龐華靖
(丹江口市衛(wèi)生學(xué)校附屬醫(yī)院檢驗科,湖北 442700)
三陰性乳腺癌與雄激素的相關(guān)性研究
龐華靖
(丹江口市衛(wèi)生學(xué)校附屬醫(yī)院檢驗科,湖北 442700)
目的探討三陰性乳腺癌與非三陰性乳腺癌患者間睪酮和雄激素受體(AR)水平的差異及臨床意義。方法按照納入標(biāo)準(zhǔn)選取該院經(jīng)病理確證為原發(fā)性乳腺癌的患者,共92例女性患者,其中三陰性乳腺癌42例,非三陰性乳腺癌50例,統(tǒng)計分析三陰性與非三陰性乳腺組患者年齡、組織學(xué)分級、病理分期、血清睪酮水平和AR的差異。結(jié)果三陰性乳腺癌組和非三陰性乳腺癌組比較,三陰性乳腺癌組血清睪酮水平低于非三陰性乳腺癌組,差異有統(tǒng)計學(xué)意義(P<0.05);三陰性乳腺癌組AR陽性率為57%,非三陰性乳腺癌AR陽性率為82%,差異有統(tǒng)計學(xué)意義(P<0.05)。結(jié)論雄激素和AR可能成為三陰性乳腺癌新的治療突破點。
睪酮; 雄激素; 雄激素受體; 三陰性乳腺癌
乳腺癌是一種激素依賴性腫瘤,多數(shù)研究認(rèn)為其發(fā)病率的增加與雌激素有關(guān)[1],雌激素受體(ER),孕激素受體(PR)已成為了臨床病理常規(guī)檢測項目,根據(jù)ER,PR,人類表皮生長因子受體2(HER2)的表達(dá)水平,將乳腺癌分為了三陰性乳腺癌和非三陰性乳腺癌。然而,雄激素和雄激素受體(AR)在乳腺癌生物學(xué)中的作用以往一直是臨床上和基礎(chǔ)研究中被忽略的領(lǐng)域[2]。目前,已有多項研究關(guān)注乳腺癌與睪酮的關(guān)系[3-6],而關(guān)于睪酮與三陰性乳腺癌和非三陰性乳腺癌之間的研究,少見報道。本研究旨在分析三陰性乳腺癌和非三陰性乳腺癌之間血清睪酮水平和AR的差異,以發(fā)現(xiàn)治療三陰性乳腺癌新突破點。
1.1 一般資料 選取2011年1月至2013年12月于本院就診的乳腺癌患者,納入條件:在本院首次診斷為原發(fā)性乳腺癌的患者;未行手術(shù)及化療前檢測了血清睪酮水平;無其他伴發(fā)疾??;未服用性激素類藥物;非少數(shù)民族;病理類型為浸潤性乳腺癌。共有三陰性乳腺癌患者42例納入研究,年齡范圍29~73歲,平均(45.75±9.24)歲。另外從同期符合納入條件的非三陰性乳腺癌患者中隨機抽取50例作為非三陰性乳腺癌組,年齡范圍30~64歲,平均(46.98±8.78)歲。
1.2 方法
1.2.1 血清標(biāo)本采集 采集空腹靜脈血2~3mL,4h內(nèi)分離血清后置-20℃冰箱保存待測。一次性復(fù)融后用化學(xué)發(fā)光法測定血清睪酮水平,試劑為美國DPC公司提供的原裝試劑,儀器為美國DPC公司的Immulite發(fā)光儀。
1.2.2 組織學(xué)分級方法及病理分期 使用Nottingham聯(lián)合組織學(xué)分級方法進行組織學(xué)分級;使用美國癌癥聯(lián)合委員會,乳腺癌TNM分期方法進行病理分期。
1.2.3 免疫組化檢測AR 采用免疫組化SP法檢測92例乳腺癌石蠟組織中AR的陽性表達(dá)情況,并分析三陰性乳腺癌和非三陰性乳腺癌的陽性表達(dá)的差異。主要免疫組化試劑包括兔抗磷酸化AR(Ser578)多克隆抗體,購自北京博奧森生物技術(shù)有限公司。
1.3 統(tǒng)計學(xué)處理 采用Excel 2003軟件錄入三陰性乳腺癌組及非三陰性乳腺組共計92例患者的年齡、組織學(xué)分級、病理分期、血清睪酮水平和AR免疫組化結(jié)果,導(dǎo)入SPSS17.0統(tǒng)計軟件,統(tǒng)計學(xué)檢驗水準(zhǔn)ɑ=0.05?;祀s因素控制方法:采用兩獨立樣本t檢驗檢測兩組樣本年齡總體均數(shù)是否存在差異,采用完全隨機設(shè)計行×列表資料的χ2檢驗檢測兩組樣本組織學(xué)分級,病理分期總體分布是否存在差異。采用完全隨機設(shè)計兩樣本資料的秩和檢驗分析三陰性乳腺癌組和非三陰性乳腺癌組血清睪酮水平總體分布是否存在差異。采用χ2檢驗分析三陰性乳腺癌組和非三陰性乳腺癌組AR陽性率是否存在差異。
2.1 兩組年齡、組織學(xué)分級和病理分期的比較 經(jīng)兩獨立樣本t檢驗分析,兩組年齡總體均數(shù)比較,差異無統(tǒng)計學(xué)意義(P=0.966);兩組樣本組織學(xué)分級構(gòu)成分布比較,差異無統(tǒng)計學(xué)意義(P=0.390);兩組臨床分期構(gòu)成分布比較,差異無統(tǒng)計學(xué)意義(P=0.293),見表1。
2.2 兩組樣本血清睪酮水平 三陰性乳腺癌組和非三陰性乳腺癌組血清睪酮水平比較,三陰性乳腺癌組血清睪酮水平低于非三陰性乳腺癌組,差異有統(tǒng)計學(xué)意義(P=0.032<0.05)。
2.3 兩組AR陽性率的比較 顯示三陰性乳腺癌與非三陰性乳腺癌AR陽性率比較,三陰性乳腺癌組的AR陽性率低于非三陰性乳腺癌組,差異有統(tǒng)計學(xué)意義(P<0.05),見表2。
乳腺癌的發(fā)生發(fā)展與體內(nèi)性激素的水平密切相關(guān)。有研究認(rèn)為雄激素對于乳腺細(xì)胞起到一種保護作用,過表達(dá)AR明顯地抑制雌激素途徑引起的乳腺上皮細(xì)胞增殖,但乳腺癌MCF-7細(xì)胞如轉(zhuǎn)染突變的AR,則沒有此現(xiàn)象[7]。Dimitrakakis等[8]在動物實驗中發(fā)現(xiàn),正常雌性猴子在接受AR拮抗劑使AR阻斷后,乳腺上皮細(xì)胞發(fā)生兩倍以上的增殖,此外在卵巢切除的猴子給予標(biāo)準(zhǔn)劑量的雌激素替代治療中,生理劑量的雄激素能夠減少雌激素引起的乳腺上皮細(xì)胞增殖,進一步證實雄激素是通過降低ERa、提高ERI3表達(dá)而參與保護乳腺上皮細(xì)胞的。
本研究中,為了排除由于三陰性乳腺癌組和非三陰性乳腺癌組兩樣本之間年齡、組織學(xué)分級、病理分期的不同而導(dǎo)致的誤差,故做了相應(yīng)統(tǒng)計學(xué)分析,統(tǒng)計分析顯示兩組之間年齡、組織學(xué)分級、病理分期的差異無統(tǒng)計學(xué)意義(P>0.05),兩組間血清睪酮水平比較,三陰性乳腺癌組低于非三陰性乳腺癌組,差異有統(tǒng)計學(xué)意義(P<0.05)。免疫組化顯示三陰性乳腺癌組AR陽性率低于非三陰性乳腺癌組,差異有統(tǒng)計學(xué)意義(P<0.05)。從三陰性乳腺癌組血清睪酮水平和AR陽性率均低于非三陰性乳腺癌組可推測雄激素對乳腺癌患者而言中是一種有利的因素,與文獻報道相符[7-8]。雄激素和AR可能成為三陰性乳腺癌新的治療突破點。
臨床上,雄激素可用于對雌激素治療失敗的乳腺癌,這說明雄激素的作用不單純是針對垂體促性腺激素的分泌,還可能通過直接的作用抑制腫瘤細(xì)胞的生長。雄激素一般與靶器官上的AR結(jié)合后方能發(fā)揮其作用[9]。已有的文獻報道,AR在乳腺癌中的表達(dá)率為35%~90%[10-11],與ER或PR的表達(dá)相當(dāng)甚至高于這兩者[12-13]。AR在乳腺癌中多表現(xiàn)為:腫瘤體積小的陽性率高;淋巴結(jié)無轉(zhuǎn)移的陽性率高;組織學(xué)分級低的陽性率高;ER、PR陽性的陽性率高等[14-17]。這預(yù)示著在腫瘤發(fā)現(xiàn)越早、惡性程度越低的情況下AR的表達(dá)陽性率就越高,AR陽性者可能預(yù)示著乳腺癌患者預(yù)后較好。Boccuzzi等[18]曾報道大劑量(200nmol/L)雙氫睪酮(DHT)有通過ER介導(dǎo)的刺激MCF-7細(xì)胞增生的作用,小劑量DHT則起抑制作用。
目前,已有相當(dāng)部分研究證實了AR在乳腺癌以及在三陰性乳腺癌中的作用。最新研究發(fā)現(xiàn),AR陰性的三陰性乳腺癌能夠提示較早復(fù)發(fā)的可能性[19],采用最低毒性劑量的雄激素抗體比卡魯胺治療AR陽性,雌、孕激素陰性的轉(zhuǎn)移性乳腺癌具有19%的臨床獲益率[20],AR可能成為三陰性乳腺癌的一種預(yù)后標(biāo)志物[21],但是這幾項研究均未列入非三陰性乳腺癌或雌、孕激素陽性的乳腺癌患者作為對照。
本研究以非三陰性乳腺癌作為對照,研究了三陰性乳腺癌的睪酮水平和AR陽性率,為將來研究雄激素和AR與三陰性和非三陰性乳腺癌的關(guān)系打下基礎(chǔ),探索發(fā)現(xiàn)雄激素和AR成為三陰性乳腺癌新的治療靶點。
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The correlation between triple negative breast cancer and androgen
Pang Huajing
(Department of Clinical Laboratory,Affiliated Hospital of Health school of Danjiangkou City,Danjiangkou,Hubei 442700,China)
ObjectiveTo investigate the difference of serum testosterone and androgen receptor(AR)concentrations between triple negative breast cancer patients and non-triple negative breast cancer patients and its clinical significance.differences and clinical significance.MethodsAccording to the inclusion criteria,a total of 92female patients were enrolled in the study including 42 patients with triple negative breast cancer and 50patients with non-triple negative breast cancer.The patients recruited all seeked medical advice in hospital and diagnosed with primary breast cancer by using pathological method.Age,histological grade,pathological stage,serum testosterone and AR concentrations were compared between triple negative breast and non-triple-negative group and statistically analyzed.ResultsCompared between triple negative breast and non-triple-negative group,the serum testosterone concentrations of triple negative breast was lower and the difference were statistically different(P<0.05);AR-positive rate of triple negative breast cancer group was 57%,AR-positive rate of non-triple-negative breast cancer was 82%,the difference was statistically significant(P<0.05).ConclusionAndrogen and AR may be a prognostic therapeutic target in triple negative breast cancer.
testosterone; androgen; androgen receptor; triple negative breast cancer
10.3969/j.issn.1673-4130.2015.03.019
A
1673-4130(2015)03-0331-03
2014-10-15)
龐華靖,男,主管檢驗師,主要從事臨床檢驗研究。