Antiestrogen treatment was introduced into breast cancer therapy based on the presumed carcinogenic capacity of endogenous estrogen hormones. In antiestrogen resistant breast cancers, increased expression and activity of estrogen receptors (ERs) is regarded as a survival technique, presuming that increased estrogen signaling is an absolutely proliferative stimulus. Unexpectedly, among certain circumstances, estrogen treatment is capable of inducing apoptotic death in tumors, even in antiestrogen resistant ones justifying the strong apoptotic capacity of estrogen. Analysis of the results of studies on both estrogen and antiestrogen treated tumors may clarify the associations among artificial ER blockade, compensatory restoration of ER signaling and the clinical behavior of cancers.
Inherited BRCA1/2 mutations may be regarded as pathologic models of defective estrogen signaling. In BRCA mutation carriers, the liganded activation of ERs is weak, while an increase in unliganded ER activation results in a more or less compensatory upregulation of ER signaling. Mutation carriers exhibit failure in their ovarian functions, while their risk for cancer is strongly increased (for breast cancer in particular). In cases carrying BRCA mutation, an increase in estrogen levels via either endogenous estrogen synthesis in pregnancy or exogenous estrogen administration via contraceptive use may reduce the risk of cancer development.
Estrogen activated ERs are the principal initiators and organizers of DNA stabilization. ERs work in an upregulative circuit with CYP19 aromatase enzyme and genome safeguarding proteins including BRCAs. The upregulative circuit ensures a strong DNA protection during the proliferation of healthy cells, whilst inducing apoptotic death in spontaneously initiated malignant cells in a Janus faced manner. By contrast, malignant cell proliferation exhibits a downregulative circuit between the low and/or defective expressions of ER and BRCA proteins. The malfunction of ER signaling is coupled with a damaged control of DNA replication resulting in an unrestrained proliferation of poorly differentiated tumor cells. In conclusion, in patients with cancer, estradiol induced upregulation of ER signaling may be an excellent means for the restoration of genome stabilizer machinery and for inducing apoptotic death in cancer cells.
Estrogen treatment upregulates the remnants of genome stabilizer machinery in breast cancer cell lines so as to induce an apoptotic death. Estrogen administration increases the expression and transcriptional activity of ERs in tumor cells, via both liganded and unliganded pathways. In patients, of all examined tumor markers, an increased expression of ERs in their breast cancer defines the prolonged survival. Moreover, the activation of ER-alpha at Ser 167 in tumors is indicative of longer disease free and overall survival in breast cancer patients.
Estrogen treatment induces ESR1 gene amplification resulting in higher expression levels of ERs in breast cancers. Patients exhibiting ESR1 gene amplification in their tumors, experience longer disease free survival than those without it.
Estradiol treatment mediates an increased expression of long non coding RNAs (lncRNAs) including HOTAIR in breast cancer cells. HOTAIR is capable of epigenetic gene modifications resulting in necessary activating mutations in the ESR1 gene. Patients with increased HOTAIR expression in their tumors were found to have lower risks for relapse and mortality than those showing low HOTAIR expression.
Estradiol treatment increases aromatase expression and activity in breast cancer cells in a dose dependent manner. Estradiol activated ERs strongly upregulate the estrogen synthesis of aromatase enzyme so as to increase estrogen signaling and to induce consequential DNA restoration and apoptotic death. Among breast cancer cases, a direct correlation was experienced between the aromatase activity of removed tumors and the patient’s survival time after surgery. Moreover, among young women with breast cancer, the absence of CYP19 aromatase activity in their surgically removed tumors carried a high risk for local cancer recurrence.
Estrogen treatment induces an upregulated expression of DNA safeguarding BRCA1 protein in breast cancer cell lines. In turn, it was found that the BRCA1 protein promotes ESR1 gene activation and transcriptionally upregulates ER-alpha expression in tumor cells. These correlations justify that ER-alpha and BRCA1 protein work in close partnership in the DNA stabilization process which provides apoptotic stimuli for breast cancer cells.
In conclusion, treatment with estrogen may strongly upregulate both estrogen signaling and DNA safeguarding in breast cancers promoting tumor responses. In antiestrogen responsive tumors, the blockade of liganded ER activation via either tamoxifen or aromatase inhibitor, provokes compensatory overexpression and hyperactivity of both ERs and aromatase enzyme via unliganded activations of partially blocked ERs. This compensatory activation of estrogen signaling may restore DNA stability promoting tumor responses. By contrast, in antiestrogen resistant tumors, a long term, exhaustive tamoxifen or aromatase inhibitor treatment induces a compensatory extreme upregulation of ER signaling; however, it may be insufficient to break through the near complete, artificially induced ER blockade. Antiestrogen resistant tumors exhibit a rapid growth in spite of the continuous administration of antiestrogens.
Bentham Science 
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