Efficacy of Estriol in Inhibiting Epithelial Proliferation in Mammary Fibroadenoma

8/18/2019 Efficacy of Estriol in Inhibiting Epithelial Proliferation in Mammary Fibroadenoma

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EFFICACY OF ESTRIOL IN INHIBITING EPITHELIAL PROLIFERATION IN

MAMMARY FIBROADENOMA: RANDOMIZED CLINICAL TRIAL.

a) Datos generaes

Rodrigo Augusto Fernandes Estevão; Edmund Chada Baracat; Ângela FláviaLogullo; Celina Tizuko Fui!ama "shima; A#onso Celso $into %azário

&astolog! 'ector o# (e)artment o# *!necolog! and (e)artment o# $atholog!+,niversidad Federal de 'ão $aulo - Escola $aulista de &edicina .,ni#es)/E$&0+1232

!) Intro"#$$%&n

Fi4roadenoma es el tumor 4enigno más com5n en el seno de la muer6 Es unaneo)lasia #ormada )or teido glandular ! #i4roso+ en )acientes 7venes de entre 32! 82 a9os6 El #i4roadenoma crece como un n7dulo 4ien delimitado ! no se une alteido vecino6 'on localizados más com5nmente en el seno iz:uierdo ! en elcuadrante eterno6 El tama9o de las lesiones va desde 3 cm hasta grandesdimensiones+ como 32 a 3< cm6

=a! muchos ti)os de tratamiento )ara el #i4roadenoma mamario6 Tumores demenos de 3 cm en diámetro )uede ir hacia una regresi7n total6 Los estr7genos+son )redis)uestos hacia la g>nesis del #i4roadenoma; >ste+ ocurre mucho en)acientes #emeninas :ue usan muchos anticonce)tivos6 Los anticonce)tivosorales contienen estr7genos sint>ticos en su #7rmula+ como el ethin!l estradiol6 Lama!or controversia hacia el uso de anticonce)tivos orales+ es la asociaci7n haciael desarrollo del cáncer de mama6

La actividad de )roli#eraci7n+ #ue evaluada en varias t>cnicas comoinmunohisto:ui?mica+ el conteo de mitosis+ @3/ ! c/m!c6 (entro de estosant?genos está k3/ descri4i7 )or )rimera vez )or *erdes et al6 Este esdetectado )or el anticuer)o monoclonal )ara k3/ .g*306 Aun:ue la #unci7n realdel ant?geno k3/ es desconocida+ es am)liamente utilizada en la )atolog?a )araevaluar el crecimiento de teidos normales ! neo)lásicos6 En tumores s7lidos+ unaasociaci7n entre el rango alto de )roli#eraci7n ! agresividad ha sido demostrado6

C/m!c tiene el rol central en el diagn7stico de la )roli#eraci7n maligna ! latrans#ormaci7n de c>lulas humanas ! animales6 El oncog>n c/m!c humano+ selocaliza en la )arte distal del 4razo del cromosoma D+ en la regi7n D:16 Lama!or?a de los tumores malignos muestran am)li#icaci7n ! una so4ree)resi7n deeste gen6 C/m!c uega un rol im)ortante en las #unciones celulares como


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re)licaci7n+ crecimiento+ meta4olismo+ di#erenciaci7n ! a)o)tosis6 En situaciones#isiol7gicas+ c/m!c es una )rote?na nuclear :ue act5a en la transcri)ci7n de#actores ! contri4u!e en todas las eta)as de la carcinogenia+ trans#ormandoc>lulas en c>lulas malignas6

$) Desarroo "e os $onten%"os %'(ortantes

'e )ro)one evaluar la )roli#eraci7n celular de este teido e)itelial+ de acuerdo a lae)resi7n de )rote?nas celulares .ki/ ! c/m!c0 entre los usuarios deanticonce)tivos orales+ con ! sin asociaci7n de estradiol6

'e em)ez7 con 2 mueres :ue asist?an a la cl?nica )or el inicio de )ro4lemasmamarios+ en el de)artamento de *inecolog?a de la Federal ,niversit!6 Las)acientes #ueron divididos cuidadosamente en dos gru)os6 *ru)o 3 .control0 con32 mueres con #i4roadenoma :ue usaron anticonce)tivos orales comolevonorgestiol .63n em)earon com tumores en seno ! :ue tam4i>n tomaron elmismo anticonce)tivo+ )ero con 1mg de estradiol6

El anticuer)o monoclonal k3/ reacciona con antigenos nucleares )resentes enc>lulas con actividad )roli#erativa mostrando )ositividad nuclear6 En el otro lado+ C/m!c )romueve la re)licaci7n en la res)uesta a signos celualres6

El #i4roadenoma es una mezcla :ue contiene cantidades varia4les de teidoe)itelial ! conuntivo+ de gran im)ortancia6 'ahne! et al+ estudiaron#i4roadenomas ! demostraron :ue una relaci7n es)ecial eiste entre la mitosis del

estroma ! las concentraciones de teido e)itelial6

El estr7geno com)onente de los anticonce)tivos orales .ethin!l estradiol0 esconocido )or ser 322 a 122 veces más #uertes :ue el estradiol+ :ue es elestr7geno generalmente encontrado en la circulaci7n6 La #uerte acci7n :ue realizael ethin!l estradiol en el e)itelio lleva a la c>lula a )roli#erar+ )romocionando lae)resi7n de )rote?nas relacionando el ciclo celular+ Tam4i>n se encontr7+ duranteel control )aracrino+ un aumento en la )roducci7n de #actores inhi4idores delestroma inducen una reducci7n de la )roli#eraci7n del estroma6

") Con$#s%&n

La inmunohisto:u?mica+ de k3/ ! C/m!c no mostr7 una di#erencia im)ortanteentre el gru)o 3 ! el gru)o 16 Lo 5nico :ue se vio #ue la tendencia hacia una ma!or e)resi7n de )rote?nas en los )acientes del gru)o 16 'e asumi7 :ue el estradiol4lo:uea el ethin!l estradiol en los anticonce)tivos orales+ )articularmente en elcom)onente e)itelial+ además induciendo una menor )roli#eraci7n en estecom)artimiento llevando a una menor )roducci7n de inhi4idores de #actores de


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crecimiento estromales+ :ue mantuvieron al estroma )roli#erando6 Al #inal la)roli#eraci7n de estroma+ )roduo #actores de crecimiento :ue mantuvieron alestroma )roli#erando6

Las mueres :ue usaron anticonce)tivos hormonales orales con estradiol )or

ciclos consecutivos demostraron :ue la e)resi7n de k3/ ! c/m!c en el e)iteliocon #i4roadenoma #ue similar a la e)resi7n demostrada )or las mueres :ueusaron anticonce)tivos orales hormonales con )lace4o )or ciclos6 'in em4argo+hu4o una ma!or tendencia a la e)resi7n de estas )rote?nas entre las usuarias deanticonce)tivos orales con estradiol6

ORIGINAL ARTICLE

Efficacy of estriol in inhibiting epithelial proliferation inmammary fibroadenoma: randomized clinical trial

Eficcia do estriol na inibi!"o da prolifera!"o epitelial nofibroadenoma mamrio: ensaio cl#nico randomizado

Rodrigo A$g$sto %ernandes Este&"o' Edm$nd Chada (aracat' )ngela %l&iaLog$llo' Celina Tiz$*o %$+iyama Oshima' Afonso Celso ,into Nazrio

Mastology Sector of Department of Gynecology and Department of Pathology,Universidade Federal de São Paulo — Escola Paulista de Medicina Unifesp!EPM", SãoPaulo, #ra$il

%ddress for correspondence

A(-TRACT

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1516-31802007000600008&lng=en&tlng=en.%2010.1590/S1516-31802007000600008.#endhttp://www.scielo.br/scielo.php?script=sci_arttext&pid=S1516-31802007000600008&lng=en&tlng=en.%2010.1590/S1516-31802007000600008.#end


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CONTE.T AN/ O(0ECTI1E: Mammary fi&roadenoma is a disease that affects a largenum&er of 'omen of reproductive age( )he aim of this study 'as to evaluate theproliferative activity of mammary fi&roadenoma through e*pression of +i!- and c!mycantigens, follo'ing administration of oral contraceptive 'ith or 'ithout estriol(/E-IGN AN/ -ETTING: Place&o!controlled dou&le!&lind randomi$ed clinical trial inthe Mastology Sector of the Department of Gynecology, Universidade Federal de São

Paulo(2ET3O/-: )hirty!three fi&roadenoma patients 'ere studied( )en 'omen group ."too/ an oral contraceptive constituted &y levonorgestrel and ethinyl estradiol together'ith place&o manufactured in the same capsule for four consecutive cycles 'ith aseven!day interval &et'een them( )he other 01 patients group 0" too/ the same oralcontraceptive together 'ith estriol, 'hich 'as put into the same capsule and used inthe same 'ay as among the group . patients( %fter four cycles, the nodules 'eresurgically removed and sent for immunohistochemical analysis of +i!- and c!myce*pression(RE-4LT-: )he +i!- and c!myc analysis did not reveal any significant differences&et'een the study groups( )he values 'ere 2(. and .3(45 for group . and .3(6 and.-(31 for group 0, respectively( )here 'as a tendency to'ards higher e*pression ofantigens in group 0(

CONCL4-ION: 7ur results sho'ed that there 'as no significant statistical differencein +i!- and c!myc e*pression &et'een our study groups, &ut only a tendency to'ardshigher e*pression among users of oral contraceptives containing estriol(

5ey 6ords: Fi&roadenoma( 8ontraceptives oral( Estriol( +i!- antigen( Myc genes(

RE-42O

CONTE.TO E O(0ETI1O: 7 fi&roadenoma mam9rio : uma doen;a etivo foi avaliar a atividadeproliferativa do fi&roadenoma mam9rio, atrav:s da e*pressão do +i!- e do c!myc,ap?s a administra;ão de anticoncepcional oral, associado ou não ao estriol(TI,O /E E-T4/O E LOCAL: Ensaio cl@nico randomi$ado, duplo!cego, place&ocontrolado, reali$ado na Universidade Federal de São Paulo a n@vel terci9rio(27TO/O-: Foram estudadas 11 pacientes portadoras de fi&roadenoma, atendidas nosetor de Mastologia da Disciplina de Ginecologia da Universidade Federal de São Paulo— Escola Paulista de Medicina Unifesp!EPM", sendo


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,ala&ras9cha&e: Fi&roadenoma( %nticoncepcionais orais( Estriol( %nt@geno +i!-(Genes myc(

INTRO/4CTION

Fi&roadenoma is the most common &enign tumor of the female &reast( Ct is aneoplasm formed &y glandular and fi&rous tissues and occurs in young patients aged03 to 13 years( Ct is the most common &enign disease among females under the age of 14 years and it occurs 'ithout symptoms in 04 of the cases( Ct is multiple in .1 to03.!1 and is more common among &lac/s than among 'hites(5!

Fi&roadenomas gro' as 'ell!limited mo&ile spherical nodules and do not &ecomeattached to neigh&oring &reast tissue( )hey are more fre


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use oral contraception, even a small rise in ris/ may represent a large num&er ofcancer cases( )he 8ancer and Steroid Iormone 8%SI" study,.4 pu&lished in .26, didnot sho' any association &et'een hormonal oral contraception and &reast cancer(March&an/s et al(. conducted a case!control study among 'omen aged 14 to 53years, and found a relative ris/ of .(3 for 'omen 'ho 'ere ta/ing oral contraceptivesand 3(2 for those 'ho had already ta/en them(

+no'ledge of cellular theory in pathology has clearly sho'n that cell &ehavior isrelated to nuclear characteristics( )his /no'ledge has evolved such that it has &eenfound that the nucleus is the locus of the genetic information that 'ill &e transmittedthrough cells(.-

Simomoto et al(.6 studied the epithelial /inetics of fi&roadenomas during menstrualcycle &y morphometric analysis( )he mitotic inde* and average nuclear volume did notsho' significant differences &et'een phases, 'hich therefore refutes the possi&ility offi&roadenoma epithelial cyclicity as occurs in normal &reasts( #ecause of the strangeproliferation of lo&ular epithelium that they o&served, they suggested thatfi&roadenoma formation 'as modulated &y paracrine mechanisms(

Iue&.2 and )aniguchi03 compared the cellular proliferative nuclear antigen 8PB%"levels in epithelium 'ith fi&roadenoma, among users and non!users of oralcontraceptives( )hey did not find any significant differences, and only a tendencyto'ards higher e*pression among non!users(

)he results from these last studies suggested that oral contraceptives did not inhi&itthe proliferative activity of epithelium 'ith fi&roadenoma( Ct 'ould therefore &e ofinterest to evaluate 'hether some su&stance, used concomitantly 'ith oralcontraceptives, might inhi&it the cellular /inetics of this tumor( )hus, 'e raised thehypothesis that estriol might &loc/ the oral contraceptive effect on fi&roadenoma(

Estriol is, in fact, the peripheral meta&olite of estrone and estradiol, rather than asecretory product from the ovary( Cts production occurs &ecause of meta&olicdeto*ification, i(e( conversion of active su&stances into less active forms(0.

Cn revie'ing the literature, 'e 'ere surprised to find that there 'as no pu&lishedresearch evaluating the effect of estriol, 'ith or 'ithout oral contraceptives, onfi&roadenomas and, in particular, on its proliferative activity(

)his proliferative activity may &e evaluated &y several techni


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%lthough the e*act function of the +i!- antigen remains un/no'n, it is 'idely utili$edin pathology to evaluate the gro'th fraction of normal and neoplastic tissues,particularly in studies implicating its possi&le prognostic value( Cn solid tumors, anassociation &et'een high proliferation rate and aggressiveness has &een proven(

8!myc 'as first descri&ed as a retroviral oncogene in chic/ens myelocytomatosis

virus" &y #ishop04

in .260( )oday, it has a central role in diagnosing malignantproliferation and transformation of human and animal cells(0 Ct 'as discovered as atransforming se


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)hey needed to have had regular menstruation during the preceding si* months, 'iththe last menstrual period /no'n and 'ith normal gynecological and colposcopice*aminations(

e e*cluded patients 'ho had endocrinopathies, 'ho 'ere pregnant or in puerperium,or 'ho presented suspicions of any carcinoma(

)his pro>ect 'as analy$ed and approved &y the Hesearch Ethics 8ommittee ofUniversidade Federal de São Paulo(

%ll the patients 'ere evaluated &y means of clinical and supplementary e*aminationssuch as anamnesis, physical e*amination, fine!needle aspiration punch, oncologicalcytology, ultrasound and, 'hen indicated, mammography(

e 'ere only a&le to ma/e complete o&servations on 11 patients, and this may haveadversely affected our results, since this caused a decrease in the statistical po'er ofthe study, considering that a total of 1- patients 'ere lost( %mong the reasons forthese losses over the course of the study period 'ere the num&er of consultation that

the patients needed to attend in order to reach an indication for surgeryJ1

their lac/ ofresources for coming to our clinicJ and their lac/ of motivation caused &y the small&enefit attained through the use of medication(

)he patients 'ere randomly divided into t'o groups, 'hich 'ere made up as follo's(Group . control" consisted of .3 'omen 'ith delineated fi&roadenoma, 'ho used oralcontraceptive constituted &y levonorgestrel 3(.4 mg" and ethinyl estradiol 3(31 mg"together 'ith place&o inside the same capsule, for up to four consecutive cycles 'ithseven!day intervals &et'een them( Group 0 consisted of 01 patients 'ho also had&enign &reast tumors and 'ho too/ the same oral contraceptive, &ut 'ith 0 mg ofestriol instead of the place&o, manufactured in the same capsule, for up to fourconsecutive cycles( )he randomi$ation into these t'o groups for su&seected to histopathologicaland immunohistochemical procedures(

3I-TO,AT3OLOGICAL 2ET3O/-

)he samples collected 'ere fi*ed in .3 &uffered formol and then dehydrated in ethylalcohol, diaphani$ed in *ylol and em&edded in paraffin &loc/s( e made serial thinsections &y means of microtomy and then made these up into slides( )hese slides 'eresent for immunohistochemical analysis in order to evaluate the +i!- and c!myce*pression(


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I224NO3I-TOC3E2ICAL 2ET3O/

e mounted sections of 1 m in thic/ness on slides and left them to dry in an oven for.0 hours( )hey 'ere then deparaffini$ed 'ith su&se


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)he t'o groups 'ere homogeneous 'ith regard to the varia&les that might act on thecellular /inetics of fi&roadenomas age, pregnancies, parity and a&ortions", as sho'nin )a&le .(

)a&les 0 to 4 sho' the percentages of stained nuclei of epithelial cells in investigating+i!- and c!myc antigens, in relation to the total num&er of nuclei analy$ed, for allpatients in the study( e also present the means and standard errors for themeasurements in groups . and 0(

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1516-31802007000600008&lng=en&tlng=en.%2010.1590/S1516-31802007000600008.#tab01http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1516-31802007000600008&lng=en&tlng=en.%2010.1590/S1516-31802007000600008.#tab02http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1516-31802007000600008&lng=en&tlng=en.%2010.1590/S1516-31802007000600008.#tab01http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1516-31802007000600008&lng=en&tlng=en.%2010.1590/S1516-31802007000600008.#tab02


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/I-C4--ION

Fi&roadenoma is a mi*ed neoplasm containing varia&le unctive tissue that has great importance, &ecause it occurs during the menacme(Some authors have considered that fi&roadenomas are a locali$ed form of nodularhyperplasia of the stroma and glandular component, i(e( a variety of fi&rocystic disease

/no'n as adenomatous hyperplasia(1 Io'ever, this condition is diffuse and does notpresent the typically nodular shapes of fi&roadenomas(1-

Sa'hney et al(05 studied fi&roadenomas and phyllodes tumors and sho'ed that aspecial relationship e*ists &et'een the mitosis in stroma and epithelial tissueconcentrations( )hey used a computeri$ed morphometric model and


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patients can &e e*plained(- Cn small num&ers of patients, this lin/ is lost andsarcomatous transformation may ta/e place 'hen the epithelium does not inhi&itstromal gro'th, or carcinomatous transformation 'hen the stroma does not &loc/epithelial proliferation &y inhi&iting gro'th factors"(

)he immunohistochemical e*pression of +i!- anti&odies MC#!." 'as studied &y

Ume/ita and Qoshida(53

)his protein is also related to the cellular cycle and to theproliferation rate in fi&roadenomas and phyllodes tumors( )hey tried to ma/e acorrelation &et'een the malignancy po'er of these tumors and discovered thatincreases in the MC#!. stromal inde* 'ere related to increases in the degree ofmalignancy, &ut that the e*pression of the anti&ody in epithelium 'as the same for all/inds of fi&roadenomas( )hey also o&served that the stromal e*pression of MC#!. inhypercellular varieties 'as 0(4 times greater than in standard fi&roadenoma( Cnrelation to phyllodes tumors, they demonstrated that there 'as lo'er e*pression of theanti&odies in epithelium and higher e*pression in stroma as the degree of malignancyincreased, thus sho'ing the importance of stromal activity for increasing the si$e ofthese tumors(

)he estrogen component of the oral contraceptives used in our study ethinyl estradiol"is /no'n to &e .33 to 033 times stronger than estradiol, 'hich is the estrogengenerally found in circulation(5. )hus, ethinyl estradiol stimulates the epithelialcompartment more strongly than estradiol does, and this action ta/es place throughmediation &y the estrogen receptors, 'hich have greater presence in fi&roadenomathan in normal tissue(1

)he greater action of ethinyl estradiol on epithelium leads it to proliferate, thus givingrise to greater e*pression of proteins relating to the cellular cycle, such as the +i!-and c!myc used in our study( Ct has also &een found that, through paracrine control,higher production of stromal gro'th inhi&itory factors may induce lo'er stromaproliferation( )he final effect is a decrease in fi&roadenoma dimensions, consideringthat the stromal compartment is responsi&le for fi&roadenoma si$e(50 )his theory 'as

corro&orated &y our findings, in 'hich 'e o&served lo'er e*pression of +i!- and c!myc 2(0 and .3(4, respectively" in group . oral contraceptive plus place&o", assho'n in )a&le (

Io'ever, the influence of oral contraceptives on fi&roadenoma is still


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estradiol on epithelium 'ith fi&roadenoma( )he mechanism for estriol action 'or/s &ycompetitive antagonism, i(e( &y &loc/ing estrogenic receptors and causing a smallerhormonal effect( Epithelium 'ith fi&roadenoma has these receptors in greater num&ersthan the stroma does(53 )hus, 'e e*pected a greater epithelial &loc/age caused &yestriol than that 'as caused &y stroma( )here might &e lo'er epithelial proliferation,'hich in turn 'ould lead to decreased production of inhi&ition gro'th factors( )hrough

the paracrine mechanism, the stroma 'ould &e less inhi&ited, 'hich 'ould then leaveit free to proliferate, there&y o&structing the overall decrease in fi&roadenomas(

7n the other hand, proliferated stroma might not only maintain the tumor dimensions'hile the cycles evolve, &ut also increase the production of gro'th factors that 'ouldact on epithelium( )his 'ould lead to epithelial proliferation and create a tendencyto'ards greater e*pression of the proteins relating to the cellular cycle +i!- and c!myc"( )his 'as seen in group 0 oral contraceptives plus estriol", in relation to group .oral contraceptives plus place&o" Figure ."(

7ur immunohistochemical analysis on +i!- and c!myc e*pression did not sho' anystatistically significant difference &et'een group . oral contraceptives plus place&o"and group 0 oral contraceptives plus estriol"( %ll 'e sa' 'as a tendency to'ardsgreater e*pression of these proteins in the group 0 patients( e surmised that estriol

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1516-31802007000600008&lng=en&tlng=en.%2010.1590/S1516-31802007000600008.#fig01http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1516-31802007000600008&lng=en&tlng=en.%2010.1590/S1516-31802007000600008.#fig01


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&loc/ed the ethinyl estradiol in the oral contraceptives, particularly in the epithelialcompartment, there&y inducing lo'er proliferation of this compartment and leading toa lo'er production of stroma!inhi&iting gro'th factors, 'hich /ept the stromaproliferated( Cn the end, the proliferated stroma produced gro'th factors that acted onepithelium to /eep it in a higher proliferated condition, there&y demonstrating atendency to'ards greater e*pression of proteins related to proliferation among the

users of oral contraceptives plus estriol group 0"( )his 'as demonstrated &y thefindings sho'n in )a&le , in 'hich the results for +i!- and c!myc 'ere 2(0 and .3(4for group . oral contraceptives plus place&o" and .3(6 and .- for group 0 oralcontraceptives plus estriol", respectively( Io'ever, 'e did not find any statisticalsignificance &ut only a tendency of &ehavior(

CONCL4-ION

)he 'omen 'ho used hormonal oral contraception com&ined 'ith estriol for fourconsecutive cycles sho'ed +i!- and c!myc protein e*pression in epithelium 'ith

fi&roadenoma that 'as similar to the e*pression sho'n &y the 'omen 'ho usedhormonal oral contraception 'ith place&o for four cycles( Bevertheless, there 'as agreater tendency to'ards e*pression of these proteins among the users of oralcontraceptives 'ith estriol(

RE%ERENCE-

.( Dent DM, 8ant P( Fi&roadenoma( orld Surg( .262J.1"N-3!.3( R Lin/s

0( %lle +M, Moss , Tenegas H, +hal/hali C, +lein SH( 8onservative management of

fi&roadenoma of the &reast( #r Surg( .22J61-"N220!1( R Lin/s

1( Green&erg H, S/ornic/ Q, +aplan 7( Management of &reast fi&roadenomas( GenCntern Med( .226J.12"N53!4( R Lin/s

5( Funder&ur/ , Hosero E, Leffall LD( #reast lesions in &lac/s( Surg Gynecol 7&stet(.2-0J.14."N46!3( R Lin/s

4( Bigro DM, 7rgan 8I r( Fi&roadenoma of the female &reast( Some epidemiologicsurprises( Postgrad Med( .2-J424"N..1!-( R Lin/s

( #arto' S%, Patha/ DH, #lac/ 8, +ey 8H, )eaf SH( Prevalence of &enign, atypical,

and malignant &reast lesions in populations at different ris/ for &reast cancer( %forensic autopsy study( 8ancer( .26-J3.."N0-4.!3( R Lin/s

-( Iaagensen 8D( Diseases of the &reast( 1rd ed( PhiladelphiaN # SaundersJ.26( R Lin/s

6( 8arty B, 8arter 8, Hu&in 8, Havichandran D, Hoyle G), )aylor C( Management offi&roadenoma of the &reast( %nn H 8oll Surg Engl( .224J--0"N.0-!13( R Lin/s

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2( il/inson S, %nderson ), Hif/ind E, 8hetty U, Forrest %P( Fi&roadenoma of the&reastN a follo'!up of conservative management( #r Surg( .262J-5"N123!.( R Lin/s

.3( Sitru/!'are LH, Ster/ers B, Mo's$o'ich C, Mauvais!arvis P( Cnade


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01( Gerdes , Sch'a& U, Lem/e I, Stein I( Production of a mouse monoclonalanti&ody reactive 'ith a human nuclear antigen associated 'ith cell proliferation( Cnt 8ancer( .261J1.."N.1!03( R Lin/s

05( Sa'hney B, Iall P%( +i!-!!structure, function, and ne' anti&odies( Pathol(.220J.60"N..!0( R Lin/s

04( #ishop M( Hetroviruses and cancer genes( %dv 8ancer Hes( .260J1-N.!10( R Lin/s

0( %mati #, %levi$opoulos +, Tlach ( Myc and the cell cycle( Front #iosci(.226J1Nd043!6( R Lin/s

0-( Dues&erg PI, #ister +, Togt P+( )he HB% of avian acute leu/emia virus M802( ProcBatl %cad Sci U S %( .2--J-5.3"N5103!5( R Lin/s

06( Beel #G, han'ar S8, 8haganti HS, Iay'ard S( )'o human c!onc genes arelocated on the long arm of chromosome 6( Proc Batl %cad Sci U S %(.260J-205"N-650!( R Lin/s

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Efficacy of Estriol in Inhibiting Epithelial Proliferation in Mammary Fibroadenoma

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