Oestrogen receptors (ORs) may act as a hub where several molecular pathways converge, while the transcriptional activity of ORs drives all cellular functions.

OR regulated genes initiate, complete and supervise the replication and recombination of DNA.

There is a unique upregulative feedback mechanism between oestrogens and ORs.

Both high and low oestrogen levels promote an increased expression and transcriptional activity of ORs so as to restore or augment cellular OR signalling.

In turn, both low and high OR expressions induce powerful oestrogen synthesis for the improvement or augmentation of crucial OR signalling.

Oestrogens induce a balanced activation of oestrogen liganded and non liganded growth factor receptor (GFR) mediated transactivation functions of ORs providing immense reserve capacities in emergency conditions.

When liganded OR signalling is endangered by either oestrogen deficiency or OR resistance, a strong compensatory upregulation of non liganded OR activation may save the surveillance of genomic machinery.

Increased oestrogen concentrations amplify both OR expression and oestrogen synthesis strongly upregulating the OR signalling and genomic stabilisation.

The DNA protective effect of high oestrogen 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 ORs and a conspicuous primacy of the ligand dependent AF2 function of ORs was established.

In turn, the activated AF1 domain of ORs 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 oestrogen rich milieu.

The development of false synthetic oestrogens, included ethinylestradiol, may be regarded as a pharmaceutical mistake.

In breast cancer cells, low doses of synthetic oestrogens exert an inhibitory effect on the ligand independent AF1 domain, while provoke compensatory activations on the superior, ligand dependent AF2 domain of ORs and oestrogen synthesis.

Oestrogen-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 OR signalling.

Women with inherited BRCA1 or BRCA2 gene mutation are at increased risk of breast and ovarian cancers attributed to a defective liganded activation of ORs.

OC use provokes a compensatory upregulation of the weak liganded activation of ORs 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 OR activations.

High doses of synthetic oestrogens induce uncompensated genome wide, chaotic disorders in OR regulated genes leading to serious toxic symptoms, unreckonable tumour responses and even to the development of new malignancies.

Carcinogenic processes induced by high doses of synthetic oestrogens were mistakenly evaluated as obvious consequences of the uncontrolled activation of many oestrogen regulated genes.

In reality, in tumour cells treated with high dose ethinylestradiol, a hardly compensated blockade of the AF1 domain of ORs strengthens the disturbances of both cellular metabolism and interactions of ORs with DNA.

Use of antioestrogens as anticancer agents is a medical mistake based on an old misbelief suggesting the carcinogenic capacity of high oestrogen concentrations.

Antioestrogens, either OR blockers or aromatase inhibitors crudely inhibit the predominant, liganded activation of ORs strongly endangering the defence of genomic machinery.

In genetically proficient patients, antioestrogen treatment leads to compensatory activations of ORs, GFRs and aromatase enzyme synthesis transiently upregulating both liganded and unliganded OR signalling and promoting tumour responses.

By contrast, in genetically challenged patients, the chaotic mixture of artificial OR blockade and the weak compensatory activation of ORs may lead to toxic symptoms, unreckonable tumour responses or aggressive tumour growth.

In antioestrogen resistant tumours, the markedly increased expression of GFRs was mistakenly regarded as a switch towards an adaptive survival technique and a key for acquired antioestrogen resistance.

In reality, the amplified GFR signalling serves as a strong compensatory increase in the non liganded activation of ORs even when it is not satisfactory for the restoration of genomic stability and for self directed tumour cell death.

The pharmaceutical development of endocrine disruptor agents could not achieve appropriate advances in the field of anticancer fight.

Use of synthetic oestrogens yielded ambiguous results in cancer therapy attributed to the blockade of unliganded activations of ORs.

The anticancer efficacy of antioestrogens proved to be much more controversial attributed to blocking the superior liganded activation of ORs.

By contrast, natural oestrogens are capable of restoring DNA surveillance even in tumour cells via a harmonised transactivation of the AF1 and AF2 domains of ORs, and they may not provoke genomic instability even in sky-high concentrations.

Source: Bentham Science Publishers