Title:Amplified Crosstalk Between Estrogen Binding and GFR Signaling Mediated Pathways of ER Activation Drives Responses in Tumors Treated with Endocrine Disruptors
VOLUME: 13 ISSUE: 4
Author(s):Zsuzsanna Suba*
Affiliation:National Institute of Oncology, Department of Molecular Pathology, Address: H-1122, Ráth György str. 7-9, Budapest
Keywords:Antiestrogen, cancer treatment, estrogen receptor, ethinylestradiol, genomic stability, growth factor receptor, synthetic
estrogen, tamoxifen, tumor response.
Abstract:Background: The pharmaceutical development of endocrine disruptors could not achieve
appropriate advances in the field of anticancer fight.
Objective: Considerations on the principles of currently used endocrine therapies.
Methods: Comparison of the results of genetic studies being performed on breast cancer cells treated
with estrogens, synthetic estrogens and antiestrogens.
Results: In breast cancer cells, increased estrogen concentrations amplify ER-signaling via a synergistic
upregulation of both liganded and unliganded ER-activations and increased aromatase expression.
The higher the upregulation of ER-signaling, the stronger is the tumor response. Low doses of synthetic
estrogens exert an inhibition on the ligand-independent AF1-domain in breast cancer cells, while
provoke compensatory activation on the superior, ligand-dependent AF2-domain of ERs and estrogen
synthesis. Conversely, high doses of synthetic estrogens induce uncompensated genome-wide disruption
in ER-regulated genes leading to toxic symptoms and unpredictable tumor responses. Treatment
with antiestrogens, either ER-blockers or aromatase inhibitors, obstructs the crucial AF2-domain of
ERs strongly deteriorating the activation of genomic machinery. Tumor responses to antiestrogen
treatment depend on the compensatory activation of ER-signaling and the restoration of genomic stability.
Recent patents provide methods for the conversion of ER-negative cancers to ER-positive ones
improving the possibility of successful treatment.
Conclusion: In tumor cells, the stabilization of genomic machinery and self-directed death may be
achieved via a balanced activation of the AF1 and AF2 domains of ERs by natural estrogen treatment.
In contrast, the blockade of either AF1 or AF2 domain by endocrine disruptors leads to toxic symptoms
and unforeseeable tumor responses.
