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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: National Institute of Oncology, Surgical and Molecular Tumor Pathology Center, Address: H-1122, Ráth György Street, 7-9, Budapest. Hungary.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Suba
mesh_terms: D001141:Aromatase / Q000235:genetics; D019313:BRCA1 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004260:DNA Repair / Q000235:genetics; D004965:Estrogen Antagonists / Q000009:adverse effects / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000009:adverse effects / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000235:genetics; D004967:Estrogens / Q000009:adverse effects / Q000494:pharmacology; D005260:Female; D006801:Humans; D009154:Mutation; D010330:Patents as Topic; D011960:Receptors, Estrogen / Q000235:genetics*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; C506487:ESR1 protein, human; D004965:Estrogen Antagonists; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D004967:Estrogens; D011960:Receptors, Estrogen; D001141:Aromatase; C561410:CYP19A1 protein, human
keywords: Activating mutations; DNA-repair; antiestrogen resistance; apoptotic tumor cell death; artificial estrogens; breast cancer; cancer
  prevention; cancer therapy; estrogen therapy; long non-coding RNAs