Title:Activating Mutations of ESR1, BRCA1 and CYP19 Aromatase Genes Confer Tumor Response in Breast Cancers Treated with Antiestrogens
VOLUME: 12 ISSUE: 2
Author(s):Zsuzsanna Suba*
Affiliation:National Institute of Oncology, Surgical and Molecular Tumor Pathology Center, Address: H-1122, Ráth György Street, 7-9, Budapest
Keywords:Activating mutations, antiestrogen resistance, apoptotic tumor cell death, artificial estrogens, breast cancer, cancer
prevention, cancer therapy, DNA-repair, estrogen therapy, long non-coding RNAs.
Abstract:Background: Four decades of erroneous breast cancer therapy with antiestrogens yielded the
chaotic mixture of manifestations of artificial ER-inhibition and compensatory activating ER-mutations
together with unreckonable tumor responses.
Objective: Due to the confusions between the anticancer and carcinogenic impacts of antiestrogens and
synthetic estrogens, the old principle needs to be revised as concerns ER-signaling induced DNAdamage
and breast cancer development.
Method: Results of genetic studies on both estrogen- and antiestrogen-treated tumors were reanalyzed
and associations among ER-blockade, compensatory restoration of ER-signaling and clinical behavior
of cancers were investigated.
Results: There are no direct correlations between estrogen concentrations and mammary tumor development;
the highest risk for breast cancer is rather the severe defect of ER-signaling. Upregulation of
ER-signaling induced by natural estrogens is a beneficial process even in tumor cells promoting their
domestication and elimination while in case of antiestrogen administration; increased ER-signaling is a
compensatory action to strengthen residual genome stabilization. In genetically proficient patients, extreme
upregulation of ER-activity and estrogen synthesis provoked by antiestrogens provides transiently
enhanced genomic stabilization with the promotion of spontaneous tumor death. Recent patents reveal
correlations between activating ESR1 mutations and antiestrogen induced tumor response. Conversely,
in the majority of patients with genetic defects, antiestrogen administration evokes weak counteractive
increase in estrogen synthesis and ER-expression, which is not satisfactory in terms of tumor response.
Conclusion: Activating mutations affecting ERs play key roles in both the machinery of genome stabilization
of healthy cells and the restoration of altered genetic pathways of DNA-repair in tumor cells.
