@conference{
author = "Božović, Ana and Mandušić, Vesna and Todorović, Lidija and Krajnović, Milena and Kožik, Bojana and Jovanović-Ćupić, Snežana and Kokanov, Nikola",
year = "2023",
abstract = "Since the estrogen receptor alpha (ERα), together with the progesterone receptor (PR) and the hercepƟ n receptor 2 (HER-2), are the dominant factors determining the groups of breast cancer (BC) paƟ ents, breast cancer treatment depends on the presence or absence of these three molecules. Approximately 70% of paƟ ents receive hormone treatment targeƟ ng the estrogen receptor alfa, with tamoxifen (selecƟ ve oestrogen receptor modulator) being the fi rst choice as it inhibits further proliferaƟ on of cancer cells. However, 30% of paƟ ents do not respond to exisƟ ng hormone therapy, raising the quesƟ on of new targets and treatment opƟ ons. Non-responders include paƟ ents who have acquired resistance to standard treatment and triple-negaƟ ve breast cancer paƟ ents (TNBC), characterized by the absence of ERα, PR and HER-2. One of the unexplored potenƟ als for treatment is a protein homologue of ERα, estrogen receptor beta (ERβ), as many studies show ERβ expression in ERα-negaƟ ve paƟ ents. The estrogen receptors alpha and beta belong to the superfamily of nuclear receptors, and their dominant ligand is estrogen. When estrogen binds to estrogen receptors, they form dimers (homo or heterodimers) and bind ERE sequences of target genes (estrogen receptor elements). In a heterodimeric state, ERβ can inhibit ERα transacƟ vaƟ on and thus infl uence the signalling pathways. ERα and ERβ are encoded by highly homologous genes (ESR1 and ESR2), resulƟ ng in two highly homologous protein structures. The human ESR2 gene contains eight exons. The last two coding exons of the ESR2 gene are alternaƟ vely spliced encoding ERβ transcripƟ onal variants (ERβ1-5), resulƟ ng in altered C-terminal domains of the ERβ protein. These transcripƟ onal variants can have dominant posiƟ ve or negaƟ ve funcƟ ons or no funcƟ on at all. While ERα is crucial for the growth and proliferaƟ on of breast Ɵ ssue, ERꞵ plays a role in the normal development of breast Ɵ ssue, ovaries, testes, brain and adrenal glands. Study reports show that ERβ has an anƟ proliferaƟ ve, pro-apoptoƟ c and tumour-suppressive funcƟ on. Its funcƟ on in breast development also implies its funcƟ on in tumourigenesis. However, the expression of ERβ mRNA and protein expression is unclear. Various studies on ERα-posiƟ ve tumours show that ERβ is a tumour suppressor. The studies on ERα-negaƟ ve tumours show controversy, whereby ERβ could be proliferaƟ ve or suppressive. ERβ expression is oŌ en associated with smaller tumour size, lower grade and the absence of metastases. In TNBC paƟ ents, the associaƟ on between clinical outcomes and ERβ is unclear. Some studies associate ERβ with prolonged survival, others with shortened survival, while in others, no associaƟ on has been demonstrated. There are many reasons for these contradicƟ ons. The fi rst reason is unprecise methods of measuring ERβ levels, with diff erences in baseline material. In some studies, the amount of ERβ is esƟ mated by quanƟ taƟ ve PCR, while in others, by anƟ bodies. Secondly, the researchers prevalently use non-specifi c anƟ bodies that cannot detect the existence of specifi c ERβ isoforms. ERβ expression changes during BC progression. In the early stages of BC, ERβ levels decrease, while more advanced stages show a complete loss of ERβ. However, some studies report increased ERβ expression in metastaƟ c Ɵ ssues. Researchers should pay parƟ cular aƩ enƟ on to the molecular mechanisms that alter ERβ expression, with epigeneƟ c mechanisms being the most crucial. One of the most important mechanisms for tumour iniƟ aƟ on and development is gene promoter methylaƟ on. DNA methylaƟ on is an inheritable epigeneƟ c modifi caƟ on in which DNA methyltransferases (DNMTs) promote the transfer of the methyl group from S-adenosyl L-methionine (SAM) to 5'-cytosine of the CpG dinucleoƟ de. CpG methylaƟ on is a crucial regulatory mechanism that begins early in embryogenesis. In the promoters of genes central to development, such as housekeeping genes and some Ɵ ssue-specifi c genes, there are unmethylated regions called CpG islands. CpG islands encompass about 500 to several thousands of base pairs, and the CpGdinucleoƟ des within them are more abundant than in the other genome locaƟ ons. CpG islands in coding genes' promoter regions of cancer cells are regularly hypermethylated, causing gene silencing. The silenced genes are commonly tumour suppressor genes, such as ERβ. ERβ gene promoter region contains two exons, exon OK and exon ON. Most studies have been done on ON exon, linking hypermethylaƟ on of ON exon with decreased ERβ expression. IniƟ ally, the researchers noƟ ced ON exon hypermethylaƟ on in prostate cancer, and prostate cancer cell treatment with a demethylaƟ on agent, 5'-AZAC, led to ERβ expression acƟ vaƟ on. Also, during the progression of prostate cancer, a hypermethylaƟ on level increased. These results were consistent with some studies on breast cancer paƟ ents and cell lines. There is scant data on the associaƟ on between ERβ hypermethylaƟ on and surv ival. Usually, studies show correlaƟ ons between ERβ1 expression and survival. The clinical potenƟ al of ERβ promoter methylaƟ on is yet to be examined. AddiƟ onal research on this molecule and its expression mechanisms should determine its predicƟ ve, diagnosƟ c, and treatment potenƟ al.",
publisher = "Belgrade : Serbian Association for Cancer Research",
journal = "Oncology Insights",
title = "Estrogen Receptor Beta promoter methylation as a possible biomarker in breast cancer",
number = "1",
pages = "26-27",
url = "https://hdl.handle.net/21.15107/rcub_vinar_12632"
}
