Estrogen therapy may still hold the key to fight specific ER resistant breast cancers
Estrogen receptors (ERs) may act as a hub where several molecular pathways converge, while the transcriptional activity of ERs drives all cellular functions. ER regulated genes initiate, complete and supervise the replication and recombination of DNA. There is a unique upregulative feedback mechanism between estrogens and ERs. Both high and low estrogen levels promote an increased expression and transcriptional activity of ERs so as to restore or augment cellular ER signaling. In turn, both low and high ER expressions induce powerful estrogen synthesis for the improvement or augmentation of crucial ER signaling. Estrogens induce a balanced activation of estrogen liganded and non liganded growth factor receptor (GFR) mediated transactivation functions of ERs providing immense reserve capacities in emergency conditions. When liganded ER signaling is endangered by either estrogen deficiency or ER resistance, a strong compensatory upregulation of non liganded ER activation may save the surveillance of genomic machinery. Increased estrogen concentrations amplify both ER expression and estrogen synthesis strongly upregulating the ER signaling and genomic stabilization. The DNA protective effect of high estrogen concentrations improves all physiologic functions of healthy cells, while suppressing the survival possibility of cancer cells in a Janus-faced manner.
Experimental studies reveal a strong interplay between liganded and non liganded transcriptional activations of ERs and a conspicuous primacy of the ligand dependent AF2 function of ERs was established. In turn, the activated AF1 domain of ERs is capable of recovering the moderately defective function of AF2 domain, while the complete blockade of AF2 function may not be compensated even in a highly estrogen rich milieu.
The development of false synthetic estrogens, included ethinylestradiol, may be regarded as a pharmaceutical mistake. In breast cancer cells, low doses of synthetic estrogens exert an inhibitory effect on the ligand independent AF1 domain, while provoke compensatory activations on the superior, ligand dependent AF2 domain of ERs and estrogen synthesis. Estrogen-like effects of oral contraceptives (OCs) comprising of low ethinylestradiol doses may strongly reduce the risk of endometrial and ovarian cancers even in anovulatory women with various genetic defects affecting ER signaling. Women with inherited BRCA1 or BRCA2 gene mutation are at increased risk of breast and ovarian cancers attributed to a defective liganded activation of ERs. OC use provokes a compensatory upregulation of the weak liganded activation of ERs in BRCA mutation carriers leading to a strong decrease in the risk of ovarian cancer. Conversely, the risk for breast cancer is not reduced by OC use in genetically challenged women, as the female breast is strongly vulnerable even to a slight imbalance of liganded and unliganded ER activations. High doses of synthetic estrogens induce uncompensated genome wide, chaotic disorders in ER regulated genes leading to serious toxic symptoms, unreckonable tumor responses and even to the development of new malignancies. Carcinogenic processes induced by high doses of synthetic estrogens were mistakenly evaluated as obvious consequences of the uncontrolled activation of many estrogen regulated genes. In reality, in tumor cells treated with high dose ethinylestradiol, a hardly compensated blockade of the AF1 domain of ERs strengthens the disturbances of both cellular metabolism and interactions of ERs with DNA.
Use of antiestrogens as anticancer agents is a medical mistake based on an old misbelief suggesting the carcinogenic capacity of high estrogen concentrations. Antiestrogens, either ER blockers or aromatase inhibitors crudely inhibit the predominant, liganded activation of ERs strongly endangering the defense of genomic machinery. In genetically proficient patients, antiestrogen treatment leads to compensatory activations of ERs, GFRs and aromatase enzyme synthesis transiently upregulating both liganded and unliganded ER signaling and promoting tumor responses. By contrast, in genetically challenged patients, the chaotic mixture of artificial ER blockade and the weak compensatory activation of ERs may lead to toxic symptoms, unreckonable tumor responses or aggressive tumor growth. In antiestrogen resistant tumors, the markedly increased expression of GFRs was mistakenly regarded as a switch towards an adaptive survival technique and a key for acquired antiestrogen resistance. In reality, the amplified GFR signaling serves as a strong compensatory increase in the non liganded activation of ERs even when it is not satisfactory for the restoration of genomic stability and for self directed tumor cell death.
The pharmaceutical development of endocrine disruptor agents could not achieve appropriate advances in the field of anticancer fight. Use of synthetic estrogens yielded ambiguous results in cancer therapy attributed to the blockade of unliganded activations of ERs. The anticancer efficacy of antiestrogens proved to be much more controversial attributed to blocking the superior liganded activation of ERs. By contrast, natural estrogens are capable of restoring DNA surveillance even in tumor cells via a harmonized transactivation of the AF1 and AF2 domains of ERs, and they may not provoke genomic instability even in sky-high concentrations.
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Reference: Zsuzsanna S., (2018). Amplified Crosstalk Between Estrogen Binding and GFR Signaling Mediated Pathways of ER Activation Drives Responses in Tumors Treated with Endocrine Disruptors. Recent Patents on Anti-Cancer Drug Discovery, Volume 13, 2018. DOI: 10.2174/1574892813666180720123732
Faizan ul Haq