Promoter hypermethylation of estrogen receptor alpha gene is correlated to estrogen receptor negativity in Iranian patients with sporadic breast cancer.
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(2) Original Article. Promoter Hypermethylation of Estrogen Receptor Alpha Gene Is Correlated to Estrogen Receptor Negativity in Iranian Patients with Sporadic Breast Cancer 3DQWHD,]DGL3K'10HKUGDG1RUX]LQLD0'3K'1 0RUWH]D.DULPLSRRU0'3K'2 0RKDPPDG+DPLG.DUEDVVLDQ0'30RKDPPDG7DJKL$NEDUL3K'1 'HSDUWPHQWRI0HGLFDO*HQHWLFV6FKRRORI0HGLFDO6FLHQFHV7DUELDW0RGDUHV8QLYHUVLW\7HKUDQ,UDQ 'HSDUWPHQWRI0ROHFXODU0HGLFLQH%LRWHFKQRORJ\5HVHDUFK&HQWHU3DVWHXU,QVWLWXWHRI,UDQ7HKUDQ,UDQ 'D\+RVSLWDO7HKUDQ,UDQ. * Corresponding Address: P.O.Box: 14115-111, Department of Medical Genetics, School of Medical Sciences, Tarbiat Modares University, Tehran, Iran Email: noruzinia@modares.ac.ir. D I. 5HFHLYHG 6HS$FFHSWHG -DQ. Abstract. 2EMHFWLYH Breast Cancer is the most common cancer in Iranian women. Breast tumors DUH FODVVL¿HG EDVHG RQ WKH HVWURJHQ UHFHSWRU DOSKD (5Į H[SUHVVLRQ VWDWXV LQWR (5 negative and ER positive tumors. ER negative tumors tend to have worse prognosis and less likely to respond to endocrine therapy. Aberrant methylation of gene promoter is one of the mechanisms for gene silencing in breast tumors. Because of its reversible nature, promoter methylation is a good target for new therapeutic strategies. We aimed WRHYDOXDWHWKHIUHTXHQF\RIWKLVHSLJHQHWLFHYHQWLQ(5ĮJHQHDQGLWVDVVRFLDWLRQWR clinicopathological features in Iranian breast cancer patients.. S f. o e. 0DWHULDOVDQG0HWKRGV ,QWKLVFDVHFRQWUROVWXG\WKHSDWLHQWVHULHVFRQVLVWHGRIVSRUDGLFSULPDU\EUHDVWFDQFHUFDVHV (5QHJDWLYHDQG (5SRVLWLYHWXPRUV 1RQHRI WKHSDUWLFLSDQWVKDGFKHPRRUUDGLRWKHUDS\EHIRUHVXUJHU\,QEUHDVWWXPRUV(5ĮSURPRWHU PHWK\ODWLRQ ZHUH DVVHVVHG ZLWK PHWK\ODWLRQ VSHFL¿F SRO\PHUDVH FKDLQ UHDFWLRQ 063 Data was collected on clinicopathological features of the patients. Correlation between (5ĮPHWK\ODWLRQDQGFOLQLFRSDWKRORJLFDOFKDUDFWHULVWLFVRIWKHSDWLHQWVZDVLQYHVWLJDWHGE\ Pearson Chi-Square and Fisher’s exact test.. v i h. 5HVXOWV (5ĮPHWK\ODWLRQZDVGHWHFWHGLQ RI(5QHJDWLYHDQGRI(5SRVLWLYH EUHDVWWXPRUV$VWURQJFRUUHODWLRQZDVIRXQGEHWZHHQ(5ĮPHWK\ODWLRQDQG(5QHJDWLYLW\LQWXPRUV S $OVR(5ĮPHWK\ODWLRQKDVDVVRFLDWHGWRSURJHVWHURQHUHFHSWRU QHJDWLYLW\ S 0.008 DQGGRXEOHUHFHSWRUQHJDWLYHVWDWXV S LQEUHDVWWXPRUV. c r. &RQFOXVLRQ (5ĮPHWK\ODWLRQRFFXUVZLWKKLJKIUHTXHQF\LQWKHEUHDVWWXPRUVRI,UDQLDQ EUHDVWFDQFHUSDWLHQWVDQGPD\SOD\DFRQVLGHUDEOHUROHLQSDWKRJHQHVLVRI(5ĮQHJDWLYH tumors as a poor prognosis and more aggressive category. The reversible nature of DNA methylation may provide new therapeutic possibilities in ER negative breast tumors.. A. Keywords: Estrogen Receptor, Methylation, Breast Cancer Cell Journal(Yakhteh), Vol 14, No 2, Summer 2012, Pages: 102-109. &LWDWLRQ ,]DGL 3 1RUX]LQLD 0 .DULPLSRRU 0 .DUEDVVLDQ 0+$NEDUL 07 3URPRWHU K\SHUPHWK\ODWLRQ RI HVWURJHQ UHFHSWRU DOSKD JHQH LV FRUUHODWHG WR HVWURJHQ UHFHSWRU QHJDWLYLW\ LQ LUDQLDQ SDWLHQWV ZLWK VSRUDGLF EUHDVW FDQFHU &HOO -RXUQDO(Yakhteh) . Introduction %UHDVW &DQFHU DV WKH PRVW FRPPRQ FDQFHU LQ Iranian women, affects women at least one decade younger than their counterparts in developed FRXQWULHV 7KHKLJKHVWIUHTXHQF\RIWKLVPDOLJ-. nancy has been observed in WKH \HDUV ROG age group (2). It is commonly accepted that estrogen and its receptor have an important role in the pathogenesis of breast malignancies. Estrogen receptor CELL JOURNAL(Yakhteh), Vol 14, No 2, Summer 2012. 102. www.SID.ir.
(3) (5Į0HWK\ODWLRQLQ,UDQLDQ%UHDVW&DQFHU3DWLHQWV. improved therapeutic choices in this poor prognosis and more aggressive type of breast cancer. Thus, in the present study we aimed to evaluate the SUHYDOHQFHRIHSLJHQHWLFVLOHQFLQJRI(5ĮYLDSURmoter methylation in Iranian patients with breast cancer and its association to ER negativity of tumors and other clinicopathological characteristics.. DOSKD (5Į H[SUHVVLRQFODVVL¿HVEUHDVWWXPRUVLQWR (5QHJDWLYHDQG(5SRVLWLYHFDQFHUV$ERXWRI EUHDVWWXPRUVDUH(5QHJDWLYH (5QHJDWLYHWXPRUV have poor prognosis in comparison to ER positive tumors. This type of tumor is more prevalent in younger patients and is not responsive to endocrine therapies. &RQVLGHULQJ WR WKH FKDOOHQJLQJ QDWXUH RI (5Į negative tumors treatment and their innate poor SURJQRVLV FODUL¿FDWLRQ RI WKH PROHFXODU PHFKDQLVPV WKDW FRQWURO H[SUHVVLRQ RI (5Į LV HVVHQWLDO 7KLVNQRZOHGJHPD\HQDEOHXVWRPRGLI\WKHVLWXDtion as such to restore sensitivity to endocrine therapies which provide us new opportunities for theraSHXWLFRSWLRQVIRU(5ĮQHJDWLYHEUHDVWWXPRUV 'HVSLWH RI PDQ\ VWXGLHV RQ WKH PHFKDQLVPV RI negativity of ER in breast tumors, many details still QHHGWREHFODUL¿HG 7KHORVVRI(5ĮH[SUHVVLRQ in breast cancer may result from different underlying causes, such as structural changes within the gene or transcriptional silencing (7). Abnormalities, such as SRLQWPXWDWLRQVGHOHWLRQVORVVRIKHWHUR]\JRVLW\RU polymorphisms within the gene have not shown to be IUHTXHQWHQRXJKWRH[SODLQ(5QHJDWLYLW\SKHQRW\SH ,QEUHDVWWXPRUVVXFKDVRWKHUW\SHVRIFDQFHU epigenetic alterations are common and related to gene H[SUHVVLRQPRGL¿FDWLRQ ,WKDVEHHQVKRZQWKDW tumor suppressor genes promoter methylation gives JURZWK DGYDQWDJH WR PDOLJQDQW FHOOV %HFDXVH of the potential reversible nature of epigenetic gene silencing, epigenetic mechanisms have been under inWHQVHLQYHVWLJDWLRQVLQWKHUHFHQW\HDUV Regarding to evidences which have been resulted from several in vitro and in vivo studies, it has been VKRZQWKDWWKHLQKLELWRUVRI'1$PHWK\OWUDQVIHUDVH DQGKLVWRQHGHDFHW\ODVHHQ]\PHVFDQUHDFWLYDWH(5Į JHQHWUDQVFULSWLRQLQ(5ĮQHJDWLYHFHOOV7KHVHHSLgenetic therapies could restore response to endocrine WKHUDS\LQQRQUHVSRQVLYH(5QHJDWLYHFHOOV These promising landscapes have encouraged reVHDUFKHUVWRIRFXVRQWKHUHODWLRQVKLSEHWZHHQ(5Į QHJDWLYHSKHQRW\SHDQG(5ĮSURPRWHUPHWK\ODWLRQ +RZHYHU KHWHURJHQHLW\ RI WKH FHOOXODU SRSXODWLRQ in breast tumors,, differences in methodological approaches, and variation of the studied populations (e.g. environmental exposures and ethnicity) have UHVXOWHG LQ YDULRXV UHSRUWHG IUHTXHQFLHV IRU (5Į methylation and its relevance to clinicopathological parameters (7, 11, 12).. Materials and Methods Patients. D I. r A. Improved understanding of the mechanisms involved in ER negative breast tumors may permit CELL JOURNAL(Yakhteh), Vol 14, No 2, Summer 2012. S f. o e. iv. h c. In this case control study the studied population consisted of 100 sporadic primary breast cancer patients UHIHUUHGWRWKH&DQFHU,QVWLWXWHRI7HKUDQ8QLYHUVLW\ RI0HGLFDO6FLHQFHV7KLVVWXG\ZDVDSSURYHGE\WKH ORFDO(WKLFDO&RPPLWWHHDW7DUELDW0RGDUHV8QLYHUVLW\:ULWWHQFRQVHQWZDVWDNHQIURPDOOSDWLHQWVHQUROOHGLQWKHVWXG\3ULPDU\EUHDVWWXPRUWLVVXHVZHUH SURYLGHGE\WKH,UDQ1DWLRQDO7XPRU%DQN2XULQFOXsion criteria were sporadic and primary breast cancer. 3DWLHQWVZKRKDGUHFXUUHQWEUHDVWWXPRUKDGFKHPR or radiotherapy before surgery, or showed breast and/ RURYDULDQFDQFHUVLQ¿UVWRUVHFRQGGHJUHHUHODWLYHV were excluded from the study. Tumor samples were obtained through a surgical resection, then an expert pathologist performed rapid macro dissection of samSOHVDQGWUDQVIHUUHGWXPRUWLVVXHVWROLTXLGQLWURJHQ reservoir, immediately. Clinical and pathological data collection The main clinicopathological features of the study population were collected. These features included DJH DW GLDJQRVLV PHQRSDXVDO VWDWXV WXPRU VL]H histological type, grade, lymph node involvement, VWDJHDQGLPPXQRKLVWRFKHPLVWU\ ,+& SDQHO (5 35DQGKHU 7RRYHUFRPHLQWHUODERUDWRU\YDULDtions, a pathologist decided the histological type, grade and immunohistochemistry evaluations, then DQRWKHU H[SHUW UHFKHFNHG DQG DSSURYHG WKHP (5 DQG 35 ZHUH FRQVLGHUHG QHJDWLYH ZKHQ QXFOHDU staining of tumor cells was less than 1%. In tumors which complete and intense membrane staining were determined in the more than 10% of tumor FHOOV+HURYHUH[SUHVVLRQZDVFRQVLGHUHGSRVLWLYH '1$H[WUDFWLRQDQGELVXOSKLWHPRGL¿FDWLRQ *HQRPLF '1$ ZDV H[WUDFWHG IURP WKH EUHDVW WXPRUV VWRUHG LQ OLTXLG QLWURJHQ WDQN '1$ ZDV REWDLQHG E\ +LJK SXUH 3&5 WHPSODWH SUHSDUDWLRQ NLW 5RFKH *HUPDQ\ 4XDQWLW\ DQG TXDOLW\ RI WKH H[-. 103. www.SID.ir.
(4) Izadi et al.. WUDFWHG'1$ZHUHHYDOXDWHGE\DVSHFWURSKRWRPHWHU 1DQRGURS7KHUPR6FLHQWL¿F86$ )RUHDFK VDPSOHJRIJHQRPLF'1$ZDVXVHGIRUVRGLXP ELVXOSKLWHPRGL¿FDWLRQDVSUHYLRXVO\GHVFULEHG 0HWK\ODWLRQVSHFL¿F3&5. DQG (5 UHJLRQV ZDV GHWHUPLQHG LQ WKH VWXG\ SRSXODWLRQ XVLQJ WKH 063 PHWKRG ,Q DQDO\]HG WXPRUVZHUHPHWK\ODWHGLQ(5UHJLRQ DQG LQ (5 UHJLRQ 7XPRUV ZHUH FODVVL¿HG DV PHWK\ODWHG LI WKHLU ELVXOIDWH WUHDWHG '1$ KDG DPSOL¿FDWLRQ ZLWK HLWKHU RQH RU ERWK PHWK\ODWHG SULPHUV$FFRUGLQJWRWKLVGH¿QLWLRQRYHUDOO(5Į PHWK\ODWLRQ ZDV GHWHFWHG LQ WXPRUV %UHDVWWXPRUVPHWK\ODWHGLQ(5UHJLRQZHUH WLPHVPRUHWKDQ(5UHJLRQ. 7ZRUHJLRQVRI(5ĮSURPRWHULQ&S*,VODQGZHUH VWXGLHGE\PHWK\ODWLRQVSHFL¿F3&5 063 7KHVH regions were selected based on the previous studies. (5DQG(5UHJLRQVZHUHLQFOXGHGLQWKH875RI SUR[LPDOSURPRWHURI(5ĮJHQH 7ZRVHSDUDWH063UHDFWLRQVZHUHFDUULHGRXWIRUHDFKUHJLRQ OLNH RQH ZLWK SULPHUV VSHFL¿HG IRU WKH PHWK\ODWHG VHTXHQFH 0 DQGWKHRWKHUZLWKSULPHUVIRUWKHXQPHWK\ODWHGVHTXHQFH 8 3ULPHUSDLUVDQG3&5FRQGLWLRQZHUHSUHYLRXVO\GHVFULEHG 063UHDFWLRQ ZDVRSWLPL]HGLQRXUODEZLWKî3&5EXIIHUP0 0J&O2DQGP0G173SHUOUHDFWLRQYROXPHV$IWHULQLWLDOGHQDWXUDWLRQXQLWV7DT'1$ polymerase (Cinaclone, Iran) was added to each reDFWLRQ PDQXDO KRW VWDUW 3RVLWLYH 063 FRQWURO IRU PHWK\ODWHGVSHFL¿FSULPHUVZDV'1$H[WUDFWHGIURP 0'$0%FHOOOLQH,WZDVVKRZQLQWKHSUHYLRXVZRUNVWKDWWKLV'1$ZDVWRWDOO\PHWK\ODWHGLQ 875RI(5Į 1HJDWLYH063FRQWUROIRUPHWK\ODWHGVSHFL¿FSULPHUVZDVWKHH[WUDFWHG'1$IURP 0&) FHOO OLQH ZKLFK ZDV VKRZQ LQ WKH SUHYLRXV ZRUNVWREHWRWDOO\XQPHWK\ODWHGLQRXUWDUJHWUHJLRQV LQ875RI(5Į 1R'1$FRQWUROZDVXVHGLQ ERWKPHWK\ODWHGDQGXQPHWK\ODWHG063UHDFWLRQVDV WKHEODQNWRVKRZDEVHQFHRIWHPSODWHFRQWDPLQDWLRQ 8QWUHDWHG'1$ZDVXVHGDVWKHFRQWURORIVSHFL¿FLW\ RIUHDFWLRQV063DPSOL¿FDWLRQSURGXFWVZHUHHOHFWURSKRUHVHGRQDDJDURVHJHOZLWK;7%(EXIIHU VWDLQHGZLWKHWKLGLXPEURPLGHDQGYLVXDOL]HGXQGHU D89OLJKW$WXPRUZDVFRQVLGHUHGPHWK\ODWHGLID EDQGZDVYLVXDOL]HGLQWKH063UHDFWLRQZLWKPHWKylated primers.. &RUUHODWLRQ RI (5Į SURPRWHU PHWK\ODWLRQ DQG ER negativity by IHC. D I. Statistical analysis. A. &RUUHODWLRQEHWZHHQ(5ĮPHWK\ODWLRQDQGFOLQicopathological characteristics of the patients was LQYHVWLJDWHG E\ 3HDUVRQ &KL6TXDUH DQG )LVKHU¶V H[DFW WHVW XVLQJ 6366 YHUVLRQ 7KH YDOXH RI S ZDVFRQVLGHUHGVLJQL¿FDQWDQGFRQ¿GHQFH LQWHUYDOVTXRWHGZHUHDWWKH OHYHO. Results 0HWK\ODWLRQ IUHTXHQF\ RI (5Į SURPRWHU LQ sporadic breast carcinomas 7KHPHWK\ODWLRQVWDWXVRI(5ĮSURPRWHULQ(5. S f. o e. v i h. c r. To determine if there is a correlation between ER methylation and loss of ER protein expression in tuPRUV EDVHGRQ,+&UHVXOWV ZHFRPSDUHGPHWK\ODWLRQIUHTXHQF\EHWZHHQ(5QHJDWLYHDQG(5SRVLWLYH WXPRUV$FFRUGLQJ WR ,+& UHVXOWV RI VDPSOHV were negative for ER expression. A strong correlaWLRQ ZDV IRXQG EHWZHHQ (5Į PHWK\ODWLRQ LQ (5 region and ER negativity in tumors. It was observed WKDW RI (5 QHJDWLYH YHUVXV RI (5 SRVLtive cases were methylated in the mentioned region S )UHTXHQF\ RI PHWK\ODWLRQ LQ (5 UHJLRQZDVORZHUWKDQ(5UHJLRQLQERWK(5QHJDWLYH DQG(5SRVLWLYH WXPRUV2YHUDOO(5Į PHWK\ODWLRQLQERWKUHJLRQVZDVVLJQL¿FDQWO\KLJKHU in ER negative tumors than ER positive cases. As we REVHUYHGRI(5QHJDWLYHWXPRUVYHUVXVRI ER positive tumors were methylated in both regions synchronously (p<0.0001). (5ĮSURPRWHUPHWK\ODWLRQDQGFRUUHODWLRQZLWK clinicopathologic features The clinicopathological characteristics of the 100 primary breast tumors are described in the table 1. There were significant correlations between estrogen receptor negativity in tumors DQGPHWK\ODWLRQLQ(5DQG(5UHJLRQVLQ(5 promoter. No correlation was found between WKH IROORZLQJV (5Į PHWK\ODWLRQ VWDWXV DJH PHQRSDXVDOVWDWXVWXPRUVL]HJUDGHQRGDOLQYROYHPHQW 710 VWDJH DQG +HU VWDWXV +RZever, there was a significant correlation beWZHHQPHWK\ODWLRQLQ(5UHJLRQDQGQHJDWLYH VWDWXV RI SURJHVWHURQH UHFHSWRU E\ ,+& LQ WXPRUV S ,QDGGLWLRQSUHVHQFHRIGRXEOH UHFHSWRUQHJDWLYLW\E\,+&LQWXPRUV (5QHJDWLYH35 QHJDWLYH VWDWXV VKRZHG D VLJQLILFDQW FRUUHODWLRQZLWK(5PHWK\ODWLRQ S CELL JOURNAL(Yakhteh), Vol 14, No 2, Summer 2012. 104. www.SID.ir.
(5) (5Į0HWK\ODWLRQLQ,UDQLDQ%UHDVW&DQFHU3DWLHQWV. 7DEOH &RUUHODWLRQEHWZHHQ(5ĮPHWK\ODWLRQLQ(5DQG(5UHJLRQVDQGFOLQLFRSDWKRORJLFIHDWXUHVRISDWLHQWV Features. ER3 status. P value. M. U. Q . . . ! Q . . . 3UHPHQRSDXVH Q . . . 3RVWPHQRSDXVH Q . . . FP Q . . . FP Q . . . FP Q . 19. . , Q . . 9. ,, Q . . 11. ,,, Q . . 9. 1RGHQHJDWLYH Q . . 9. 0.7. QRGH Q . 20. . QRGH Q . . . QRGH Q . 9. . , Q . . . ,, Q . . 12. ,,, Q . 27. . ,9 Q . 2. 1. o e. . . . . 1. ER5 status M. U. P value. Age at diagnosis (Year) . . . . . 27. . 29. 21. 10. . . . . 12. 11. . . Menopause status . . Tumor size (cm) . . D I. Grade . S f. Nodal status. Stage. 'XFWDO Q 1RQGXFWDO Q . r A. Estrogen receptor status 1HJDWLYH Q . iv. h c. Tumor type. . . . . 1HJDWLYH Q . . . 3RVLWLYH Q . 17. . (535 Q . . . (535 Q . . 9. (535 Q . 17. (535 Q . 0.9. . 21. 12. 20. . . 12. 10. 10. . 7. . . . . . 22. 2. 1. . . 2. . . . 21. . . 29. 17. . . . . . . 17. . 0. 1. 0. 1. +HUQHJDWLYH Q . . . . . +HUSRVLWLYH Q . 29. 11. 21. 19. 3RVLWLYH Q . 0.0001. . . 0.7. 0.1. . . Progesterone Receptor status. . . ER/PR status. 0.0001. . Her2 status . . M; Means presence of methylated region in MSP. U; Means presence of unmethylated region in MSP.. CELL JOURNAL(Yakhteh), Vol 14, No 2, Summer 2012. 105. www.SID.ir.
(6) Izadi et al.. Discussion. other hand, in a recent population based on casecontrol study on 200 breast tumors, it has been sugJHVWHGWKDWWKHUHODWLRQVKLSEHWZHHQ'1$PHWK\ODtion in ER promoter and ER protein expression is ZHDN 6R WKHVH UHVHDUFKHUV KDYH FRQFOXGHG WKDW (5 PHWK\ODWLRQ LV XQOLNHO\ WR UHSUHVHQW D PDMRU PHFKDQLVPRIUHFHSWRUVLOHQFLQJ %HFDXVHRI WKHUHYHUVLEOHQDWXUHRI'1$PHWK\ODWLRQLIWKHUH is a major mechanism for ER silencing in breast tumors, it will potentially provide new options for ER negative tumors treatment in the future. Thus, we aimed to evaluate this relationship in our study population and reveal the strong correlation beWZHHQ(5ĮQHJDWLYLW\ EDVHGRQ,+&UHVXOWV DQG (5Į PHWK\ODWLRQ LQ FRQFRUGDQFH ZLWK WKH SUHYLRXVZRUNV ,WVHHPVWKDW(5 methylation can be an important mechanism for ER silencing at least in Iranian breast cancer patients.. %UHDVWFDQFHUDIIHFWV,UDQLDQSDWLHQWVDWOHDVW one decade earlier than western patients (1, 2, (VWURJHQ UHFHSWRU DOSKD QHJDWLYH WXmors are more prevalent in young patients with DZRUVHSURJQRVLVWKDQ(5SRVLWLYHWXPRUV 'LIIHUHQW PHFKDQLVPV LQFOXGLQJ DEVHQFH RI specific transcription factor, presence of repressors, and epigenetic changes in CpG Island are potentially associated with ER negative phenoW\SH 3UHYLRXVVWXGLHVKDYHVKRZQWKDW HSLJHQHWLFVLOHQFLQJRI(5ĮLVDPDMRUPHFKDnism for ER negative phenotypes in breast cancer cells (7, 11) and the reversible nature of this mechanism may provide new therapeutic avHQXHVIRU(5QHJDWLYHEUHDVWWXPRUV In the present study, methylation status of WZRLPSRUWDQWUHJLRQVRIWKH(5Į&S*,VODQG with respect to ER expression was investigated. 3UHYLRXVVWXGLHVKDYHVKRZQWKDW(5SURPRWHU PHWK\ODWLRQKDVDVVRFLDWLRQZLWKODFNRI(5H[SUHVVLRQLQEUHDVWWXPRUV 2QWKH. D I. S f. 0HWK\ODWLRQ IUHTXHQF\ RI (5Į JHQH LQ WKH present study was higher in comparison to the previous investigations in the different study populations (Table 2).. o e. 7DEOH &RPSDULVRQRIRYHUDOO(5ĮPHWK\ODWLRQLQEUHDVWWXPRUVLQYDULRXVVWXGLHV. v i h. References. Study population ethnicity. Investigated UHJLRQ V LQ(5Į CpG island. ER methylation in ER positive tumors. ER methylation in ER negative tumors. Zhao et al. (2008) (12). Chinese. . . Mirza et al. (2007) (21). c r. (5(5. Indian. (5. . . Caucasian and African-American. (5(5(5(5. . . Australian. 1RWVSHFL¿HG. . . Pirouzpanah et al. (2010) (26). Iranian. (5. . . Lapidus et al. (1998) (7). American. (5(5. . 11/11 (100%). Present study. Iranian. (5(5. . ( ). Wei et al. (2008) (23). Li et al. (2006) (22). A. CELL JOURNAL(Yakhteh), Vol 14, No 2, Summer 2012. 106. www.SID.ir.
(7) (5Į0HWK\ODWLRQLQ,UDQLDQ%UHDVW&DQFHU3DWLHQWV. 7KH GLIIHUHQFHV EHWZHHQ (5Į PHWK\ODWLRQ IUHTXHQFLHV LQ YDULRXV VWXGLHV PD\ EH GXH WR variation in ethnicity and carcinogenic exposures of populations studied. Also, technical LVVXHV LQ 063 FRQGLWLRQV VXFK DV DQQHDOLQJ temperature; cycles number and selection of targets regions in CpG Islands may influence on ILQDOIUHTXHQF\:HKDYHVKRZQSUHVHQFHRI(5 PHWK\ODWLRQLQDVL]DEOHIUDFWLRQRI(5SRVLWLYH cases. This observation maybe correlated to cellular heterogeneity in breast tumors. Classification of breast tumors based on their ER status into ER negative and ER positive groups may cause partial loss of information (27). ER positivity in breast tumors is a dynamic phenotype and over the natural course of cancer progression, Estrogen Receptor can be lost and many (5 SRVLWLYH WXPRUV EHFRPH (5 QHJDWLYH Resistance to endocrine therapy in a significant fraction of ER positive breast tumors and recurrence of many ER positive tumors as ER QHJDWLYH RQHV HPSKDVL]H DJDLQ WKDW WKLV JURXS LVPRUHKHWHURJHQHRXVWKDQH[SHFWHG3UHVHQFH RI (5Į PHWK\ODWLRQ LQ (5 SRVLWLYH WXPRUV LV a manifestation of this heterogeneity and may contribute to endocrine therapy resistance or reFXUUHQFH0RUHLQYHVWLJDWLRQVQHHGHGWRFODULI\ WKH FRQWULEXWLRQ RI (5Į PHWK\ODWLRQ LQ HQGRcrine therapy resistance and recurrence in ER positive breast tumors.. DQ LQFUHDVLQJ WUHQG LQ (5Į PHWK\ODWLRQ ZLWK PDOLJQDQW SURJUHVVLRQ 7KH VLJQLILFDQW FRUUHODWLRQEHWZHHQPHWK\ODWLRQLQ(5UHJLRQ and progesterone receptor status in tumors was not unexpected due to the fact that progesterone receptor expression is under ER control. This relationship was not independent of ER status of tumor because this association was observed RQO\LQ(5QHJDWLYH35QHJDWLYHWXPRUV QRWLQ (5 SRVLWLYH35 QHJDWLYH FDVHV $OVR ZH GLG not see any correlation between progesterone VWDWXV DQG PHWK\ODWLRQ LQ (5 UHJLRQ RI (5 SURPRWHU,WLVNQRZQWKDWWKHLPSDFWVRIPHWKylation in various CpGs in a CpG Island are not HTXDODQGPHWK\ODWLRQLQVRPHUHJLRQVLVPRUH critical in gene silencing. It may be due to less LQIOXHQFH RI PHWK\ODWLRQ LQ WKH (5 UHJLRQ RQ ER gene expression. Although, finding underlying mechanism of this observation needs more investigations.. D I. o e. v i h. c r. Investigation of clinicopathological assoFLDWLRQ ZLWK (5Į PHWK\ODWLRQ VKRZHG WKDW WKLV phenomenon is not an age-related event in our breast cancer patients (Table 1). The relationVKLS EHWZHHQ DJH DQG (5Į PHWK\ODWLRQ LQ GLIferent studies was controversial. In one study on $XVWUDOLDQ SDWLHQWV (5Į PHWK\ODWLRQ ZDV associated with younger patient (22). In other VWXGLHV WKHUH ZDV QR FRUUHODWLRQ EHWZHHQ (5Į methylation and age in breast tumors (11, 12, . A. In our study, we did not see any correlations EHWZHHQ(5ĮPHWK\ODWLRQWXPRUVL]HDQGFDQcer stage in concordance to other investigations %XW LQ RQH VWXG\ WKH FRPSDULVRQ RI '&,6 'XFWDO &DUFLQRPD ,Q 6LWX LQYDVLYH ductal carcinoma and metastatic lesions showed. CELL JOURNAL(Yakhteh), Vol 14, No 2, Summer 2012. S f. Conclusion. 2XUUHVXOWVKRZHGWKDWPHWK\ODWLRQRI(5ĮLV a prevalent epigenetic phenomenon in Iranian EUHDVWFDQFHUSDWLHQWV6LQFH RI(5QHJDWLYH WXPRUV KDG PHWK\ODWLRQ LQ (5 (5 RU ERWK UHJLRQV LW VHHPV WKDW (5Į ZDV D PDMRU target of methylation in our population studLHG7KHUHIRUHWKHUROHRI(5ĮPHWK\ODWLRQLQ the etiology of ER negative phenotype, which might be regarded as a common phenomenon in Iranian patients, should be investigated furWKHU +LJKHU SUHYDOHQFH RI (5 PHWK\ODWLRQ LQ Iranian patients may be due to environmental exposures or carcinogenic lifestyles which must investigate in the future surveys. AlWKRXJK '1$ PHWK\ODWLRQ LQ SURPRWHU UHJLRQ RI D JHQH KDV HTXDO LPSDFW ZLWK D PXWDWLRQ epigenetic modifications are potentially reversible, so they are good targets for new therapeutic strategies.. Acknowledgements 7KLVVWXG\ZDVDSDUWRID3K'WKHVLVLQ0HGLcal Genetics delivered by the first author and VXSSRUWHG E\ D JUDQW IURP IDFXOW\ RI 0HGLFDO 6FLHQFHVRI7DUELDW0RGDUHV8QLYHUVLW\. 107. www.SID.ir.
(8) Izadi et al.. 7KH DXWKRUV DUH JUDWHIXO WR 'U )RURX]DQGHK )HUHLGRRQL 'U =DKUD 0RVWDNKGHPLQH +RVVHLQL 'U )DWHPHK .DPDOL DQG 0U $Kmad Joulaie for their valuable collaborations in gathering clinicopathological information DQGWR'U1DWHJKLIRUVWDWLVWLFDODQDO\VLV7KH authors declare that they have no conflict of interest.. . References. 15.. 1.. 2. . 5.. . 7.. 8.. 9.. 11.. 12.. . . Panahi M, Ashourzadeh S, Abedian Z. Expressional correlation of human epidermal growth factor receptor 2, estrogen/progestron receptor and protein LQ EUHDVW FDQFHU &HOO -RXUQDO <DNKWHK 6XSSO Harirchi I, Karbakhsh M, Kashefi A, Momtahen AJ. %UHDVWFDQFHULQ,UDQ UHVXOWVRIDPXOWLFHQWHUVWXG\ $VLDQ3DF-&DQFHU3UHY Ariazi EA, Ariazi JL, Cordera F, Jordan VC. Estrogen receptors as therapeutic targets in breast canFHU&XUU7RS0HG&KHP Brinkman JA, El-Ashry D. ER re-expression and resensitization to endocrine therapies in ER-negative breast cancers. J mammary Gland Biol Neoplasia. Yoshida T, Eguchi H, Nakachi K, Tanimoto K, Higashi Y, Suemasu K, et al. Distinct mechanisms of loss of estrogen receptor alpha gene expression in KXPDQEUHDVWFDQFHU PHWK\ODWLRQRIWKHJHQHDQG alteration of trans-acting factors. Carcinogenesis. Lopez-Tarruella S, Schiff R. The dynamics of esWURJHQUHFHSWRUVWDWXVLQEUHDVWFDQFHU UHVKDSLQJ WKHSDUDGLJP&OLQ&DQFHU5HV Lapidus RG, Nass SJ, Butash KA, Parl FF, Weitzman SA, Graff JG, et al. Mapping of ER gene CpG island methylation-specific polymerase chain reacWLRQ&DQFHU5HV Pinzone JJ, Stevenson H, Strobl JS, Berg PE. Molecular and cellular determinants of estrogen recepWRU DOSKD H[SUHVVLRQ 0RO &HOO %LRO Giacinti L, Claudio PP, Lopez M, Giordano A. Epigenetic information and estrogen receptor alpha exSUHVVLRQLQEUHDVWFDQFHU2QFRORJLVW 1-8. Esteller M. Epigenetics in cancer. N Engl J Med. Iwase H, Omoto Y, Iwata H, Toyama T, Hara Y, Ando Y, et al. DNA methylation analysis at distal and proximal promoter regions of the oestrogen receptor JHQHLQEUHDVWFDQFHUV%U-&DQFHU Zhao L, Wang L, Jin F, Ma W, Ren J, Wen X, et al. Silencing of estrogen receptor alpha (ERalpha) gene by promoter hypermethylation is a frequent event in Chinese women with sporadic breast cancer. Breast &DQFHU5HV7UHDW Ferguson AT, Lapidus RG, Baylin SB, Davidson NE. Demethylation of the estrogen receptor gene in es-. 17.. 18.. 19.. A. D I. S f. o e. v i h. c r. trogen receptor- negative breast cancer cells can reactive estrogen receptor gene expression. CanFHU5HV Fan J, Yin WJ, Lu JS, Wang L, Wu J, Wu FY, et al. ER alpha negative breast cancer cells restore response to endocrine therapy by combination treatment with both HDAC inhibitor and DNMT inhibitor. -&DQFHU5HV&OLQ2QFRO Herman JG, Graff JR, Myöhänen S, Nelkin BD, BayOLQ6%0HWK\ODWLRQVSHFLILF3&5 DQRYHO3&5DVsay for methylation status of CpG islands. Proc Natl $FDG6FL86$ Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. Mousavi SM, Gouya MM, Ramazani R, Davanlou M, Hajsadeghi N, Seddighi Z. Cancer incidence DQGPRUWDOLW\LQ,UDQ$QQ2QFRO Mousavi SM, Montazeri A, Mohagheghi MA, Jarrahi AM, Harirchi I,Najafi M, et al. Breast cancer LQ ,UDQ $Q HSLGHPLORJLFDO UHYLHZ %UHDVW - deGraffenried LA, Hopp TA, Valente AJ, Clark RA, Fuqua SA. Regulation of the estrogen receptor alpha minimal promoter by SP1, USF-1 and ERalpha. %UHDVW&DQFHU5HV7UHDW Wang R, Li LW, Wang RL, Fan QX, Zhao PR, Wang LX, et al. Demethylation of estrogen receptor gene and its re-expression in estrogen receptor-negative EUHDVW =KRQJKXD =KRQJ /LX =D =KL Mirza S, Sharma G, Prasad CP, Parshad R, Srivastava A, Gupta SD, et al. Promoter hypermethylation of TMS1, BRCA1, ERalpha and PRB in serum and tumor DNA of invasive ductal breast carcinoma paWLHQWV/LIH6FL Li S, Rong M, Iacopetta B. DNA hypermethylation in breast cancer and its association with clinicoSDWKRORJLFDO IHDWXUHV &DQFHU /HWW Wei M, Xu J, Dignam J,Nanda R, Sveen L, Fackenthal J, et al. Estrogen receptor alpha, BRCA1, and FANCF promoter methylation occur in distinct subsets of sporadic breast cancers. Breast Cancer Res 7UHDW Gaudet MM, Campan M, Figueroa JD, Yang XR, Lissowska J, Peplonska B, et al. DNA hypermethylDWLRQRI(65DQG3*5LQEUHDVWFDQFHU SDWKRORJLF and epidemiologic associations. Cancer Epidemiol %LRPDUNHUV3UHY Nass SJ, Herman JG, Gabrielson E, Iversen PW, Parl FF, Davidson NE, et al. Aberrant methylation of the estrogen receptor and E-cadherin 5' CpG islands increases with malignant progression in KXPDQ EUHDVW FDQFHU &DQFHU 5HV Pirouzpanah S, Taleban FA, Atri M, Abadi AR, MehdiSRXU 3 7KH HIIHFW RI PRGL¿DEOH SRWHQWLDOV RQ K\SHUmethylation status of retinoic acid receptor-beta2 and estrogen receptor-alpha genes in primary breast canFHU &DQFHU &DXVHV &RQWURO 2111.. . 21.. 22.. . . 25.. . CELL JOURNAL(Yakhteh), Vol 14, No 2, Summer 2012. 108. www.SID.ir.
(9) (5Į0HWK\ODWLRQLQ,UDQLDQ%UHDVW&DQFHU3DWLHQWV. cella A, et al. Nonrandom distribution of aberrant promoter methylation of cancer-related genes in sporadic breast tuPRUV&OLQ&DQFHU5HV . 27. Gown AM. Current issues in ER and HER2 testing E\,+&LQEUHDVWFDQFHU0RG3DWKRO VXSSO 66 28. Parrella P, Poeta ML, Gallo AP, Prencipe M, Scintu M, Api-. D I. S f. o e. v i h. c r. A. CELL JOURNAL(Yakhteh), Vol 14, No 2, Summer 2012. 109. www.SID.ir.
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