was to determine the BRCA1/2 genes prognostic significance for progression-free and overall survival in the event of advanced ovarian cancer. In case of advanced ovarian cancer the BRCA1/2 mutation frequency was 51,4 %. Among all determined BRCA1/2 gene mutations BRCA1 4035delA or founder mutation was most frequent. It amounted to 63.6%. Non-optimal cytoreduction (p<0,0001 ) , patients’ older age (p=0,005) and absence of BRCA1/2 mutations (p=0,049) are closely connected with a shorter PFS and OS. Only non-optimal cytoreduction was related to a shorter OS (p=0,010). / Bendrojoje populiacijoje 1 iš 72 moterų suserga kiaušidžių vėžiu ir 1 iš 95 moterų miršta nuo šios ligos. Tyrimų duomenys rodo, kad ligos eiga nėra priklausoma vien tik nuo klasikinių prognozinių rodiklių, tokių kaip histologinis naviko tipas, naviko diferenciacija, ligos stadija, taikytas gydymas.Prognozinių veiksnių paieška krypstą link genetinių veiksnių galinčių įtakoti ligos eigą. Literatūros duomenys apie klinikinę BRCA1/2 genų reikšmę yra kontroversiški – nuo visiškai bereikšmio iki ženkliai teigiamo poveikio ligos eigai prognoziniu požiūriu.. Mūsų tyrėjų grupės atlikto tyrimo tikslas buvo nustatyti BRCA1/2 genų mutacijų dažnį ir jų įvairovę tarp pacienčių, sergančių išplitusiu kiaušidžių vėžiu, ir įvertinti šių mutacijų įtaką berecidyviam ir bendrajam išgyvenamumui. Mes nustatėme , kad tarp pacienčių sergančių išplitusių epiteliniu kiaušidžių vėžiu buvo net 51,4 proc. BRCA 1/2 mutacijų genuose turinčių pacienčių. 98,2 proc. šių pacienčių sirgo serozine papiline adenokarcinoma. Šios histologinės formos kiaušidžių vėžio buvo ženkliai daugiau mutuotų BRCA1/2 genų pacienčių grupėje nei tarp pacienčių be mutacijų (p-0,029). Tyrimo metu nustatėme dažniausiai sutinkamą arba bendro protėvio BRCA 1 4035 delA mutaciją bei taip kad statistiškai reikšmingos įtakos sergančiųjų išplitusiu kiaušidžių vėžiu berecidyviam išgyvenamumui turi pacienčių amžius (p=0,005), BRCA1/2 genų mutacijos(p=0,049) bei operacijos apimtis (p<0,0001), o bendrajam išgyvenamumui – tik operacijos... [toliau žr. visą tekstą]

Bendrojoje populiacijoje 1 iš 72 moterų suserga kiaušidžių vėžiu ir 1 iš 95 moterų miršta nuo šios ligos. Tyrimų duomenys rodo, kad ligos eiga nėra priklausoma vien tik nuo klasikinių prognozinių rodiklių, tokių kaip histologinis naviko tipas, naviko diferenciacija, ligos stadija, taikytas gydymas.Prognozinių veiksnių paieška krypstą link genetinių veiksnių galinčių įtakoti ligos eigą. Literatūros duomenys apie klinikinę BRCA1/2 genų reikšmę yra kontroversiški – nuo visiškai bereikšmio iki ženkliai teigiamo poveikio ligos eigai prognoziniu požiūriu.. Mūsų tyrėjų grupės atlikto tyrimo tikslas buvo nustatyti BRCA1/2 genų mutacijų dažnį ir jų įvairovę tarp pacienčių, sergančių išplitusiu kiaušidžių vėžiu, ir įvertinti šių mutacijų įtaką berecidyviam ir bendrajam išgyvenamumui. Mes nustatėme , kad tarp pacienčių sergančių išplitusių epiteliniu kiaušidžių vėžiu buvo net 51,4 proc. BRCA 1/2 mutacijų genuose turinčių pacienčių. 98,2 proc. šių pacienčių sirgo serozine papiline adenokarcinoma. Šios histologinės formos kiaušidžių vėžio buvo ženkliai daugiau mutuotų BRCA1/2 genų pacienčių grupėje nei tarp pacienčių be mutacijų (p-0,029). Tyrimo metu nustatėme dažniausiai sutinkamą arba bendro protėvio BRCA 1 4035 delA mutaciją bei taip kad statistiškai reikšmingos įtakos sergančiųjų išplitusiu kiaušidžių vėžiu berecidyviam išgyvenamumui turi pacienčių amžius (p=0,005), BRCA1/2 genų mutacijos(p=0,049) bei operacijos apimtis (p<0,0001), o bendrajam išgyvenamumui – tik operacijos... [toliau žr. visą tekstą] / In general population 1 of 72 women develop ovarian cancer and to 1 of 95 women this disease is lethal. A great number of clinical trials have shown that the course of the disease is not dependent only on the classical prognostic indicators such as histological tumor type, tumor differentiation, stage of the disease or treatment modalities. More than two decades ago the first publications on heredity factors indicated similarity among the patients diagnosed ovarian malignancies and their first degree relatives. The first genetic autosomal dominant inheritance was determined in the high-risk cancer tumor suppressor BRCA1/2 genes. In spite of the abundant number of trials studying the BRCA1/2 genes role in breast and ovarian carcinogenesis still it is not sufficiently clear the influence of these genes for the disease prognosis. The aim of our conducted trial was to determine the BRCA1/2 genes prognostic significance for progression-free and overall survival in the event of advanced ovarian cancer. In case of advanced ovarian cancer the BRCA1/2 mutation frequency was 51,4 %. Among all determined BRCA1/2 gene mutations BRCA1 4035delA or founder mutation was most frequent. It amounted to 63.6%. Non-optimal cytoreduction (p<0,0001 ) , patients’ older age (p=0,005) and absence of BRCA1/2 mutations (p=0,049) are closely connected with a shorter PFS and OS. Only non-optimal cytoreduction was related to a shorter OS (p=0,010).

Bakgrund: Bröstcancer är den vanligaste cancerdiagnosen och mutation av BRCA 1/2-gener ökar bröstcancerrisken. Drabbade kvinnor får information kring behandlingsstrategier vilka diskuteras med eventuella närstående samt vårdpersonal och grundlägger val av behandling. Kvinnors upplevelser av profylaktisk mastektomi påverkas av flera aspekter, och påvisar därmed vikten av sjuksköterskans kompetens inom omvårdnad. Syfte: Att sammanställa och syntetisera kvalitativ forskning som utforskat vad som påverkar kvinnors beslutsfattande vid profylaktisk mastektomi vid risk för bröstcancer eller vid befintlig ensidig bröstcancer. Metod: En litteraturöversikt med kvalitativ ansats utifrån 13 originalartiklar vilka analyserades med tematisk innehållsanalys. Resultat: Tre teman identifierades; ”Existentiella val”, ”Informationens betydelse” samt ”Kroppslig påverkan”. Temat ”Existentiella val” gav två subteman, ”Mastektomi som oroslindrande” samt ”Minska risk för (åter)insjuknande”. Ur temat ”Informationens betydelse” identifierades två subteman, ”Informationsbehov” samt ”Omgivningens erfarenheter/åsikter” och temat ”Kroppslig påverkan” resulterade i subtemana ”Synen på kropp och kvinnlighet” och ”Amning”.  Slutsats: Litteraturstudien påvisar kvinnors beslutsfattande avseende profylaktisk mastektomi såsom rädslor, otillräckligt anpassad information samt kroppsliga aspekter. Resultatet påvisar ett behov av vidare forskning avseende dessa kvinnors upplevelser för att ge en djupare förståelse och ökad kompetens inom vården för att möjliggöra en personcentrerad och holistisk vård. / Background: Breast cancer is the most common cancer diagnosis, and BRCA 1/2 gene mutations increases breast cancer risk. Affected women receive information about treatment strategies, which are discussed with relatives and healthcare professionals and lay the foundation for treatment choices. Women´s experiences of prophylactic mastectomy are affected by many aspects, highlighting the importance of nursing competence.  Aim: To synthesize qualitative research exploring aspects affecting women´s decision-making regarding prophylactic mastectomy in case of increased breast cancer risk or existing unilateral breast cancer.    Method: A literature review with a qualitative approach based on 13 original articles, analyzed using thematic content analysis.   Result: Three themes were identified; “Existential choices”, “The importance of information” and “Physical impact”. “Existential choices” resulted in the subthemes, “Mastectomy as anxiety reliever” and “Reducing the risk of (re)occurrence”. “The importance of information” presented the subthemes “Informational needs” and “The experiences/opinions of others”. “Physical impact” offered subthemes “View of body and femininity” and “Breastfeeding”.   Conclusion: Aspects influencing women's decision-making regarding prophylactic mastectomy were revealed, e.g. fears, information and physical aspects. The results indicate a need for further research to deepen understanding and enhance healthcare competence for person-centered and holistic care.