Statin-induced anti-proliferative effects via cyclin D1 and p27 in a window-of-opportunity breast cancer trial.
Statin-induced anti-proliferative effects via cyclin D1 and p27 in a window-of-opportunity breast cancer trial.
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DOI：
10.1186/s12967-015-0486-0
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发表时间：
2015-04-29
影响因子：
7.4
通讯作者：
Borgquist S
中科院分区：
文献类型：
--
作者：
Feldt M;Bjarnadottir O;Kimbung S;Jirström K;Bendahl PO;Veerla S;Grabau D;Hedenfalk I;Borgquist S
降低胆固醇的他汀类药物已被证明对乳腺癌发挥抗肿瘤作用，通过Ki67测量减少增殖。抗增殖作用背后的生物学机制仍然难以捉摸。本研究的目的是研究他汀类药物对中枢细胞周期调节因子cyclin D1和p27的潜在影响。该II期机会窗口试验（试验注册：ClinicalTrials.gov NCT00816244， NIH）纳入了50例原发性浸润性乳腺癌患者。术前两周给患者开大剂量阿托伐他汀（80mg /天）。免疫组化分析他汀类药物治疗前后石蜡包埋的肿瘤标本中雌激素受体（ER）、孕激素受体（PR）、人表皮生长因子受体2 （HER2）以及细胞周期调节因子cyclin D1和p27的表达。分析相应的冷冻肿瘤样本对分别编码cyclin D1和p27、CCND1和CDKN1B基因的表达情况。42例患者完成了所有研究部分，30对肿瘤中ER和PR获得免疫组化评价，29对肿瘤中HER2获得免疫组化评价，30对肿瘤中cyclin D1获得免疫组化评价，33对肿瘤中p27免疫组化评价。ER、PR和HER2的表达在阿托伐他汀治疗后无明显变化。配对肿瘤样本中，他汀类药物治疗后Cyclin D1的核强度表达显著降低（P = 0.008）。肿瘤抑制因子p27的蛋白表达，无论是以染色肿瘤细胞的比例还是以细胞质强度来评估，都显著增加（P = 0.03和P = 0.02）。在转录水平上，细胞周期蛋白D1 （CCND1）和p27 （CDKN1B）的mRNA表达无显著差异。然而，CCND1在阿托伐他汀治疗的肿瘤中表达较低，增殖减少，但不显著（P = 0.08）。我们之前报道过他汀类药物在乳腺癌中的抗增殖作用。本研究提示细胞周期调节作用可能通过细胞周期蛋白D1和p27参与这些抗增殖作用。本文的在线版本（doi:10.1186/s12967-015-0486-0）包含补充材料，可供授权用户使用。
Cholesterol lowering statins have been demonstrated to exert anti-tumoral effects on breast cancer by decreasing proliferation as measured by Ki67. The biological mechanisms behind the anti-proliferative effects remain elusive. The aim of this study was to investigate potential statin-induced effects on the central cell cycle regulators cyclin D1 and p27. This phase II window-of-opportunity trial (Trial registration: ClinicalTrials.gov NCT00816244, NIH) included 50 patients with primary invasive breast cancer. High-dose atorvastatin (80 mg/day) was prescribed to patients for two weeks prior to surgery. Paired paraffin embedded pre- and post-statin treatment tumor samples were analyzed using immunohistochemistry for the expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and the cell cycle regulators cyclin D1 and p27. Corresponding frozen tumor sample pairs were analyzed for expression of the genes coding for cyclin D1 and p27, CCND1 and CDKN1B, respectively. Forty-two patients completed all study parts, and immunohistochemical evaluation of ER and PR was achievable in 30 tumor pairs, HER2 in 29 tumor pairs, cyclin D1 in 30 tumor pairs and p27 in 33 tumor pairs. The expression of ER, PR and HER2 did not change significantly following atorvastatin treatment. Cyclin D1 expression in terms of nuclear intensity was significantly decreased (P = 0.008) after statin treatment in paired tumor samples. The protein expression of the tumor suppressor p27, evaluated either as the fraction of stained tumor cells or as cytoplasmic intensity, increased significantly (P = 0.03 and P = 0.02, respectively). At the transcriptional level, no significant differences in mRNA expression were detected for cyclin D1 (CCND1) and p27 (CDKN1B). However, CCND1 expression was lower in tumors responding to atorvastatin treatment with a decrease in proliferation although not significantly (P = 0.08). We have previously reported statin-induced anti-proliferative effects in breast cancer. This study suggests that cell cycle regulatory effects may contribute to these anti-proliferative effects via cyclin D1 and p27. The online version of this article (doi:10.1186/s12967-015-0486-0) contains supplementary material, which is available to authorized users.
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DOI：
10.1158/1055-9965.epi-13-0562
发表时间：
2013-10
期刊：
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
影响因子：
--
作者：
Desai P;Chlebowski R;Cauley JA;Manson JE;Wu C;Martin LW;Jay A;Bock C;Cote M;Petrucelli N;Rosenberg CA;Peters U;Agalliu I;Budrys N;Abdul-Hussein M;Lane D;Luo J;Park HL;Thomas F;Wactawski-Wende J;Simon MS
通讯作者：
Simon MS
影响因子：
3.8
作者：
Garwood, Elisabeth R.;Kumar, Anjali S.;Baehner, Frederick L.;Moore, Dan H.;Au, Alfred;Hylton, Nola;Flowers, Chris I.;Garber, Judy;Lesnikoski, Beth-Ann;Hwang, E. Shelley;Olopade, Olofunmilao;Port, Elisa Rush;Campbell, Michael;Esserman, Laura J.
通讯作者：
Esserman, Laura J.
DOI：
10.1016/s1470-2045(14)70119-6
发表时间：
2014-09
期刊：
The Lancet. Oncology
影响因子：
--
作者：
Ahern TP;Lash TL;Damkier P;Christiansen PM;Cronin-Fenton DP
通讯作者：
Cronin-Fenton DP
p27（Kip1）作为乳腺癌的预后因素：系统评价和荟萃分析。
影响因子：
5.3
作者：
Guan X;Wang Y;Xie R;Chen L;Bai J;Lu J;Kuo MT
通讯作者：
Kuo MT
影响因子：
2.1
作者：
Irizarry, RA;Hobbs, B;Speed, TP
通讯作者：
Speed, TP