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 language | English |
|---|---|
| Pages (from-to) | 136-147 |
| Number of pages | 12 |
| Journal | Recent Patents on Anti-Cancer Drug Discovery |
| Volume | 12 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - máj. 1 2017 |
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ASJC Scopus subject areas
- Oncology
- Drug Discovery
- Cancer Research
- Pharmacology (medical)
Cite this
Activating mutations of ESR1, BRCA1 and CYP19 aromatase genes confer tumor response in breast cancers treated with antiestrogens. / Suba, Z.
In: Recent Patents on Anti-Cancer Drug Discovery, Vol. 12, No. 2, 01.05.2017, p. 136-147.Research output: Review article
}
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
UR - http://www.scopus.com/inward/record.url?scp=85022186163&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85022186163&partnerID=8YFLogxK
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 -