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1 Journal of Breast Cancer ISSN J Breast Cancer 2008; September 11 (3): ORIGINAL ARTICLE 관상피내암, 관상피내암을포함한침윤성유관암및점액성암에서 와 의발현양상 한선욱 최윤영 우희두 손두민 배상호 강길호 김성용 백무준 임철완 이문수 김창호 이민혁 노진혁 1 조현득 1 오미혜 1 김의한 1 조무식 순천향대학교천안병원외과학교실 1 병리학교실 Expression of and in Ductal Carcinoma in situ, Invasive Ductal Carcinoma with Ductal Carcinoma in situ and Mucinous Carcinoma Sun-Wook Han, Yoon-Young Choi, Hee-Doo Woo, Doo-Min Sohn, Sang-Ho Bae, Gil-Ho Gang, Sung-Yong Kim, Moo-Jun Baek, Cheol-Wan Lim, Moon-Soo Lee, Chang-Ho Kim, Min-Hyuk Lee, Jin-Hyuk Rho 1, Hyun-Deuk Cho 1, Mee Hye Oh 1, Eui-Han Kim 1, Moo-Sik Cho Departments of Surgery and 1 Pathology, College of Medicine, Soonchunhyang University, Cheonan Hospital, Cheonan, Korea Purpose: We purpose to determine the correlation of HER-2/ neu and paxillin expression in ductal carcinoma in situ (DCIS), invasive ductal carcinoma with ductal carcinoma in situ (IDC with DCIS) and mucinous carcinoma. Methods: To evaluate the expression of and paxillin, the immunohistochemical staining was performed for 13 cases of DCIS, 13 cases of IDC with DCIS and 6 cases of mucinous carcinoma. Results: The DCIS and IDC were associated with infiltration of the inflammatory cells, especially in the comedo type and solid type of tumor. In cases with infiltration of the inflammatory cells, and paxillin were strongly expressed. When comparing the expression level of from adjacent normal tissue between DCIS and IDC with DCIS, expression of was similar to that of normal tissue adjacent to DCIS. However, in the adjoining normal ductal epithelial cells, paxillin was highly expressed in cells of all of the tumor types, and especially for IDC with DCIS. and paxillin were not expressed in mucinous carcinoma cells in all cases. Conclusion: in the DCIS and IDC with infiltration of inflammatory cells shows higher expression than non-inflammatory DCIS and IDC. If normal duct epithelial cells show a high level of expression, the epithelial cells have a high probability of transformation into anaplastic cells. However, paxillin appears to have no value as a prognostic factor. The difference of expression of between IDC with DCIS and DCIS suggests a different origin of tumor cells. The growth pattern of mucinous carcinoma cell is different from the that of DCIS or IDC cell, which grow slowly. Key Words :,, Ductal carcinoma in situ, Invasive ductal carcinoma, Mucinous carcinoma 중심단어 :,, 관상피내암, 침윤성유관암, 점액성암 서 론 책임저자 : 김성용 충남천안시봉명동 23-20, 순천향대학교천안병원외과 Tel: , Fax: sykim@schch.co.kr 접수일 : 2008 년 1 월 14 일게재승인일 : 2008 년 6 월 9 일 * 본논문의요지는 2007 년 Global Breast Cancer Conferrence 에서 poster 발표되었음. 세포는세포내외에분포하고있는단백물질들의상호작용에의해서성숙및분화를하고운동성을유지하며, 증식과자연사를일으키게된다. 이러한상호작용은세포외의물질을받아들이는수용체가세포막에있어이수용체를통하여세포외물질과결합한후그정보가핵안의유전자에전달되어나타난다. 현재까지 109

2 110 Sun-Wook Han, et al. 알려진세포증식에관여하는신호전달의경로중에상피성장인자수용체 (Epidermal growth factor receptors, EGFR) 를만드는유전자를자극하여세포막에많은수용체를분포시켜더많은외부자극을수용할수있게하는단백으로인간상피성장인자수용체군 (Human epidermal growth factor receptors, HER) 이있으며이중에서 가여기에속한다. 또하나는국소부착키나아제 (focal adhesion kinase, FAK) 를통하여외부정보를받는방법으로이러한작용을일으키는데, 이들중주된역할을하는것이 integrin이다. 이 integrin은세포외기질의 fibrinonectin이나 laminin 등과결합하여세포내로신호를전달하여세포의증식, 분화에관여한다고한다. 세포막에는 integrin 수용체와 vinculin, FAK, Prolin-rich Tyrosine Kinase-2 (PYK2), SRC, Crk 등과같은단백질들이모여서이루어진국소부착단백 (focal adhesion proteins, FAP) 들이분포되어있다. 은이러한 FAP의한종류이며 FAP 와 integrin이결합하여생성된신호는세포골격 (cytoskeleton) 을이루는 actin과결합하여핵으로전달되어세포의증식, 분화등을일으키도록유도하며성장인자를통하여전달된신호에의해서일어난세포의증식, 분화등과더불어세포주기에중요한역할을하고있다.(1-6) 유방에서의 paxillin의양은정상조직이나양성조직에서는차이가없으나악성종양에서는양이저하되며분화가나쁠수록양은더적게관찰되며예후와관계가깊다고하였다.(8) 그러나 paxillin의과발현은세포의악성세포로의전환에관계가있을수있지만예후와는관계가없다고하는보고도있다.(9-12) 또한분열하는세포에서도 paxillin의양은저하된다고한다.(10) 는강하게나타날수록예후가좋지않으며 HER- 2/neu가과발현되는유방암에서는일반항암제가아닌 Trastuzumab (Herceptin, Genetech/Roche, San Francisco, USA) 이라는표적치료항암제에만효과가있는것으로되어있다. 정상유방에서 는관상피에약한반응을보인다고하였으며,(13-15) 증식성상피에서는발현이안되는것으로알려졌다.(16-18) 또한 paxillin과 와의관계를보면 가과발현되는경우 paxillin도증가된다고하였다. (12,16) 이에저자들은관상피내암, 관상피내암을포함한침윤성관암, 점액성암에서면역조직화학적방법으로 와 paxillin 을염색하여그차이를알아보고자하였으며또한암종주변의염증세포의침윤정도에따른발현양상의차이및암종주변의정상유관상피와암종에서의발현양상의상관관계도알아보기위해본연구를시행하였다. 방법 1. 실험재료순천향대학교천안병원에서조직학적생검및수술로얻어진유방암조직중 13 예의관상피내암, 13 예의관상피내암을포함하고있는침윤성관암및 6예의점액성암을대상으로하였다. 염증세포의침윤은상피내에염증세포의침윤정도를 50% 를기준으로하여경도 (low) 와중증 (high) 으로만구분하였다. 관상피내암은면포형 (comedo type), 사상형 (cribriform type), 충실형 (solid type) 과유두형 (papillary type) 으로분류하였으며, 그중면포형이 3예, 사상형이 5예, 충실형이 3예, 유두형이 2예였다. 침윤성관암은 Bloom-Richardson 분류 (19) 에따라3등급 (grade) 으로나누는데, 본실험에서는같은등급간의비교를위하여 6-7 점에해당하는 2등급만을대상으로하였다. 2. 실험방법포르말린에고정된파라핀포매조직블록을 4 m 두께로박절하여 Snowcoat X-tra slide (Surgipath, Richmond, USA) 에부착하여 60 오븐에 15 분간넣은후자일렌으로실온에서 2분간 4회반복처리하여파라핀을제거하였다. 100% 알코올로 10초간 3회처리하여자일렌을완전히제거한후, 95%, 80%, 70% 알코올을순서대로각각 2회씩처리한다음 1차증류수로함수했다. 항원을회복시키기위해 0.01 M의구연산완충용액 (ph 6.0) 에슬라이드를넣고마이크로파전자렌지에서 20 분동안처리하여실온에서식힌후 phosphate-buffered saline (PBS) 로 5분씩 3회세척하였다. 그후과정은 Bond-X 자동염색기 (Leica Biosystems Pty Ltd, Mt Waverley, Australia) 로시행하였으며, 1 차항체는 paxillin (Neomarker, Fremont, USA) 을 1:800으로, (DAKO, Glostrup, Denmark) 를 1:1,000으로희석하여사용하였다. 염색이끝난슬라이드는증류수에수세후 95% 알코올에 1분, 100% 알코올에 1분씩 2회씩처리후자일렌으로 1분씩 3회투명과정을거친후비수용성봉입체로봉입하고광학현미경으로관찰하였다. 3. 실험판정 1) 세포막에갈색으로염색된것을양성으로판정하였으며염색강도에따라 2명이상의병리의사가 HercepTest TM interpretation manual (Table 1) 을참조하여 score 0-3까지등급을정했다.

3 Expression of and 111 2) 세포막이나세포질내에갈색으로염색된것을양성으로판정하였으며 score는 의판정기준에따랐다.(31) 3) 통계분석 통계프로그램인 SPSS 12.0 (SPSS, Chicago, USA) 을이용하여각군에서 와 paxillin의발현양상의차이를 Pearson Chi-square test를이용하여검정하였다. Table 1. Guidelines for scoring Score protein to overexpression Staining pattern report assessment 0 Negative No staining observed or membrane staining observed in less than 10% of tumor cells 1+ Negative A faint/barely perceptible membrane staining is seen in more than 10% of tumor cells 2+ Positive A week to moderate complete membrane staining is observed in more than 10% of tumor cells 3+ Positive A strong complete membrane staining is observed in more than 10% of tumor cells 결과관상피내암에서염증세포의침윤을보면면포형과충실형에서는중증의염증세포의침윤을보였으나유두형과사상형에서는경도의염증세포침윤을보였다. 의발현을보면 13 예중 8예에서 3등급의강한발현양상을보였으나사상형에서는 5예모두 0-2 등급의발현양상을보였다. 암종주변의정상유관에서의발현은유두형에서만 2예모두 3등급의발현양상을보이고충실형에서는 3예모두 2등급을보인반면면포형및사상형에서는 1등급미만의약한발현양상을보였다. 의발현양상을보면면포형에서는 1예에서 2등급, 나머지 2예에서 3등급을나타냈고충실형에서는 3예모두 3등급의강한발현양상을보였으나사상형과유두형에서는모두 1등급이하의약한발현양상을보였다. 와 paxillin과의발현양상은 p-value가 0.431로유의한통계학적차이는없었다 (Table 2). 암종주변의정상유관에서 paxillin의발현은 와달리암종의발현과같은발현양상을보이고있었다. 중증의염증침윤이있는경우에는 가 5예모두 3등급으로강하게발현되고 paxillin 역시 5예모두 3등급으로강하게발현되어암종주변의정상유관에서 는암세포의유형에상관없이약하게발현되나 paxillin은암세포에서의발현등급이높으면정상유관에서의발현등급도높아졌고통계학적으로도 Table 2. Expression of and paxillin in ductal carcinoma in situ Table 3. Expression of and paxillin in normal ducts epithelium adjacent to tumor nests Degree of inflammation Degree of inflammation (number) Comedo Cribriform Solid Papillary Comedo Cribriform Solid Papillary Table 4. Expression of and paxillin in part of infiltrating ductal carcinoma and part of ductal carcinoma in situ IDC DCIS Grade (number) (number) Degree of inflammation Comedo Cribriform Solid Papillary IDC=infiltrating ductal carcinoma; DCIS=ductal carcinoma in situ.

112 Sun-Wook Han, et al. Fig 1. The showed score 3 pattern in solid type DCIS portion and invasive portion ( 40). Fig 2.

Expression of and paxillin in normal ducts epithelium adjacent to tumor nests IDC DCIS Grade Degree of inflammation 0 1 2 3 0 1 2 3 2 2 8 3 3 2 8 Comedo 2 2 2 Cribriform 2 2 4 3 1 Solid 2 3 5 1 4 1

관상피내암을포함하고있는침윤성관암에서관상피내암부위에서의염증세포의침윤정도를보면면포형과충실형에서 5예의중증의염증세포의침윤이나타나관상피내암만있는경우와 비슷한소견을보였다 (Table 4). 침윤성관암에서침윤된부위에서의 의발현양상을보면 3등급은 13예중 3예를보여 23.

4 112 Sun-Wook Han, et al. Fig 1. The showed score 3 pattern in solid type DCIS portion and invasive portion ( 40). Fig 2. The showed score 3 pattern in solid type DCIS portion and invasive portion in area in Fig 1 ( 40). Table 5. Expression of and paxillin in normal ducts epithelium adjacent to tumor nests IDC DCIS Grade Degree of inflammation Comedo Cribriform Solid Papillary IDC=infiltrating ductal carcinoma; DCIS=ductal carcinoma in situ. Fig 3. The showed score 0 in mucinous carcinoma ( 40). p-value가 0.047로의의가있었다 (Table 3). 관상피내암을포함하고있는침윤성관암에서관상피내암부위에서의염증세포의침윤정도를보면면포형과충실형에서 5예의중증의염증세포의침윤이나타나관상피내암만있는경우와 비슷한소견을보였다 (Table 4). 침윤성관암에서침윤된부위에서의 의발현양상을보면 3등급은 13예중 3예를보여 23.1% 의발현율을보였으나관상피내암부위에서의 3등급은면포형에서는 2예중 2예, 사상형에서는 4예중 1예, 충실형에서는 5예중 3예, 유두형에서는 2예중 1예를차지하여모두 13 예중 7예로 53.8% 를보여침윤된부위에서의발현등급과차이를보였으나 p-value 으로통계학적으로침윤된부위와관상피내암부위에서의유의한차이는없었다 (Table 4, Fig 1). 의발현양상을보면침윤된부위에서 3등급은 13 예중 8예를보였으나관상피내암부위에서는충실형에서 5예중 3예, 그리고사상형에서 4예중 1예를차지하여모두 13 예중 4예에서 3등급의발현양상을보여각각 61.5% 와 30.7% 로나타났으나 p-value 0.116으로통계학적인의의는없었다 (Table 4, Fig 2). 관상피내암만있는경우와침윤성관암내관상피내암부위에서의발현양상을보면 는 3등급이각각 13 예중 8 예와 13예중 7예를나타냈고 paxillin의경우에는각각 13 예중 6예, 13예중 4예에서 3등급의소견을보이고있었다.

5 Expression of and 113 Table 6. Expression of and paxillin in mucinous carcinoma and normal ducts epithelium adjacent tumor nests Mucinous carcinoma 6 6 Normal duct epithelium 6 6 암종주변의정상유관상피에서의 와 paxilin의발현양상을보면 는암세포의발현양상과상관없이거의 0에서 1등급의발현양상을보였고, paxillin은관상피내암만있는경우와침윤성관암내관상피내암부위가비슷한발현양상을보였으나, 유두형에서는암종의발현양상과상관없이 3 등급의강한발현양상을보이고있었다 (Table 5). 점액성암종에서의 와 paxillin의발현양상을보면 6예전예에서음성반응을보였으며 (Fig 3), 암종주변의정상유관상피도전예에서음성반응을보였다 (Table 6). 고 세포가외부자극에의해수용체가자극되어세포내에신호를전달하여세포를증식하게하는데는몇가지의전달경로들이있는데, 일반적으로알려진바로는성장인자와내인성타이로신키나아제수용체 (Intrinsic tyrosine kinase receptor) 가결합하여 phosphoinositide 3 (PI3) 키나아제, 분열촉진물질-활성화단백질 (Mitogen-activating protein, MAP) 키나아제, 이노시톨 1, 4, 5 삼인산 (IP3) 키나아제경로들을통하여성장인자의생성을증가시키거나성장인자수용체의생성을증가시키는경우,(20,21) G 단백질커플수용체 (G-protein coupled recptor) 와결합하여 camp 경로를통하여세포가증식되는경우,(22-26) 사이토카인과내인성타이로신키나아제가없는수용체가결합하여 The Janus kinase-signal transducer and activator of transcription (JAK/STAT) 경로를통하여세포를증식하게하는경우와 (27) 세포외기질이 intergrin과결합하고이것이 FAP 와결합하여국소부착복합체 (Focal adhesion complexes) 를형성하고세포골격에있는 actin을자극하여세포의증식을일으키는경우등이알려져있다.(28-30) 는성장인자와내인성타이로신키나아제수용체의결합경로를통한세포증식에관여한다. 는 C-erb-B2라고도하며상피성장인자수용체를만들어내는유전자를자극하여세포의증식을증가시킨다.(20,21) 찰 Grade 은 integrin의결합경로를통한세포의증식에관여하고있으며, 12 번째염색체장완의 24 부분에존재하고 68 kda 의무게를가지고있다.(7) 이는세포외기질의국소부착 (focal adhesions) 이라불리우는곳에위치하고있는단백질로세포골격단백질 (cytoskeletal proteins) 이나타이로신키나아제, 세린 / 트레오닌키나아제, GTPase 활성화단백질등에결합하는단백질로작용하여,(3) 신호전달을통한세포의확산이나운동성에핵심적인역할을하는것으로알려져있다.(2,7) 세포외에서발생한 integrin과성장인자자극에의하여생긴신호를 paxillin 의인산화과정을통해원형질막 (plasma membrane) 에축적시켜이러한작용을조절한다.(1) 따라서 paxillin의양이저하되면 FAP과 integrin과의결합이안되고신호전달이방해되어세포의운동성이감소한다고하였다.(8) 은혈관근육, 자궁근육, 임파구, 대식구에많이존재하고, 뇌에는적게존재하며혈소판에는없는것으로알려져있다.(1) 또한 paxillin의양이감소되면암의침습성이증가하는것과도연관이있는것으로나타나있다. 실제로이전에연구된결과에서는 paxillin이증가된관상피내암에서는침습성이거의없고, 침윤성관암에서 paxillin이높게발현되는경우림프절전이가드물다는주장도있다.(2) 는 paxillin의전사과정을증가시키고또한인산화과정을일으키는데영향을미치는것으로알려져왔다. 따라서 가과발현되는경우가 가발현이안되는경우보다 paxillin이증가된다고하였다.(12) 본실험결과에서관상피내암의유형에따른염증세포침윤을보면면포형과충실형에서중증의염증세포의침윤이관찰되며사상형과유두형에서는염증세포의침윤이거의관찰되지않았다. 유형에따른발현양상을보면면포형, 충실형, 유두형에서 HER-2/ neu는 3등급의강한반응을보인반면사상형에서는약한반응을보였고 paxillin은면포형과충실형에서는강한반응을보인반면사상형과유두형에서는약한반응을보여관상피내암의형과염증세포의침윤에따라반응양상이차이가있었다. 또한암종주위의정상유관과의상관관계를보면 는암세포의발현양상과상관없이거의 1등급미만의낮은발현양상을보였으나 paxillin은암세포의발현양상과유사한발현양상을보였다 (p=0.047). 이는관상피내암중에서도유형및염증침윤정도에따라 와 paxillin의발현이차이를보이고있음을알수있으며, 주위정상유관상피의발현양상은 는암세포에서는강한반응을보인반면정상유관상피에서는활성화되지않았음을알수있었다. 따라서유두형처럼정상유관에서 3등급의강한발현양상을보이는유관이악성세포로변할가능성이높을것같은데왜유두형에서만강한반응을보이는지는더연구를해봐야될것같다. 그러나 paxillin은

6 114 Sun-Wook Han, et al. 암세포나정상세포에서그기능의차이를보이지않았다. 관상피내암을포함한침윤성관암에서의염증침윤양상을보면주로관상피내암이있는부위에서만침윤이보였으며, 중증의염증세포의침윤이면포형과충실형에서만관찰되어관상피내암만있는경우와비슷한소견을보였다. 침윤된암종에서의 발현양상을보면 2-3 등급이 13예중 11예이며 paxillin은 13 예중 10 예에서 2-3등급의발현양상을보였다. 관상피내암부위에서의 의발현양상을보면관상피내암만있는경우와비슷한소견을보였는데특이할사항은 3등급의경우, 침윤된암종부위에서는 3예, 관상피내암이있는부위에서는 7예로침윤된부위보다관상피내암부위에서더높은발현양상을보였으나통계학적인유의성이적어두부위에서발현양상의차이를알수는없었지만만약차이가있을경우일반적으로생각하는관상피내암은시간이경과되면침윤성으로변한다는개념에서관상피내암을거치지않고바로침윤성유방암으로발병하는것이아닌가를조심스럽게생각해볼수있겠다. 실제로임상에서관상피내암이있는침윤성관암은유방보존술후재발률이더높은것으로알려져있다.(32) 또한분화가나쁠수록 의발현이강하게나타난다 (33) 는견해와는일치되지않아이에대한연구가더진행되어야할것으로본다. 관상피내암부위에서의 paxillin의발현양상을보면관상피내암만있는경우보다약간낮은등급의발현양상을보이고있었으나유두형에서만 3등급의높은발현양상을보였다. 암종주위의정상유관에서발현양상을보면관상피내암만있는경우와비슷하게 는암세포의발현양상과상관없이거의 0에서 1등급의발현양상을보인반면 paxillin은암세포와비슷하거나오히려더높은등급의발현양상을보였다. 이는 나 paxillin은암세포에서의발현양상은비슷하나정상유관상피에서의발현은차이를나타내, 정상유관상피에서 HER-2/ neu가강하게발현되면암세포로변할가능성이있는지표로삼을수있으나 paxillin은그렇지않음을보여주었다. 따라서 HER- 2/neu는예후인자로서의가치가있으나 (34) paxillin은그가치에대해좀더연구를해봐야하겠다. 점액성암에서의 와 paxillin의발현양상을보면전예에서 0등급의발현양상을보였고암종주변의정상유관상피도암종과마찬가지로전예에서 0등급의발현양상을보였다. 이는점액성암의성장에첫번째와네번째의경로가관여하지않고, 따라서 와 paxillin은점액성암과는연관성이떨어진다고생각된다. 이는점액성암을이루고있는암세포의성장이다른형의유방암에비해느리고비교적예후가좋은것으로보아 (35) 그기전이다를것으로생각되나이에대한연구는좀더진행되어야할것이다. 결론 와 paxillin의반응양상및반응정도를 13 예의관상피내암, 13 예의관상피내암을포함한침윤성관암, 6예의점액성암암을대상으로면역조직화학적방법으로검색하여다음과같은결과를얻었다. 첫째, 관상피내암은염증세포의침윤을동반하는경우가많으며특히면포형과충실형에서침윤이두드러진다. 둘째, 관상피내암에서암종주변의정상유관에서 paxillin은암세포에서의발현등급이높으면정상유관에서의발현등급도높아졌다. 셋째, 암종주변의정상유관상피에서 가높은등급의발현양상을보이면암세포로의전환가능성이높다는것을의미한다. 넷째, paxillin은암세포와주변정상유관상피와발현양상이비슷하여 와달리예후적인자로서진단적가치에대해서는좀더연구를해봐야할것이다. 다섯째, 점액성암의 와 paxillin의발현양상은전예에서음성반응을보이고이암종이다른두암종과는달리굉장히느리게성장하며따라서그기전이다르다는것을나타내고있다. 참고문헌 1. Turner CE. Paxiliin. Int J Biochem Cell Biol 1998;30: Madan R, Smolkin MB, Cocker R, Fayyad R, Oktay MH. Focal adhesion proteins as markers of malignant transformation and prognostic indicators in breast carcinoma. Hum Pathol 2006;37: Schaller MD. : a focal adhesion-assocatied adaptor protein. Oncogene 2001;20: Scibelli A, d Angelo D, Pelagalli A, Tafuri S, Avallone L, Della Morte R, et al. Expression levels of focal adhesion-associated proteins paxillin and p130cas in carine and feline mammary tumors. Vet Res 2003; 34: Yamaguchi R, Mazaki Y, Hirota K, Hashimoto S, Sabe H. Mitosis specific serine phosphorylation and downregulation of one of the focal adhesion proteins, paxillin. Oncogene 1997;15: Salgia R, Li JL, Ewaniuk DS, Wang YB, Sattler M, Chen LB, et al. Expression of the focal adhesion protein paxillin in lung cancer and its relation to cell motility. Oncogene 1999;18: Pelagalli A, Scibelli A, Lombardi P, d Angelo D, Tortora G, Staiano N, et al. Expression of the focal adhesion protein paxillin in normal

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Jkbcs032.hwp Clinical Correlation of HER-2/neu Overexpression in Patients with Breast Cancer Sung Yong Kim, Tae Yoon Kim, Jae Jun Kim, Chang Ho Kim, Ok Pyung Song, Min Hyuk Lee, Eui Han Kim 1, and Moo Sik Cho Departments