in 1938 , the first cheap synthetic estrogen - like chemical ( diethylstilbestrol )   was made available to patients , first as an experimental drug , then a few years later with fda approval . in previous decades , the benefits of estrogen as a supposed remedy for a variety of diseases provided fertile ground for subsequent pharmaceutical exploitations . yet , even as early as the late 1800s , clinicians observed a link between hormones and cancer [ 2 , 3 ] , and in 1932 , controlled laboratory research showed that estrogen can induce breast cancers . surprisingly , over the last 75  years , and despite the subsequent tragedy that resulted from the diethylstilbestrol , the molecular mechanism behind how estrogen exerts its oncogenic effects remained mostly elusive . tests , including the ames mutagenesis assay , were unable to show any significant effect of estrogen as a dna - damaging agent . this led to the prevailing conclusion that estrogen - induced cancer through its ability to activate cell proliferation . more recently , other theories have tried to explain the oncogenic potential of estrogen , they included : inhibition of apoptosis , inactivation of dna repair , and radicals from oxidative stress or metabolic derivatives of estrogen ( if present at high concentrations ) forming dna adducts ( reviewed in [ 57 ] ) . although each theory addresses a particular aspect of estrogen s oncogenic potential , none are fully satisfactory in explaining how physiological amounts of estrogen can be oncogenic . in 2002 , we discovered a novel molecular mechanism that explained how antibody genes were diversified after antigen encounter during a humoral immune response . although known to shuttle between the nucleus and the cytoplasm , activation - induced deaminase ( aid ) is a predominantly cytoplasmic enzyme that , upon activation , enters the nucleus and is targeted to the immunoglobulin ( ig ) locus . the enzyme then deaminates cytosine bases ( dc ) to uracil ( du ) in single - stranded dna ( fig . the protein itself had been identified a few years earlier , as an essential gene for antibody diversification ( i.e. class switching ( csr ) and somatic hypermutation ( shm ) ) , and was named aid [ 12 , 13 ] . usually the dna lesion ( either as du or as a du : dg mismatch ) is faithfully repaired back to cytosine ( fig . 1b ) , but in the ig locus it leads to dna mutations and dna recombination ( fig . , single point mutations are introduced into the dna of the ig locus , which manifest themselves as , and are selected for , amino acid changes in the antigen - binding site . targeting the constant region of the ig locus with aid during csr , allows for homologous dna regions to recombine and loop out the intervening sequence , thereby placing a different constant domain into the active ig locus . this change allows for the antibody to obtain a different effector function ( e.g. , from a predominantly membrane - bound igm to a soluble ige ) . the hallmark for both events is a natural protein - inducing dna damage that does not lead to dna repair , but to dna alterations in somatic cells . ( a ) aid uses hydrolytic deamination to form uracil in single - stranded dna , thereby inducing a twofold lesion in the dna , an unusual base and a base mismatch . ( b ) normally , various dna repair pathways repair the lesion back to cytosine . ( c ) and ( d ) at the immunoglobulin locus , the aid - induced lesion leads to shm and csr . ( e ) aid can induce oncogenic translocations during csr , if the c - myc promoter rearranges into the ig locus rather than another ig constant region the function and consequence of aid . ( a ) aid uses hydrolytic deamination to form uracil in single - stranded dna , thereby inducing a twofold lesion in the dna , an unusual base and a base mismatch . ( b ) normally , various dna repair pathways repair the lesion back to cytosine . ( c ) and ( d ) at the immunoglobulin locus , the aid - induced lesion leads to shm and csr . ( e ) aid can induce oncogenic translocations during csr , if the c - myc promoter rearranges into the ig locus rather than another ig constant region although a number of aid s functions are unique to antibody diversification , further analysis has shown that our genome contains a family of dna deaminases , some of which are active anti - viral agents  the aid evolutionary descendant apobec3 family of proteins [ 1416 ] . apobec3 g s dna deamination activity is known to inhibit hiv replication , thought to be by inactivating the first - strand cdna of the hiv genome during viral replication . the discovery of dna deaminases showed for the first time , that naturally occurring unaltered enzymes could mutate the dna of somatic cells . this was in direct contrast to the dogma that somatic cells should maintain a stable genome , and made these enzymes obvious candidate oncogenes . aid s oncogenicity was demonstrated when overexpression of aid in transgenic mice caused tumor formation in different tissues ( lung , lymphatic , and liver ) . more recently , it was shown that aid was required for the c - myc / igh translocations of burkitt lymphomas [ 1921 ] . as shown in fig . 1e , during this translocation c - myc s promoter recombines with the ig locus , causing oncogenic expression of the c - myc gene . aside from c - myc , it has been known that the process of shm ( or aid ) targeting can occur outside the ig locus [ 23 , 24 ] , leading to dna - deaminase - induced mutation in tumor suppressors or proto - oncogenes . importantly though , the oncogenicity and dna mutability of the dna deaminases are not due to a genetic defect in the proteins , but rather a consequence of their normal ( albeit mis - regulated ) function . with the potential to mutate our genomes on a daily basis , understanding how aid is regulated in our recent publication , we were able show that estrogen could stimulate the production of aid in primary b cells . although primary mature b cells are differentiated and the aid locus may be  available ( in terms of chromatin status ) , we did not require any co - stimulatory signals to detect the estrogen enhancement . we also confirmed that the increased production in mrna showed a concomitant increase in aid protein . furthermore , we observed a direct correlation with estrogen treatment , aid mrna production and aid function in ig class switching , and somatic hypermutation . interestingly , the most significant correlation occurred between estrogen treatment and the number of potentially oncogenic c - myc / ig translocations . we also observed this estrogen - induced response with most of the apobec3s , indicating that the response to hormones is ancient and conserved . in terms of molecular mechanisms , we were able to demonstrate that the cellular estrogen receptor ( er ) is bound to the aid promoter after estrogen treatment . this seems to recruit a transcription activator complex , and thereby drive the transcription of the aid gene . interestingly , when we co - stimulated the cells both with estrogen and through the nfb pathway , we observed an enhanced binding of nfb to the promoter ( known to activate aid mrna production ) , and enhanced aid mrna production , which was greater than from either stimulus alone . this may have immune consequences , in that during an immune reaction , additional stimulatory signals provided by estrogen would enhance aid production , leading to a potential hyperactive humoral immune response . there is a large body of evidence that females can have a more pronounced immune reaction upon infection , which has also been observed at the level of ig production [ 28 , 29 ] . this gender bias is also seen in immune pathologies that are dependent on antibodies , such as systemic lupus erythematosus ( sle ) [ 30 , 31 ] , an autoimmune disease that is ten times more prevalent in women than in men . therefore , the ability of estrogen to enhance or even hyper - activate aid production , could partially explain the molecular mechanisms of certain autoimmune pathologies , via aid s role in antibody maturation . although men have estrogen as part of their endocrine system , the levels are much reduced compared to women . in terms of overall immune - fitness though , there does not appear to be a strong bias of men vs. women . why then , is a potentially highly oncogenic protein under the control of such a panpleiotropic hormone ? one can only speculate on the evolutionary origins , but a plausible hypothesis is that aid ( or its ancestor ) was a genome guardian against foreign dna ( as mentioned in [ 8 , 10 , 14 ] ) . the enzyme could act on a mobile dna element and inactivate it through deamination/ mutation . this is partially substantiated by the following observations : ( 1 ) aid can partially inhibit retroviral infections ; ( 2 ) the apobec3 proteins predominately act to inhibit retroviral infections and retroelement mobility [ 14 , 15 , 33 ] ; and ( 3 ) the ig gene and its recombination potential was evolutionary derived from a retroelement [ 34 , 35]thereby linking the activity of aid to an invading dna . as a genome guardian , it would be advantageous to have expression during the most vulnerable stage for retroelement infection of development  the unfertilized oocyte . already 5  years ago , we were able to show that aid is expressed in isolated mouse oocytes and embryonic germ cells . in our current work , estrogen was able to increase aid mrna in ovarian - derived primary cells by over 20-fold . this provides good evidence that aid - induced deamination is not limited to b cells . in line with a more global response of aid expression due to estrogen , analysis of cell lines derived from breast , ovarian , placental , and prostate tissue , also showed that aid was upregulated in response to estrogen . analogously , the other dna deaminases ( apobec3 members ) were also activated in various tissues and cell lines after estrogen treatment . it is not fully understood how aid , or its evolutionary descendants , can inactivate foreign dna . aside from mutating cytosines in mobile elements in our genomes , 5mecs in the context of cpgs usually inactivate the mobility of dna elements , but some elements are resistant to this mark . we have already demonstrated that aid can deaminate 5mecpg , and recent genetic evidence has linked aid to cpg dna demethylation . it is therefore possible that estrogen - driven mutation of cpgs during oncogenesis may also be due to aberrant aid expression . 2 ) may have brought us a step closer in understanding how estrogen can directly induce mutations leading to cancer in higher vertebrates . we suggest that endogenous or exogenous estrogen is absorbed by the target cell . in the cytoplasm , the dormant estrogen receptor ( er ) will bind to the ligand and dimerizes . these structural alterations allow the receptor  ligand complex to enter the nucleus and target estrogen responsive genes . at the promoter of the dna deaminase gene aid , the er  estrogen complex recruits proteins for mrna transcription . if these dna lesions are not repaired , the consequence is mutation and translocations  leading to autoimmunity or oncogenesis . as the model predicts , the activity of estrogen is not dependent on cell replication , occurs in cells that are estrogen responsive , and does not require any a priori genetic mutations for manifestation . estrogen enters the cell and is bound by the er . the dimeric er  estrogen complex enters the nucleus and induces aid expression . this leads to an increase in mutations and translocations , and potentially cancer model of how estrogen induces dna damage .
it is well established that hormones can cause cancer , much less known is how they induce this change in our somatic cells . 
 this review highlights the recent finding that estrogen can exert its dna - damaging potential by directly activating dna deaminases . 
 this recently discovered class of proteins deaminate cytosine to uracil in dna , and are essential enzymes in the immune system . 
 the enhanced production of a given dna deaminase , induced by estrogen , can lead not only to a more active immune response , but also to an increase in mutations and oncogenic translocations . 
 identifying the direct molecular link between estrogen and a mutation event provides us with new targets for studying and possibly inhibiting the pathological side - effects of estrogen .