Activating mutations of ESR1, BRCA1 and CYP19 aromatase genes confer tumor response in breast cancers treated with antiestrogens

Research output: Review article

5 Citations (Scopus)

Abstract

Background: Four decades of erroneous breast cancer therapy with antiestrogens yielded the chaotic mixture of manifestations of artificial ER-inhibition and compensatory activating ER-mutations together with unreckonable tumor responses. Objective: Due to the confusions between the anticancer and carcinogenic impacts of antiestrogens and synthetic estrogens, the old principle needs to be revised as concerns ER-signaling induced DNAdamage and breast cancer development. Method: Results of genetic studies on both estrogen- and antiestrogen-treated tumors were reanalyzed and associations among ER-blockade, compensatory restoration of ER-signaling and clinical behavior of cancers were investigated. Results: There are no direct correlations between estrogen concentrations and mammary tumor development; the highest risk for breast cancer is rather the severe defect of ER-signaling. Upregulation of ER-signaling induced by natural estrogens is a beneficial process even in tumor cells promoting their domestication and elimination while in case of antiestrogen administration; increased ER-signaling is a compensatory action to strengthen residual genome stabilization. In genetically proficient patients, extreme upregulation of ER-activity and estrogen synthesis provoked by antiestrogens provides transiently enhanced genomic stabilization with the promotion of spontaneous tumor death. Recent patents reveal correlations between activating ESR1 mutations and antiestrogen induced tumor response. Conversely, in the majority of patients with genetic defects, antiestrogen administration evokes weak counteractive increase in estrogen synthesis and ER-expression, which is not satisfactory in terms of tumor response. Conclusion: Activating mutations affecting ERs play key roles in both the machinery of genome stabilization of healthy cells and the restoration of altered genetic pathways of DNA-repair in tumor cells.

Original languageEnglish
Pages (from-to)136-147
Number of pages12
JournalRecent Patents on Anti-Cancer Drug Discovery
Volume12
Issue number2
DOIs
Publication statusPublished - máj. 1 2017

Fingerprint

Aromatase
Estrogen Receptor Modulators
Breast Neoplasms
Mutation
Estrogens
Genes
Neoplasms
Up-Regulation
Genome
Estradiol Congeners
Patents
DNA Repair

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Cancer Research
  • Pharmacology (medical)

Cite this

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title = "Activating mutations of ESR1, BRCA1 and CYP19 aromatase genes confer tumor response in breast cancers treated with antiestrogens",
abstract = "Background: Four decades of erroneous breast cancer therapy with antiestrogens yielded the chaotic mixture of manifestations of artificial ER-inhibition and compensatory activating ER-mutations together with unreckonable tumor responses. Objective: Due to the confusions between the anticancer and carcinogenic impacts of antiestrogens and synthetic estrogens, the old principle needs to be revised as concerns ER-signaling induced DNAdamage and breast cancer development. Method: Results of genetic studies on both estrogen- and antiestrogen-treated tumors were reanalyzed and associations among ER-blockade, compensatory restoration of ER-signaling and clinical behavior of cancers were investigated. Results: There are no direct correlations between estrogen concentrations and mammary tumor development; the highest risk for breast cancer is rather the severe defect of ER-signaling. Upregulation of ER-signaling induced by natural estrogens is a beneficial process even in tumor cells promoting their domestication and elimination while in case of antiestrogen administration; increased ER-signaling is a compensatory action to strengthen residual genome stabilization. In genetically proficient patients, extreme upregulation of ER-activity and estrogen synthesis provoked by antiestrogens provides transiently enhanced genomic stabilization with the promotion of spontaneous tumor death. Recent patents reveal correlations between activating ESR1 mutations and antiestrogen induced tumor response. Conversely, in the majority of patients with genetic defects, antiestrogen administration evokes weak counteractive increase in estrogen synthesis and ER-expression, which is not satisfactory in terms of tumor response. Conclusion: Activating mutations affecting ERs play key roles in both the machinery of genome stabilization of healthy cells and the restoration of altered genetic pathways of DNA-repair in tumor cells.",
keywords = "Activating mutations, Antiestrogen resistance, Apoptotic tumor cell death, Artificial estrogens, Breast cancer, Cancer prevention, Cancer therapy, DNA-repair, Estrogen therapy, Long non-coding RNAs",
author = "Z. Suba",
year = "2017",
month = "5",
day = "1",
doi = "10.2174/1574892812666170227110842",
language = "English",
volume = "12",
pages = "136--147",
journal = "Recent Patents on Anti-Cancer Drug Discovery",
issn = "1574-8928",
publisher = "Bentham Science Publishers B.V.",
number = "2",

}

TY - JOUR

T1 - Activating mutations of ESR1, BRCA1 and CYP19 aromatase genes confer tumor response in breast cancers treated with antiestrogens

AU - Suba, Z.

PY - 2017/5/1

Y1 - 2017/5/1

N2 - Background: Four decades of erroneous breast cancer therapy with antiestrogens yielded the chaotic mixture of manifestations of artificial ER-inhibition and compensatory activating ER-mutations together with unreckonable tumor responses. Objective: Due to the confusions between the anticancer and carcinogenic impacts of antiestrogens and synthetic estrogens, the old principle needs to be revised as concerns ER-signaling induced DNAdamage and breast cancer development. Method: Results of genetic studies on both estrogen- and antiestrogen-treated tumors were reanalyzed and associations among ER-blockade, compensatory restoration of ER-signaling and clinical behavior of cancers were investigated. Results: There are no direct correlations between estrogen concentrations and mammary tumor development; the highest risk for breast cancer is rather the severe defect of ER-signaling. Upregulation of ER-signaling induced by natural estrogens is a beneficial process even in tumor cells promoting their domestication and elimination while in case of antiestrogen administration; increased ER-signaling is a compensatory action to strengthen residual genome stabilization. In genetically proficient patients, extreme upregulation of ER-activity and estrogen synthesis provoked by antiestrogens provides transiently enhanced genomic stabilization with the promotion of spontaneous tumor death. Recent patents reveal correlations between activating ESR1 mutations and antiestrogen induced tumor response. Conversely, in the majority of patients with genetic defects, antiestrogen administration evokes weak counteractive increase in estrogen synthesis and ER-expression, which is not satisfactory in terms of tumor response. Conclusion: Activating mutations affecting ERs play key roles in both the machinery of genome stabilization of healthy cells and the restoration of altered genetic pathways of DNA-repair in tumor cells.

AB - Background: Four decades of erroneous breast cancer therapy with antiestrogens yielded the chaotic mixture of manifestations of artificial ER-inhibition and compensatory activating ER-mutations together with unreckonable tumor responses. Objective: Due to the confusions between the anticancer and carcinogenic impacts of antiestrogens and synthetic estrogens, the old principle needs to be revised as concerns ER-signaling induced DNAdamage and breast cancer development. Method: Results of genetic studies on both estrogen- and antiestrogen-treated tumors were reanalyzed and associations among ER-blockade, compensatory restoration of ER-signaling and clinical behavior of cancers were investigated. Results: There are no direct correlations between estrogen concentrations and mammary tumor development; the highest risk for breast cancer is rather the severe defect of ER-signaling. Upregulation of ER-signaling induced by natural estrogens is a beneficial process even in tumor cells promoting their domestication and elimination while in case of antiestrogen administration; increased ER-signaling is a compensatory action to strengthen residual genome stabilization. In genetically proficient patients, extreme upregulation of ER-activity and estrogen synthesis provoked by antiestrogens provides transiently enhanced genomic stabilization with the promotion of spontaneous tumor death. Recent patents reveal correlations between activating ESR1 mutations and antiestrogen induced tumor response. Conversely, in the majority of patients with genetic defects, antiestrogen administration evokes weak counteractive increase in estrogen synthesis and ER-expression, which is not satisfactory in terms of tumor response. Conclusion: Activating mutations affecting ERs play key roles in both the machinery of genome stabilization of healthy cells and the restoration of altered genetic pathways of DNA-repair in tumor cells.

KW - Activating mutations

KW - Antiestrogen resistance

KW - Apoptotic tumor cell death

KW - Artificial estrogens

KW - Breast cancer

KW - Cancer prevention

KW - Cancer therapy

KW - DNA-repair

KW - Estrogen therapy

KW - Long non-coding RNAs

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U2 - 10.2174/1574892812666170227110842

DO - 10.2174/1574892812666170227110842

M3 - Review article

C2 - 28245776

AN - SCOPUS:85022186163

VL - 12

SP - 136

EP - 147

JO - Recent Patents on Anti-Cancer Drug Discovery

JF - Recent Patents on Anti-Cancer Drug Discovery

SN - 1574-8928

IS - 2

ER -