Clinicopathological Characteristics and Factors Affecting Recurrence of Ductal Carcinoma In Situ in Korean Women

Purpose: As breast cancer screening becomes more popular in Korea, incidence of ductal carcinoma in situ (DCIS) of breast has increased to more than 10% of all breast cancer diagnosed. We aimed to show the clinicopathological characteristics and factors affecting recurrence of DCIS in Korean women. Methods: We retrospectively reviewed 152 DCIS patients who underwent breast conserving surgery in Seoul National University Hospital between January 1995 and December 2005. Results: Mean age at diagnosis was 46.7 years (24 to 66 years). Mean follow up duration of the patients was 73.82 months (0.80 to 168.43 months). Recurrence of disease occurred in 19 (12.5%) patients: 2 in contralateral breast, 15 in ipsilateral breast, and 2 in axilla. One patient showed ipsilateral breast recur after excision of axillary metastasis. Eight (42.11%) of all recurrence was infiltrating ductal carcinoma and one of them showed bone metastasis during follow up. In an multivariate analysis of factors affecting recurrence, younger age at diagnosis and omission of radiotherapy had significant association with recurrence (p=0.005 and p=0.002, respectively). However, tumor size (p=0.862), microinvasion (p=0.988), histologic grade (p=0.157), estrogen receptor status (p=0.401) and resection margin status (p=0.112) were not significantly correlated with recurrence. There was no breast cancer associated mortality. Conclusion: In this study, we found that the younger age at diagnosis and omission of adjuvant radiotherapy are independent predictors of recurrence in Korean DCIS patients.Pinder SE, 2010, BRIT J CANCER, V103, P94, DOI 10.1038/sj.bjc.6605718Bundred NJ, 2010, CLIN CANCER RES, V16, P1605, DOI 10.1158/1078-0432.CCR-09-1623Virnig BA, 2010, J NATL CANCER I, V102, P170, DOI 10.1093/jnci/djp482Allegra CJ, 2010, J NATL CANCER I, V102, P161, DOI 10.1093/jnci/djp485Thomas J, 2010, BRIT J CANCER, V102, P285, DOI 10.1038/sj.bjc.6605513Collins LC, 2009, AM J SURG PATHOL, V33, P1802Hughes LL, 2009, J CLIN ONCOL, V27, P5319, DOI 10.1200/JCO.2009.21.8560Shah DN, 2009, BREAST J, V15, P649, DOI 10.1111/j.1524-4741.2009.00838.xGoodwin A, 2009, BREAST, V18, P143, DOI 10.1016/j.breast.2009.04.003Chung YS, 2009, J BREAST CANCER, V12, P106, DOI 10.4048/jbc.2009.12.2.106Dunne C, 2009, J CLIN ONCOL, V27, P1615, DOI 10.1200/JCO.2008.17.5182Kuerer HM, 2009, J CLIN ONCOL, V27, P279, DOI 10.1200/JCO.2008.18.3103Luini A, 2009, BREAST CANCER RES TR, V113, P397, DOI 10.1007/s10549-008-9929-0von Smitten K, 2008, J SURG ONCOL, V98, P585, DOI 10.1002/jso.21038Ko SS, 2008, J SURG ONCOL, V98, P318, DOI 10.1002/jso.21110Sakorafas GH, 2008, CANCER TREAT REV, V34, P483, DOI 10.1016/j.ctrv.2008.03.001Morrow M, 2008, ANN SURG ONCOL, V15, P2641, DOI 10.1245/s10434-008-0083-zIntra M, 2008, ANN SURG, V247, P315, DOI 10.1097/SLA.0b013e31815b446bAllred DC, 2008, CLIN CANCER RES, V14, P370, DOI 10.1158/1078-0432.CCR-07-1127RHEE J, 2008, BMC CANCER, V8, pNIL19, DOI DOI 10.1186/1471-2407-8-307Moore KH, 2007, ANN SURG ONCOL, V14, P2911, DOI 10.1245/s10434-007-9414-8Sontag L, 2005, J THEOR BIOL, V232, P179, DOI 10.1016/j.jtbi.2004.08.002Boland GP, 2003, BRIT J SURG, V90, P426, DOI 10.1002/bjs.4051Vicini FA, 2002, J CLIN ONCOL, V20, P2736, DOI 10.1200/JCO.2002.07.137Neuschatz AC, 2002, CANCER, V94, P1917, DOI 10.1002/cncr.10460Bartelink H, 2001, NEW ENGL J MED, V345, P1378Bijker N, 2001, J CLIN ONCOL, V19, P2263LEE HD, 2001, J KOREAN SURG SOC, V60, P495FRYKBERG ER, 1997, BREAST J, V3, P227

The Change of Practice Patterns of the Hereditary Breast Cancer Management in Korea after the Korean Hereditary Breast Cancer Study

본 논문은 2010 한국유방암학회 춘계학술대회에서 구연 발표되었음.Purpose: The objective of this study was to evaluate the change in the practice patterns for managing hereditary breast and ovarian cancer (HBOC) among Korean physicians after the Korean Hereditary Breast Cancer (KOHBRA) study. Methods: The first survey was performed from July to August 2007, at the initiation of the KOHBRA study, and the follow-up survey was conducted from July to December 2009. Members of the Korean Breast Cancer Society were invited to participate in the study by e-mail. The 2009 survey was conducted with a self-administered questionnaire concerning HBOC management and was identical to the previous questionnaire. Results: According to the 2009 survey, most physicians (60.0%) tended to draw a pedigree (48.0% in 2007 survey). The rate of genetic test recommendations for patients at risk for HBOC was higher in the 2009 survey (84.0%) than that in the 2007 survey (64.0%). Physicians tended to select a BRCA genetic testing candidate more appropriately than in the previous survey (42.4% answered right in 2007 survey; 74.4% in 2009 survey). Fifteen of 25 participants (60.0%) provided genetic counseling before their patients underwent a genetic test, which was higher than that (40.0%) in the 2007 survey. According to the 2009 survey, half of the genetic counseling was being conducted by KOHBRA study research nurses; whereas most of the genetic counseling was conducted by physicians in 2007. Conclusion: The KOHBRA study has played an important role in the appropriate selection of candidates for genetic testing. However, more effort should be placed on improving the pre-test genetic counseling rate.본 연구는 보건복지부 암정복연구비의 지원을 받아 시행되었음(과제번호 0720450).Robson ME, 2010, J CLIN ONCOL, V28, P893, DOI 10.1200/JCO.2009.27.0660Han SA, 2009, J BREAST CANCER, V12, P92, DOI 10.4048/jbc.2009.12.2.92Ko SS, 2008, J SURG ONCOL, V98, P318, DOI 10.1002/jso.21110Kim KS, 2008, J BREAST CANCER, V11, P95Kim EK, 2007, J BREAST CANCER, V10, P241Chenevix-Trench G, 2007, BREAST CANCER RES, V9, DOI 10.1186/bcr1670Fisher B, 2005, J NATL CANCER I, V97, P1652, DOI 10.1093/jnci/dji372Eisen A, 2005, J CLIN ONCOL, V23, P7491, DOI 10.1200/JCO.2004.00.7138Nelson HD, 2005, ANN INTERN MED, V143, P362Green MJ, 2004, JAMA-J AM MED ASSOC, V292, P442Choi DH, 2004, J CLIN ONCOL, V22, P1638, DOI 10.1200/JCO.2004.04.179Ahn SH, 2004, J KOREAN MED SCI, V19, P269Rebbeck TR, 2004, J CLIN ONCOL, V22, P1055, DOI 10.1200/JCO.2004.04.188Antoniou A, 2003, AM J HUM GENET, V72, P1117Rebbeck TR, 2002, NEW ENGL J MED, V346, P1616KANG HC, 2002, HUM MUTAT, V20, P235Malone KE, 2000, CANCER, V88, P1393Hartmann LC, 1999, NEW ENGL J MED, V340, P77Fisher B, 1998, J NATL CANCER I, V90, P1371Ford D, 1998, AM J HUM GENET, V62, P676Parmigiani G, 1998, AM J HUM GENET, V62, P145ShattuckEidens D, 1997, JAMA-J AM MED ASSOC, V278, P1242Dinkel MK, 1997, J CLIN ONCOL, V15, P2157Claus EB, 1996, CANCER, V77, P2318WOOSTER R, 1995, NATURE, V378, P789OH JH, 1995, J KOREAN CANC ASS, V27, P1061FRIEDMAN LS, 1994, NAT GENET, V8, P399*NAT COMPR CANC NE, NCCN CLIN PRACT GUID

The effect of a-melanocyte stimulating hormone on renal ischemia-reperfusion injury

신장 이식 시 허혈/재관류 손상은 이식 신의 기능지연 및 급만성 거부반응과 연관이 있는 것으로 보고되고 있으며, 허혈성 손상에 의한 급성 신부전은 혈관 수축 및 세뇨관 폐쇄등의 요인 외에 염증성 싸이토카인 증가 및 신 실질로의 중성구 침윤을 동반한 염증성, 세포독성의 손상 기전이 중요하게 작용한다. 알파 멜라닌 세포 자극 호르몬(α-Melanocyte stimulating hormone, 이하 α-MSH로 칭함)은 다양한 동물 실험에서 강력한 항염증효과가 증명된 내인성 호르몬으로 IFN-γ, TNF- α, IL-8등의 싸이토카인의 분비를 억제시키며, 산화 질소 경로를 억제하여 산화 라디칼과 산화 질소에 의한 조직손상도 감소시키는 효과를 갖는다. 본 연구에서는 백서에서 신혈관경을 결찰하는 허혈/재관류 모델을 이용하여 허혈전과, 재관류전, 그리고 재관류 18시간후에 α-MSH(n=19)를 투여하고, 허혈만 가한 대조군(n=15), 허혈을 가하지 않은 Sham군(n=6)으로 나누어 재관류 후 24시간과 48시간의 혈청 크레아티닌과 신장 조직의 변화를 관찰하였다. α-MSH 실험군은 허혈 대조군에 비하여 24시간 혈청 크레아티닌이 의미있게 감소하였으며 ( 3.01 ± 0.64 vs 4.21 ± 1.14) 그 감소 폭은 48시간에 더 현저하게 나타났다( 1.15 ± 1.11 vs 4.21 ± 1.03 ). 조직학적 소견에서도 α-MSH군에서 세뇨관 괴사와 염증성 침윤의 정도가 허혈 대조군에 비교하여 감소한 소견을 보였으며, Sham군과 α-MSH군에서는 실험동물의 치사가 없었던 반면, 허혈대조군에서는 33.3%(5/15)의 치사율을 나타내었다. 따라서 α-MSH는 허혈/재관류 손상에 의한 신 손상을 예방할 뿐만 아니라 생존률에서도 향상된 결과를 보였다. 이 연구에서 45분간 양측 신허혈을 가하였는데 이는 대조군에서의 높은 사망률에서 확인되듯이 좀 더 비가역적인 신 손상에 가까운 것으로 생각되고 이러한 손상 정도에서도 α-MSH의 효과를 확인할 수 있었다는데 의의가 있다. 또한 α-MSH군에서 손상 후 24시간의 혈청 크레아티닌보다 48시간 크레아티닌 수치가 더 의미있게 감소한 소견은 α-MSH가 허혈/재관류에 의한 신 손상을 예방할 뿐 만 아니라, 이미 신 손상이 진행된 조직에서 그 손상 정도를 감소시키는데 더 큰 역할을 한다는 것을 알 수 있었다. ;Ischemia and reperfusion induces renal injuries. Cytokines, chemoattractant chemokines, adhesion molecules and nitric oxide play role on these renal injuries. α-Melanocyte stimulating hormone(α-MSH) is a potent anti-inflammatory cytokine and has therapeutic effect on an ischemic acute renal failure. In male Spraque-Dawley rats, both renal pedicle were clamped for 45 minutes. α-MSH(50 ㎍) was injected intravenously three times, immediately before ischemia and reperfusion and 18 hour after reperfusion. Serum creatinine and histologic change was analyzed between groups(Sham, ischemic control group, and α-MSH group). Serum creatinine level decreased significantly in α-MSH treated animals (SCr24 0.78±0.23㎎/㎗, 4.21±1.14 ㎎/㎗, 3.01±1.19 ㎎/㎗ (p=0.008)), especially serum creatinine level 48 hr after reperfusion was much more dicreased in α-MSH group (SCr48 0.67±0.16 ㎎/㎗, 4.21±2.03 ㎎/㎗, 1.15±1.11 ㎎/㎗ (p=0.004)). Tubular neccrosis and neutrophil infiltration decreased signigicantly in α-MSH treated group(p=0.001). mortality was noted 33.3% only at ischemic conrol group. In conclusion, we demonstrated the fact that α-MSH has therapeutic role on injured tissues as well as protective effects on ischemic renal injury and and improves survival rates. Therefore α-MSH is a potential therapeutic drug in acute renal faiure.논문개요 = vii Ⅰ. 서론 = 1 Ⅱ. 대상 및 방법 = 4 A. 실험동물과 허혈/재관류 = 4 B. 생화학적 검사 = 5 C. 조직학적 검사 = 5 D. 통계학적 분석방법 = 6 Ⅲ. 결과 = 7 A. 혈청크레아티닌 = 7 B. 병리조직학적염색 = 8 C. 생존률 = 8 Ⅳ. 고찰 = 9 Ⅴ. 결론 = 12 참고문헌 = 19 ABSTRACT = 2

렙틴은 에스트로젠 수용체 양성 유방암 세포주에서 타목시펜 치료에 대한 반응을 조절한다

여성의 비만과 유방암은 현대 사회에서 계속 증가하고 있으며, 비만은 특히 폐경후 여성에서 유방암의 위험인자로 잘 알려져 있다는 점에서 주목할 만하다. 렙틴은 지방세포에서 분비되는 강력한 아디포카인이며 렙틴신호는 유방암의 발달과 침윤에 있어서 중요한 역할을 한다. 렙틴은 렙틴 수용체에 결합하여 신호를 전달하며 또한 렙틴수용체는 에스트로젠수용체와의 상호작용을 통하여 체내의 에스트로젠 합성과 아로마타아제의 표현을 증가시키다고 알려져 있다. 따라서 호르몬 수용체 양성유방암 중 25%를 차지하는 호르몬 저항성의 원인으로 렙틴의 역할에 주목하였으며, 연구의 목적은 렙틴이 에스트로젠 수용체 양성 유방암 세포주에서 타목시펜 치료에 대한 반응에 어떤 영향을 미치는지 알아보고자 하였다. 에스트로젠 수용체 양성 유방암 세포주에서 타목시펜치료에 대한 렙틴의 영항을 알아보기 위하여 먼저 본 연구에서는 다양한 유방암 세포주에서 웨스턴블럿 어세이를 이용하여 렙틴과 렙틴수용체 단백 발현을 분석하였다. 다른 농도의 에스트로젠 조건에서 렙틴과 타목시펜을 투여하였을 때의 세포증식을 측정하여 렙틴의 작용에 대한 에스트로젠 농도의 영항도 분석하였으며, 또한 에스트로젠 수용체 양성 유방암세포에서 렙틴이타목시펜의 치료에 어떤 영향을 주는지 에스트로젠, 렙틴, 그리고 타목시펜을 병합치료하여 각각의 효과를 비교 분석하였으며, 이에 대한 세포신호전달의 변화를 확인하기위해 각 치료후 5분과 10분, 1시간, 6시간에 MCF-7 세포와 T-47D세포에서 total ERK1/2, phospho-ERK1/2, total STAT3, 그리고 phospho- STAT3의 활성화를 알아보았다. 웨스턴 분석에서 렙틴발현은 MCF-7, T-47D, HCC-70, MDA-MB453 세포에서 관찰되었고, 즉 에스트로젠 수용체 양성 세포에서 주로 강한 발현을 보였다. 렙틴수용체중 활성형 (Ob-Rb)의 발현은 MCF-7, SK-BR3, MDA-MB453, MDA-MB231에서 확인 되었으며 이는 비활성형 수용체 (Ob-Ra)에 비해 유방암세포에서 정상세포보다 발현이 증가되는 경향을 보였다. 에스트로젠 수용체 양성이며 렙틴과 렙틴수용체를 모두 발현하는 유방암 세포주인 MCF-7은 에스트로젠과 렙틴을 각각 단독 투여 하였을 때는 아무것도 투여하지 않은 대조군에 비해 유의한 증식효과 (p < 0.001)를 보였으며 타목시펜을 단독 투여하였을 때도 유의하게 대조군에 비해 억제 효과를 나타냈다 (p < 0.001). 하지만 MCF-7과 T-47D에서 에스트로젠만 투여 하였을 때와 비교하여 렙틴을 추가하였을 경우 렙틴 추가에 따른 부가적인 증식효과는 없었으며, 타목시펜의 경우도 렙틴을 추가하였을 때 타목시펜을 작용에 영향을 주지 않았다. 이에 비해 T47D 세포는 에스트로젠 수용체 양성, 렙틴양성이며 렙틴 수용체는 없는 유방암세포주로 에스트로젠을 투여하였을 때는 증식효과를 보였지만 렙틴은 증식효과를 나타내지 않았고 타목시펜의 억제효과는 유의하였다. T-47D에서도 에스트로젠이나 타목시펜에 렙틴을 병합하였을때에는 렙틴의 추가적인 호과는 나타나지 않았다. 즉 MCF-7이나 T-47D 세포에서 모두 렙틴은 에스트로젠이나 타목시펜의 단독치료시 그 효과에 영향을 주지않았다. 하지만 흥미롭게도, 에스트로젠 농도가 20 nM 일때 렙틴은 MCF-7과 T-47D 세포 모두에서 타목시펜 10 μM의 항에스트로젠 효과를 유의하게 억제하였으며, T-47D에서는 에스트로젠 농도가 10 nM일때도 같은 효과를 나타냈다. 이러한 효과는 렙틴수용체 양성인 MCF-7에서는 ERK1/2와 STAT3의 세포신호전달의 활성화를 통해 이루어짐을 확인하였으며, 렙틴수용체 음성인 T-47D에서는 ERK1/2과 STAT3가 활성화되지 않는 것을 확인하였다. 결론적으로 에스트로젠 수용체 양성 유방암 세포주인 MCF-7과 T-47D세포 에서 렙틴은 에스트로젠이 작용하는 조건하에서 타목시펜의 항에스트로젠 작용을 유의하게 억제하며 따라서 호르몬수용체 양성 유방암에서 렙틴의 작용을 억제시키면 호르몬 반응을 증강시킬 수 있다는 것을 의미하며, 따라서 렙틴의 억제는 호르몬 저항성을 극복할 수 있는 유망한 방법으로 생각된다.;Obesity is known as a risk factor for breast cancer in postmenopausal women. Leptin is a potent adipokine which mainly produced by adipose tissue and leptin signaling plays a significant role in tumor development and invasion of breast cancer. Leptin binds the leptin receptor (Ob-R) that activates JAK/STAT and the ERK signaling pathways. And ERα and Ob-R have been found coexpressed in malignant mammary tissue and breast cancer cell lines. Therefore, it is also possible that both signaling systems are　involved in a functional cross‐talk contributing to tumor development. In recent study, leptin induced aromatase gene expression, elevating aromatase activity and increasing estrogen synthesis in MCF-7 cell. Leptin was also able to enhance estrogen receptor α (ERα)–dependent transcription by decreasing ERα ubiquitination and degradation. And this implies some important roles that leptin may play on hormone resistance of ER-positive breast cancer. The aims of this study is to evaluate whether leptin modulates the effect on tamoxifen treatment in estrogen receptor (ER)-positive breast cancer cell. At first, to assess the effect of leptin on tamoxifen treatment in ER-positive breast cancer cell, we examined leptin and Ob-R expression by western blot assay in various breast cancer cells and cell proliferation by cell viability assay in combination with leptin and tamoxifen under estradiol (E2) treatment. And we analyzed the effect of leptin on the response of tamoxifen treatment in ER-positive breast cancer cells and which result from activation of ERK1/2 and STAT3 signaling pathway in leptin treatment. Leptin expressions were noted in MCF-7, T-47D, HCC-70, MDA-MB453 cells and Ob-R expressions in MCF-7, SK-BR3, MDA-MB453, MDA-MB231 cells by western blot analysis. The single treatment of E2, leptin and tamoxifen had a significant effect on MCF-7 and T-47D cells comparing to control (p < 0.001). But, leptin had no additional effect on both E2-only treated and tamoxifen-only treated‐breast cancer cells including both MCF-7 and T-47D cells. High dose leptin (100 ng/㎖) had the proliferative effect on MCF-7 comparing to control (p < 0.001). But leptin, even in high dose, had no proliferative effect on T-47D cells. Leptin had an inhibitory effect on tamoxifen especially in high E2 (20 nM) setting in both MCF-7 and T-47D cells. We examined the effects of different treatment conditions on the activation of different Ob-R signaling pathway in MCF-7 and T-47D cells. The total- and phospho- ERK1/2 were detectable in MCF-7 cell at 5 minutes, were maximal at 1 hour and then reduced at 6 hours. Tamoxifen prominently inhibited the total- and phospho-ERK1/2 maximal at 6 hours. Interestingly, when leptin was added to combination treatment of E2 and tamoxifen, the total- and phospho- of ERK1/2 was more activated than combination without leptin at 1 hour in MCF-7. The total-STAT3 was also maximal at 1 hour. Tamoxifen relatively reduced the activation of total- and phospho-STAT3 at 6 hours in MCF-7 cell. When added leptin to combination of E2 and tamoxifen, activation of total- and phospho-STAT3 were relatively remarkable at 1 hour comparing to combination without leptin. In T-47D cell, the total- and phospho-ERK1/2 were also detectable at 5 minutes, maximal at 1 hour and then declined at 6 hours. Tamoxifen definitely inhibited total- and phospho-ERK1/2 maximal at 6 hours. When leptin was added to combination of E2 and tamoxifen, leptin relatively induced the activation of total ERK1/2 compared to combination of E2 and tamoxifen without leptin. But this result was not shown in phospho-ERK1/2 signaling. In STAT3 signaling, which is similar to ERK1/2, tamoxifen significantly inhibited total- and phospho-STAT3 at 6 hours. Interestingly, when lepin was added to the combination of E2 and tamoxifen, the activation of total STAT3 was prominent compared to the combination without leptin at 1 hour but this result not shown in phospho-STAT3 signaling in T-47D cell. We concluded that leptin interfere with the anti-estrogenic effects of tamoxifen under E2 condition both in MCF-7 and in T-47D ER-positive breast cancer cells through activation not only of Ob-R but also of crosstalk with other signaling systems. These results imply that inhibition of leptin is expected to enhance the hormone response in ER-positive breast cancer, and therefore, suggests a promising way to overcome hormonal resistance.I. Introduction 1 II. Materials and Methods 3 A. Cell culture and Therapeutic agents 3 B. Charcol-stripped fetal bovine serum and cell stimulation 3 C. Western blot analysis and Antibodies 4 D. Cell proliferation assay 5 E. Statistical analysis 5 III. Results 6 A. Leptin was expressed in ER-positive breast cancer cell lines 6 B. Ob-Rb was strongly expressed in breast cancer cell lines 6 C. Leptin enhances the proliferation of MCF-7 cells 6 D. Leptin did not interfere the effect of E2 and tamoxifen 7 E. Leptin inhibited the antiestrogenic effect of tamoxifen under E2 treated condition 8 F. Leptin activates Multiple Signaling Pathways under combination with Estradiol and Tamoxifen in MCF-7 and T-47D cells 8 IV. Discussion 10 V. Conclusion 13 References 32 국문초록 3