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DNA stabilization by the upregulation of estrogen signaling in BRCA gene mutation carriers.

Suba Z - Drug Des Devel Ther (2015)

Bottom Line: In BRCA-proficient cases, estrogen signaling orchestrates the activity of cell proliferation and differentiation with high safety, while upregulating the expression and DNA-stabilizing impact of BRCA genes.Natural estrogens have numerous benefits in tumor prevention and therapy even in BRCA mutation carriers.There are no toxic effects even in sky-high doses and all physiologic cellular functions are strongly upregulated, while malignant tumor cells are recognized and killed in a Janus-faced manner.

View Article: PubMed Central - PubMed

Affiliation: Surgical and Molecular Tumor Pathology Centre, National Institute of Oncology, Budapest, Hungary.

ABSTRACT
Currently available scientific evidence erroneously suggests that mutagenic weakness or loss of the BRCA1/2 genes may liberate the proliferative effects of estrogen signaling, which provokes DNA damage and genomic instability. Conversely, BRCA mutation seems to be an imbalanced defect, crudely inhibiting the upregulation of estrogen receptor expression and liganded transcriptional activity, whereas estrogen receptor-repressor functions become predominant. In BRCA-proficient cases, estrogen signaling orchestrates the activity of cell proliferation and differentiation with high safety, while upregulating the expression and DNA-stabilizing impact of BRCA genes. In turn, BRCA proteins promote estrogen signaling by proper estrogen synthesis via CYP19 gene regulation and by induction of the appropriate expression and transcriptional activity of estrogen receptors. In this exquisitely organized regulatory system, the dysfunction of each player may jeopardize genome stability and lead to severe chronic diseases, such as cancer development. Female organs, such as breast, endometrium, and ovary, exhibiting regular cyclic proliferative activity are particularly vulnerable in case of disturbances in either estrogen signaling or BRCA-mediated DNA repair. BRCA mutation carrier women may apparently be healthy or exhibit clinical signs of deficient estrogen signaling in spite of hyperestrogenism. Even women who enjoy sufficient compensatory DNA-defending activities are at risk of tumor development because many endogenous and environmental factors may jeopardize the mechanisms of extreme compensatory processes. Natural estrogens have numerous benefits in tumor prevention and therapy even in BRCA mutation carriers. There are no toxic effects even in sky-high doses and all physiologic cellular functions are strongly upregulated, while malignant tumor cells are recognized and killed in a Janus-faced manner.

No MeSH data available.


Related in: MedlinePlus

Protein–protein interplay between ERα and BRCA1 expressions during physiologic and malignant cell proliferations.Notes: Outer circle: Self-generating mutual upregulation between E2-liganded ERα and BRCA1 protein expressions during physiologic cell proliferation. Increasing ERα expression upregulates both BRCA1 mRNA and BRCA1 protein expressions, ensuring a high level of DNA safeguarding. In turn, increased BRCA1 protein concentration induces higher expression of both ERα mRNA and ERα protein, resulting in strengthened ER signaling. Inner circle: Self-repressing mutual downregulation between low and/or defective E2-liganded ERα and BRCA1 protein expressions during malignant cell proliferation. Failure of ERα expression represses both BRCA1 mRNA and BRCA1 protein synthesis, inhibiting appropriate DNA safeguarding. In turn, failure of BRCA1 protein synthesis downregulates both ERα mRNA and ERα protein expression and suppresses ERα signaling. Coactivators: AhR, p300, cyclin D, and Oct-1; corepressor: ID4. ↑= upregulation, ↓= downregulation.Abbreviations: AhR, aromatic hydrocarbon receptor; E2, estradiol; ER, estrogen receptor; ID4, inhibitor of differentiation 4; Oct-1, octamer-binding transcriptional factor 1.
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f1-dddt-9-2663: Protein–protein interplay between ERα and BRCA1 expressions during physiologic and malignant cell proliferations.Notes: Outer circle: Self-generating mutual upregulation between E2-liganded ERα and BRCA1 protein expressions during physiologic cell proliferation. Increasing ERα expression upregulates both BRCA1 mRNA and BRCA1 protein expressions, ensuring a high level of DNA safeguarding. In turn, increased BRCA1 protein concentration induces higher expression of both ERα mRNA and ERα protein, resulting in strengthened ER signaling. Inner circle: Self-repressing mutual downregulation between low and/or defective E2-liganded ERα and BRCA1 protein expressions during malignant cell proliferation. Failure of ERα expression represses both BRCA1 mRNA and BRCA1 protein synthesis, inhibiting appropriate DNA safeguarding. In turn, failure of BRCA1 protein synthesis downregulates both ERα mRNA and ERα protein expression and suppresses ERα signaling. Coactivators: AhR, p300, cyclin D, and Oct-1; corepressor: ID4. ↑= upregulation, ↓= downregulation.Abbreviations: AhR, aromatic hydrocarbon receptor; E2, estradiol; ER, estrogen receptor; ID4, inhibitor of differentiation 4; Oct-1, octamer-binding transcriptional factor 1.

Mentions: There is strong regulatory protein–protein interplay between BRCA1 and ER-alpha expressions during cell proliferation (Figure 1). These interactions are fairly complex; therefore, the majority of studies mistakenly support the concept that both functional BRCA1 gene and BRCA1 protein suppress ESR1 gene expression and ER-alpha-mediated transactivation of its downstream target genes so as to keep the “dangerous” estrogen signaling in check.


DNA stabilization by the upregulation of estrogen signaling in BRCA gene mutation carriers.

Suba Z - Drug Des Devel Ther (2015)

Protein–protein interplay between ERα and BRCA1 expressions during physiologic and malignant cell proliferations.Notes: Outer circle: Self-generating mutual upregulation between E2-liganded ERα and BRCA1 protein expressions during physiologic cell proliferation. Increasing ERα expression upregulates both BRCA1 mRNA and BRCA1 protein expressions, ensuring a high level of DNA safeguarding. In turn, increased BRCA1 protein concentration induces higher expression of both ERα mRNA and ERα protein, resulting in strengthened ER signaling. Inner circle: Self-repressing mutual downregulation between low and/or defective E2-liganded ERα and BRCA1 protein expressions during malignant cell proliferation. Failure of ERα expression represses both BRCA1 mRNA and BRCA1 protein synthesis, inhibiting appropriate DNA safeguarding. In turn, failure of BRCA1 protein synthesis downregulates both ERα mRNA and ERα protein expression and suppresses ERα signaling. Coactivators: AhR, p300, cyclin D, and Oct-1; corepressor: ID4. ↑= upregulation, ↓= downregulation.Abbreviations: AhR, aromatic hydrocarbon receptor; E2, estradiol; ER, estrogen receptor; ID4, inhibitor of differentiation 4; Oct-1, octamer-binding transcriptional factor 1.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4440422&req=5

f1-dddt-9-2663: Protein–protein interplay between ERα and BRCA1 expressions during physiologic and malignant cell proliferations.Notes: Outer circle: Self-generating mutual upregulation between E2-liganded ERα and BRCA1 protein expressions during physiologic cell proliferation. Increasing ERα expression upregulates both BRCA1 mRNA and BRCA1 protein expressions, ensuring a high level of DNA safeguarding. In turn, increased BRCA1 protein concentration induces higher expression of both ERα mRNA and ERα protein, resulting in strengthened ER signaling. Inner circle: Self-repressing mutual downregulation between low and/or defective E2-liganded ERα and BRCA1 protein expressions during malignant cell proliferation. Failure of ERα expression represses both BRCA1 mRNA and BRCA1 protein synthesis, inhibiting appropriate DNA safeguarding. In turn, failure of BRCA1 protein synthesis downregulates both ERα mRNA and ERα protein expression and suppresses ERα signaling. Coactivators: AhR, p300, cyclin D, and Oct-1; corepressor: ID4. ↑= upregulation, ↓= downregulation.Abbreviations: AhR, aromatic hydrocarbon receptor; E2, estradiol; ER, estrogen receptor; ID4, inhibitor of differentiation 4; Oct-1, octamer-binding transcriptional factor 1.
Mentions: There is strong regulatory protein–protein interplay between BRCA1 and ER-alpha expressions during cell proliferation (Figure 1). These interactions are fairly complex; therefore, the majority of studies mistakenly support the concept that both functional BRCA1 gene and BRCA1 protein suppress ESR1 gene expression and ER-alpha-mediated transactivation of its downstream target genes so as to keep the “dangerous” estrogen signaling in check.

Bottom Line: In BRCA-proficient cases, estrogen signaling orchestrates the activity of cell proliferation and differentiation with high safety, while upregulating the expression and DNA-stabilizing impact of BRCA genes.Natural estrogens have numerous benefits in tumor prevention and therapy even in BRCA mutation carriers.There are no toxic effects even in sky-high doses and all physiologic cellular functions are strongly upregulated, while malignant tumor cells are recognized and killed in a Janus-faced manner.

View Article: PubMed Central - PubMed

Affiliation: Surgical and Molecular Tumor Pathology Centre, National Institute of Oncology, Budapest, Hungary.

ABSTRACT
Currently available scientific evidence erroneously suggests that mutagenic weakness or loss of the BRCA1/2 genes may liberate the proliferative effects of estrogen signaling, which provokes DNA damage and genomic instability. Conversely, BRCA mutation seems to be an imbalanced defect, crudely inhibiting the upregulation of estrogen receptor expression and liganded transcriptional activity, whereas estrogen receptor-repressor functions become predominant. In BRCA-proficient cases, estrogen signaling orchestrates the activity of cell proliferation and differentiation with high safety, while upregulating the expression and DNA-stabilizing impact of BRCA genes. In turn, BRCA proteins promote estrogen signaling by proper estrogen synthesis via CYP19 gene regulation and by induction of the appropriate expression and transcriptional activity of estrogen receptors. In this exquisitely organized regulatory system, the dysfunction of each player may jeopardize genome stability and lead to severe chronic diseases, such as cancer development. Female organs, such as breast, endometrium, and ovary, exhibiting regular cyclic proliferative activity are particularly vulnerable in case of disturbances in either estrogen signaling or BRCA-mediated DNA repair. BRCA mutation carrier women may apparently be healthy or exhibit clinical signs of deficient estrogen signaling in spite of hyperestrogenism. Even women who enjoy sufficient compensatory DNA-defending activities are at risk of tumor development because many endogenous and environmental factors may jeopardize the mechanisms of extreme compensatory processes. Natural estrogens have numerous benefits in tumor prevention and therapy even in BRCA mutation carriers. There are no toxic effects even in sky-high doses and all physiologic cellular functions are strongly upregulated, while malignant tumor cells are recognized and killed in a Janus-faced manner.

No MeSH data available.


Related in: MedlinePlus