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
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
Estradiol treatment mediates an
Estrogen treatment induces an
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.
In clinical practice, estrogen emerged as a key factor in restoring the response of antiestrogen resistant cancers in both male and female patients. Moreover, estrogen treatment induced rapid apoptotic death in breast cancer cell lines resistant to either tamoxifen or long term estrogen deprivation. Considering the strong compensatory upregulation of both ERs and GFRs in antiestrogen resistant tumors, estrogen gains an enormous potential to induce a strong balanced activation of ERs through both liganded and unliganded pathways. Estrogen treatment does not return antiestrogen resistant tumors to ‘antiestrogen responsiveness’, but rather it exerts its physiological antiproliferative effect by overcoming the artificial blockade of ERs.
Upregulation of ER-signaling induced by natural estrogens is a beneficial, physiological process even in tumor cells promoting their domestication and elimination. In contrast, in case of antiestrogen blockade of tumors, a compensatory upregulation of ER-signaling will more or less strengthen the machinery of genomic stabilization. Cancer therapy with antiestrogen treatment may be successful, when the compensatory activation of estrogen signaling is capable of defeating the blockade of ERs.
Keywords: Activating mutations; antiestrogen resistance; apoptotic tumor cell death; artificial estrogens; BRCA mutation; breast cancer; cancer prevention; cancer therapy; DNA-repair; ER blockade; ESR1 gene activation; estrogen therapy; HOTAIR; long non-coding RNA; overexpression of ERs.
Reference: Suba Z. Activating mutations of ESR1, BRCA1 and CYP19 aromatase genes confer tumor response in breast cancers treated with antiestrogens. Recent Patents on Anticancer Drug Discovery 2017; 12(2): 136-147.