本文選題：乳腺癌 + PI3K　； 參考：《中國(guó)科學(xué)院大學(xué)(中國(guó)科學(xué)院上海藥物研究所)》2016年博士論文

【摘要】：PI3K信號(hào)通路參與細(xì)胞存活、生長(zhǎng)、增殖和代謝等重要過(guò)程,在多種不同組織來(lái)源的腫瘤中異常活化。其中,約有70%的乳腺癌發(fā)生PI3K信號(hào)通路高度活化,編碼PI3Kα催化亞基的PIK3CA基因突變率高達(dá)30%,散布于所有乳腺癌類(lèi)型。大量分子生物學(xué)和遺傳學(xué)研究證明PI3Kα異常激活能夠促進(jìn)乳腺癌發(fā)生發(fā)展,而抑制PI3K活性能夠阻止乳腺癌形成和發(fā)展,因此PI3Kα是乳腺癌治療的重要靶標(biāo)。目前,國(guó)際上已有多個(gè)泛PI3K抑制劑和四個(gè)PI3Kα選擇性抑制劑進(jìn)入臨床試驗(yàn)以單藥或聯(lián)合用藥形式治療不同類(lèi)型乳腺癌,顯示出良好的應(yīng)用前景。因此,研究和開(kāi)發(fā)新的具有我國(guó)自主知識(shí)產(chǎn)權(quán)的新型PI3Kα選擇性抑制劑具有重要意義。已有的臨床試驗(yàn)數(shù)據(jù)顯示PI3Kα選擇性抑制劑對(duì)乳腺癌的療效顯示出較大差異性,在部分患者中療效顯著。因此,發(fā)現(xiàn)和確證預(yù)測(cè)PI3Kα抑制劑療效的生物標(biāo)志物是促進(jìn)PI3Kα選擇性抑制劑研究和開(kāi)發(fā)以及提高療效的重要策略。本研究的目的是系統(tǒng)性地探索本實(shí)驗(yàn)室發(fā)現(xiàn)的新結(jié)構(gòu)PI3Kα選擇性抑制劑CYH33抗乳腺癌作用;探索能夠預(yù)測(cè)PI3Kα抑制劑在乳腺癌中抗腫瘤療效的生物標(biāo)志物。CYH33是本實(shí)驗(yàn)室前期研究工作發(fā)現(xiàn)的全新PI3Kα選擇性抑制劑,能夠廣泛抑制多種組織來(lái)源腫瘤細(xì)胞的增殖。通過(guò)檢測(cè)CYH33對(duì)一系列乳腺癌細(xì)胞的增殖抑制作用,我們發(fā)現(xiàn)低濃度CYH33即能夠顯著抑制多種乳腺癌細(xì)胞增殖,其活性與泛PI3K抑制劑GDC0941相當(dāng),優(yōu)于處于III期臨床試驗(yàn)的同類(lèi)型抑制劑BYL719。以對(duì)CYH33敏感的T47D和MCF-7細(xì)胞以及對(duì)CYH33耐受的MDA-MB-231細(xì)胞為例,我們初步探索了CYH33抑制乳腺癌細(xì)胞增殖的作用機(jī)制。CYH33能夠濃度依賴(lài)性且同等程度地抑制T47D、MCF-7和MDA-MB-231細(xì)胞中PI3K下游蛋白激酶AKT磷酸化。CYH33能夠下調(diào)敏感乳腺癌細(xì)胞中m TORC1下游p70S6K和S6磷酸化水平,而在耐受乳腺癌細(xì)胞中無(wú)此作用。在敏感乳腺癌細(xì)胞中,CYH33通過(guò)下調(diào)Rb磷酸化和cyclin D1含量以及p27累積,將細(xì)胞阻滯于G1期從而發(fā)揮細(xì)胞增殖抑制作用,而在耐受乳腺癌細(xì)胞中CYH33對(duì)細(xì)胞周期分布影響微弱。CYH33作用72小時(shí)不能誘導(dǎo)敏感或耐受乳腺癌細(xì)胞發(fā)生凋亡。因此,CYH33主要通過(guò)將細(xì)胞阻滯于G1期發(fā)揮細(xì)胞增殖抑制作用,而AKT磷酸化下調(diào)不能夠預(yù)測(cè)乳腺癌細(xì)胞對(duì)CYH33的敏感性。與體外CYH33顯著的乳腺癌細(xì)胞增殖抑制作用一致,CYH33能夠有效地抑制T47D SCID小鼠移植瘤和PIK3CAH1047R基因工程小鼠自發(fā)瘤的生長(zhǎng),且活性?xún)?yōu)于BYL719。此外,CYH33和BYL719長(zhǎng)期作用于乳腺癌模型動(dòng)物對(duì)小鼠體重和血糖調(diào)節(jié)功能影響不大,均在安全范圍之內(nèi)。我們初步分析了不同分子分型乳腺癌細(xì)胞對(duì)CYH33的敏感性,發(fā)現(xiàn)管腔型和HER2擴(kuò)增型乳腺癌細(xì)胞對(duì)CYH33更加敏感,而基底樣乳腺癌細(xì)胞對(duì)CYH33耐受。分析PI3K信號(hào)通路內(nèi)關(guān)鍵分子改變與乳腺癌細(xì)胞對(duì)CYH33敏感性的關(guān)系,我們發(fā)現(xiàn)PIK3CA突變和HER2分子擴(kuò)增的乳腺癌細(xì)胞對(duì)CYH33更加敏感,而PTEN缺失的乳腺癌細(xì)胞對(duì)CYH33耐受。盡管乳腺癌細(xì)胞不同分子分型或PI3K信號(hào)通路內(nèi)關(guān)鍵蛋白分子改變與乳腺癌細(xì)胞對(duì)CYH33的敏感性存在一定的相關(guān)性,部分基底樣乳腺癌細(xì)胞或PI3K信號(hào)通路正常的乳腺癌細(xì)胞對(duì)CYH33敏感。因此,探索基于作用機(jī)制的PI3Kα選擇性抑制劑療效預(yù)測(cè)生物標(biāo)志物是提高該類(lèi)抑制劑療效的重要策略。PI3K和MAPK信號(hào)通路是參與調(diào)節(jié)乳腺癌細(xì)胞增殖的兩條關(guān)鍵信號(hào)通路,二者存在廣泛的交互通話(huà),抑制其中一條信號(hào)通路通常引起另一條信號(hào)通路的反饋性激活,提示同時(shí)靶向兩條信號(hào)通路有希望達(dá)到更顯著的抗腫瘤療效。我們發(fā)現(xiàn)CYH33能夠同時(shí)下調(diào)T47D細(xì)胞中AKT和ERK磷酸化,進(jìn)一步研究CYH33這一作用機(jī)制有可能揭示其與CYH33抗腫瘤活性之間的關(guān)系。以敏感乳腺癌T47D和MCF-7細(xì)胞為研究對(duì)象,多個(gè)PI3K抑制劑能夠同時(shí)抑制AKT和ERK磷酸化,而PDK1、AKT和m TORC抑制劑在發(fā)揮靶標(biāo)抑制作用的同時(shí)對(duì)ERK磷酸化影響微弱甚至升高ERK磷酸化水平,表明PI3K調(diào)節(jié)ERK磷酸化不依賴(lài)其經(jīng)典PDK1/AKT/m TOR下游信號(hào)通路。抑制RAF和MEK引起ERK磷酸化下調(diào),而高表達(dá)RAF和MEK拮抗PI3K抑制劑對(duì)ERK磷酸化的抑制,表明PI3K調(diào)節(jié)ERK磷酸化依賴(lài)Raf/Mek。進(jìn)一步研究發(fā)現(xiàn)RAS活性不受PI3K抑制劑影響,但是高表達(dá)RAS能夠逆轉(zhuǎn)PI3K抑制劑對(duì)ERK磷酸化的抑制作用,表明PI3K和RAS二者協(xié)同調(diào)節(jié)ERK磷酸化。激活細(xì)胞內(nèi)EGFR活性能夠升高胞內(nèi)RAS-GTP含量繼而阻止PI3K抑制劑對(duì)ERK磷酸化的抑制,進(jìn)一步確證了PI3K和RAS在調(diào)節(jié)ERK磷酸化中發(fā)揮的協(xié)同作用,同時(shí)表明低活性的EGFR使ERK磷酸化依賴(lài)PI3K,高活性的EGFR使ERK磷酸化依賴(lài)RAS�；贓GFR的活性能夠決定ERK磷酸化是否依賴(lài)于PI3K,我們研究了在乳腺癌組織中頻繁高表達(dá)的受體酪氨酸激酶IGF-1R、HER3、FGFR和c-MET在PI3K調(diào)節(jié)ERK磷酸化中發(fā)揮的作用。激活EGFR、HER3、FGFR和/或c-MET活性能夠拮抗BYL719對(duì)乳腺癌細(xì)胞T47D、MCF-7和HCC1954中ERK磷酸化的抑制,而且能夠部分逆轉(zhuǎn)BYL719對(duì)相應(yīng)乳腺癌細(xì)胞的增殖抑制作用。然而,激活I(lǐng)GF-1R并未觀察到上述現(xiàn)象。我們檢測(cè)了一系列乳腺癌細(xì)胞中RTKs表達(dá)譜和PI3K抑制劑對(duì)其AKT和ERK磷酸化的影響,發(fā)現(xiàn)在PI3K抑制劑能夠同時(shí)下調(diào)AKT和ERK磷酸化的乳腺癌細(xì)胞(該類(lèi)細(xì)胞定義為A組)中,受體酪氨酸激酶IGF-1R和HER2表達(dá)水平較高,EGFR和c-MET表達(dá)水平較低;相反地,在PI3K抑制劑能夠抑制AKT磷酸化但不抑制ERK磷酸化的乳腺癌細(xì)胞(該類(lèi)細(xì)胞定義為B組)中,受體酪氨酸激酶EGFR和c-MET表達(dá)水平較高,而IGF-1R和HER2表達(dá)水平較低。統(tǒng)計(jì)分析A、B兩組乳腺癌細(xì)胞對(duì)PI3Kα抑制劑CYH33和BYL719的敏感性差異,我們發(fā)現(xiàn)A組乳腺癌細(xì)胞對(duì)CYH33和BYL719更加敏感。在此基礎(chǔ)之上,我們考察了乳腺癌細(xì)胞中RTKs表達(dá)量與PI3Kα抑制劑對(duì)其增殖抑制活性之間的相關(guān)性,發(fā)現(xiàn)EGFR和c-MET表達(dá)水平與PI3Kα抑制劑增殖抑制活性呈負(fù)相關(guān)性,即乳腺癌細(xì)胞內(nèi)EGFR和c-MET表達(dá)水平越高,其對(duì)PI3Kα抑制劑更加耐受;而HER2和IGF-1R表達(dá)水平與其呈正相關(guān)性,即乳腺癌細(xì)胞內(nèi)HER2和IGF-1R表達(dá)水平越高,其對(duì)PI3Kα抑制劑更敏感。BYL719對(duì)三例病人來(lái)源的乳腺癌移植瘤(PDX)的生長(zhǎng)抑制活性與腫瘤組織RTKs表達(dá)量之間的關(guān)系進(jìn)一步驗(yàn)證了RTKs表達(dá)譜合力決定乳腺癌對(duì)PI3Kα選擇性抑制劑的敏感性。綜上,我們發(fā)現(xiàn)CYH33具有顯著的體內(nèi)外抗腫瘤活性,且活性?xún)?yōu)于處于III期臨床試驗(yàn)的同類(lèi)抑制劑BYL719,有希望成為我國(guó)第一個(gè)具有自主知識(shí)產(chǎn)權(quán)的PI3Kα選擇性抑制劑。我們發(fā)現(xiàn)乳腺癌細(xì)胞/組織中RTKs表達(dá)譜決定PI3K對(duì)ERK磷酸化和活性的調(diào)控,從而決定乳腺癌對(duì)PI3Kα選擇性抑制劑的敏感性。其中IGF-1R和/或HER2高表達(dá),EGFR,c-MET和/或FGFR1低表達(dá)預(yù)示PI3K調(diào)節(jié)ERK活性,乳腺癌對(duì)PI3K抑制劑敏感;相反地,IGF-1R和/或HER2低表達(dá),EGFR,c-MET和/或FGFR1高表達(dá)預(yù)示ERK磷酸化不依賴(lài)PI3K,乳腺癌對(duì)PI3K抑制劑耐受。因此,RTKs表達(dá)譜有希望成為預(yù)測(cè)乳腺癌患者對(duì)PI3Kα抑制劑響應(yīng)的生物標(biāo)志物,為PI3Kα抑制劑臨床患者的選擇提供依據(jù)。
[Abstract]:PI3K signaling pathway plays an important role in cell survival, growth, proliferation and metabolism, and is abnormally activated in a variety of different tissue sources. About 70% of breast cancers are highly activated by PI3K signaling pathway, and the PIK3CA gene mutation rate of the encoded PI3K a catalytic subunit is up to 30%, scattered in all types of breast cancer. A large number of molecular biology And genetic studies have shown that abnormal activation of PI3K a can promote the development of breast cancer, and the inhibition of PI3K activity can prevent the formation and development of breast cancer. Therefore, PI3K alpha is an important target for the treatment of breast cancer. Currently, there are many universal PI3K inhibitors and four PI3K alpha selective suppressor agents entering clinical trials with single or combined drug use. It is of great significance to study and develop new PI3K alpha selective inhibitors with independent intellectual property rights in China. The clinical trial data show that PI3K alpha selective inhibitors have a greater difference in the efficacy of breast cancer and are treated in some patients. Therefore, the discovery and confirmation of the biomarkers for predicting the efficacy of PI3K alpha inhibitors is an important strategy to promote the study and development of PI3K alpha selective inhibitors and to improve the efficacy of this study. The purpose of this study is to systematically explore the effect of the new structure of the new PI3K a selective inhibitor, CYH33, on the anti breast cancer effect found in our laboratory, and to explore the prediction of PI3K The biomarker of the antitumor effect of alpha inhibitor in breast cancer,.CYH33, is a new PI3K alpha selective inhibitor found in the previous research work in our laboratory. It can widely inhibit the proliferation of tumor cells from a variety of tissue sources. By detecting the proliferation inhibition effect of CYH33 on a series of breast cancer cells, we found that low concentration of CYH33 is capable of being able to inhibit the proliferation of a series of breast cancer cells. The proliferation of multiple breast cancer cells was significantly inhibited, and its activity was equivalent to that of the pan PI3K inhibitor GDC0941. It was superior to the same type of inhibitor BYL719. in III clinical trials, as an example of CYH33 sensitive T47D and MCF-7 cells and MDA-MB-231 cells tolerant to CYH33. We initially explored the mechanism.CYH33 of CYH33 to inhibit the proliferation of breast cancer cells. In a concentration dependent and equal degree of inhibition of T47D, the downstream protein kinase AKT phosphorylated.CYH33 in MCF-7 and MDA-MB-231 cells can downregulate the downstream p70S6K and S6 phosphorylation levels of M TORC1 in sensitive breast cancer cells, but not in breast cancer cells. In sensitive breast cancer cells, CYH33 by down-regulation of Rb phosphorylation and depletion. The content of in D1 and the accumulation of p27, inhibit the cell proliferation and inhibit the proliferation of cells in G1 stage, but in the tolerance of breast cancer cells, CYH33 can not induce sensitivity or tolerance to the apoptosis of breast cancer cells for 72 hours. Therefore, CYH33 mainly inhibits cell proliferation and inhibits cell proliferation by blocking the cells in G1 phase. The inhibition of AKT phosphorylation can not predict the sensitivity of breast cancer cells to CYH33. It is consistent with the inhibitory effect of CYH33 on the proliferation of breast cancer cells in vitro. CYH33 can effectively inhibit the growth of spontaneous tumor in T47D SCID mice and PIK3CAH1047R gene engineering mice, and the activity is better than BYL719. in addition to CYH33 and BYL719 for a long time. The model animals used in breast cancer had little influence on the weight and blood glucose regulation of mice and were within the safety range. We preliminarily analyzed the sensitivity of different molecular types of breast cancer cells to CYH33, and found that the lumen and HER2 expanded breast cancer cells were more sensitive to CYH33, and the base like breast cancer cells were tolerant to CYH33. The PI3K letter was analyzed. The relationship between the changes of key molecules in the pathway and the sensitivity of breast cancer cells to CYH33 sensitivity, we have found that the PIK3CA mutation and HER2 amplification of breast cancer cells are more sensitive to CYH33, while the PTEN deficient breast cancer cells are tolerant to CYH33. Although the key protein molecules in the different molecular types of the breast cancer cells or the key protein molecules in the PI3K signaling pathway are altered with the mammary gland There is a certain correlation between the sensitivity of cancer cells to CYH33 and the sensitivity of some basal like breast cancer cells or normal breast cancer cells in the PI3K signaling pathway to CYH33. Therefore, the exploration of biomarkers based on the mechanism of PI3K alpha selective inhibitors is an important strategy to improve the efficacy of these inhibitors,.PI3K and MAPK signaling pathways. There are two key signaling pathways involved in the regulation of breast cancer cell proliferation. There are extensive interaction between the two and one of the signaling pathways that usually cause feedback activation of another signal pathway, suggesting that the target two signal pathways are expected to achieve a more significant antitumor effect. We found that CYH33 can reduce the T47D finer at the same time. AKT and ERK phosphorylation in the cell, further research on the mechanism of CYH33 may reveal its relationship with the anti-tumor activity of CYH33. T47D and MCF-7 cells in sensitive breast cancer are the research object, and multiple PI3K inhibitors can inhibit AKT and ERK phosphorylation simultaneously, while PDK1, AKT and M inhibitors are at the same time playing the target inhibition effect. Phosphorylation weakly affects or even increases the phosphorylation level of ERK, indicating that PI3K regulated ERK phosphorylation is not dependent on its classical PDK1/AKT/m TOR downstream signal pathway. Inhibition of RAF and MEK causes ERK phosphorylation down down, while high expression RAF and MEK antagonize the inhibition of PI3K inhibitor to ERK phosphorylation. RAS activity is not affected by PI3K inhibitors, but high expression of RAS can reverse the inhibitory effect of PI3K inhibitors on ERK phosphorylation, which indicates that PI3K and RAS two regulate ERK phosphorylation. Activation of EGFR activity in cells can increase the intracellular RAS-GTP content and prevent the inhibition of ERK phosphorylation by PI3K inhibitors. The synergistic effect of ERK phosphorylation indicates that the low activity of EGFR makes ERK phosphorylation dependent on PI3K, and the highly active EGFR makes ERK phosphorylation dependent on RAS. based on EGFR activity to determine whether ERK phosphorylation is dependent on PI3K. 3K regulates the role of ERK phosphorylation. Activation of EGFR, HER3, FGFR and / or c-MET activity can antagonize the inhibition of BYL719 on T47D, MCF-7 and HCC1954 ERK phosphorylation in breast cancer cells, and can partly reverse the inhibitory effect of BYL719 on the proliferation of corresponding breast cancer cells. The expression of RTKs in a series of breast cancer cells and the effect of PI3K inhibitor on its phosphorylation of AKT and ERK found that the expression level of AKT and ERK phosphorylated breast cancer cells (defined as A group) at the same time the PI3K inhibitor was defined as the A group, the expression level of receptor tyrosine kinase IGF-1R and HER2 was higher, and the expression level of EGFR and c-MET was lower; on the contrary, it was suppressed. The preparation can inhibit AKT phosphorylation but not inhibit ERK phosphorylation of breast cancer cells (the cell defined as B), receptor tyrosine kinase EGFR and c-MET expression level is higher, and IGF-1R and HER2 expression level is lower. Statistical analysis A, B two group breast cancer cells for PI3K alpha inhibitors CYH33 and BYL719 sensitivity difference, we found breast breast Cancer cells were more sensitive to CYH33 and BYL719. On this basis, we examined the correlation between the expression of RTKs in breast cancer cells and the inhibitory activity of PI3K a inhibitor on its proliferation. It was found that the expression level of EGFR and c-MET was negatively correlated with the inhibitory activity of PI3K a inhibitor, that is, the higher the level of EGFR and c-MET expression in breast cancer cells. It is more tolerant to PI3K alpha inhibitors, and the expression level of HER2 and IGF-1R is positively correlated with the higher expression level of HER2 and IGF-1R in breast cancer cells, which is more sensitive to the relationship between the inhibitory activity of.BYL719 and the growth inhibitory activity of the breast cancer transplantation tumor (PDX) in three patients with the PI3K alpha inhibitor, and the relationship between the expression of the tumor tissue and the expression of the tumor tissue is further examined. It is demonstrated that the RTKs expression profile determines the sensitivity of breast cancer to the PI3K alpha selective inhibitors. To sum up, we have found that CYH33 has significant antitumor activity in the body and in vivo, and the activity is better than that of the same kind of inhibitor, BYL719, which is in the clinical trial of III. We hope to be the first selective inhibitor of PI3K alpha with self principal intellectual property rights. The expression profiles of RTKs in breast cancer cells / tissues determine the regulation of the phosphorylation and activity of ERK by PI3K, which determines the sensitivity of breast cancer to PI3K alpha selective inhibitors. IGF-1R and / or HER2 are highly expressed, EGFR, c-MET and / or FGFR1 low expression indicates PI3K regulation ERK activity, breast cancer is sensitive to PI3K inhibitors; conversely, and / or low High expression of EGFR, c-MET and / or FGFR1 indicates that ERK phosphorylation is not dependent on PI3K, and breast cancer is tolerated to PI3K inhibitors. Therefore, the RTKs expression profile is expected to be a biomarker for predicting the response of breast cancer to PI3K a inhibitors, and the basis for the selection of clinical patients with the PI3K alpha inhibitors.
【學(xué)位授予單位】：中國(guó)科學(xué)院大學(xué)(中國(guó)科學(xué)院上海藥物研究所)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類(lèi)號(hào)】：R96

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4 張維彬,汪波,石靈春;中醫(yī)藥在現(xiàn)代乳腺癌治療中的運(yùn)用[J];中國(guó)中西醫(yī)結(jié)合急救雜志;2002年01期

5 薛志勇;食物與乳腺癌[J];山東食品科技;2002年04期

6 王旬果,王建軍,鄭國(guó)華;乳腺癌相關(guān)標(biāo)志物的研究進(jìn)展[J];山東醫(yī)藥;2002年33期

7 陸尚聞;;男人也患乳腺癌[J];環(huán)境;2003年12期

8 ;新技術(shù)清晰拍攝早期乳腺癌細(xì)胞[J];上海生物醫(yī)學(xué)工程;2005年04期

9 田富國(guó);郭向陽(yáng);張華一;;乳腺癌診治研究新進(jìn)展[J];腫瘤研究與臨床;2005年S1期

10 馬濤,谷俊朝;血管內(nèi)皮生長(zhǎng)因子與乳腺癌的臨床研究進(jìn)展[J];國(guó)外醫(yī)學(xué)(外科學(xué)分冊(cè));2005年01期

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3 龐朋沙;伍會(huì)健;;乳腺癌治療靶標(biāo)的研究進(jìn)展[A];北方遺傳資源的保護(hù)與利用研討會(huì)論文匯編[C];2010年

4 陸勁松;邵志敏;吳炅;韓企夏;沈鎮(zhèn)宙;;新型維甲酸抑制乳腺癌細(xì)胞的生長(zhǎng)及誘導(dǎo)凋亡的機(jī)制研究[A];2000全國(guó)腫瘤學(xué)術(shù)大會(huì)論文集[C];2000年

5 劉愛(ài)國(guó);胡冰;;乳腺癌臨床治療進(jìn)展[A];安徽省抗癌協(xié)會(huì)第四次代表大會(huì)暨乳腺癌、肺癌專(zhuān)業(yè)委員會(huì)成立會(huì)議、安徽省腫瘤防治進(jìn)展學(xué)術(shù)研討會(huì)論文匯編[C];2001年

6 張嘉慶;王殊;喬新民;;乳腺癌的現(xiàn)狀和遠(yuǎn)景[A];第一屆全國(guó)中西醫(yī)結(jié)合乳腺疾病學(xué)術(shù)會(huì)議論文匯編[C];2002年

7 劉清俊;;乳腺癌綜合治療的新進(jìn)展[A];山西省抗癌協(xié)會(huì)第六屆腫瘤學(xué)術(shù)交流會(huì)論文匯編[C];2003年

8 邵志敏;;21世紀(jì)乳腺癌治療的展望[A];第三屆中國(guó)腫瘤學(xué)術(shù)大會(huì)教育論文集[C];2004年

9 陳松旺;張明;;乳腺癌治療的回顧與展望[A];西部地區(qū)腫瘤學(xué)學(xué)術(shù)會(huì)議論文匯編[C];2004年

10 白霞;傅建新;丁凱陽(yáng);王兆鉞;阮長(zhǎng)耿;;組織因子途徑抑制物-2在乳腺癌細(xì)胞中的表達(dá)研究[A];第10屆全國(guó)實(shí)驗(yàn)血液學(xué)會(huì)議論文摘要匯編[C];2005年

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2 記者 鄭曉春;乳腺癌細(xì)胞擴(kuò)散基因被找到[N];科技日?qǐng)?bào);2007年

3 中國(guó)軍事醫(yī)學(xué)科學(xué)院腫瘤中心主任 宋三泰;乳腺癌有了新療法[N];中國(guó)婦女報(bào);2002年

4 王艷紅;抑制ＤＮＡ修補(bǔ)可消滅乳腺癌細(xì)胞[N];醫(yī)藥經(jīng)濟(jì)報(bào);2005年

5 詹建;乳腺癌飲食 兩個(gè)時(shí)期不一樣[N];中國(guó)中醫(yī)藥報(bào);2006年

6 辛君;乳腺癌擴(kuò)散基因“浮出水面”[N];大眾衛(wèi)生報(bào);2009年

7 記者 毛黎;美發(fā)現(xiàn)有效抑制乳腺癌細(xì)胞生長(zhǎng)的分子[N];科技日?qǐng)?bào);2010年

8 記者 吳春燕　通訊員 王麗霞;乳腺癌治療將有新途徑[N];光明日?qǐng)?bào);2011年

9 王樂(lè)　沈基飛;我科學(xué)家發(fā)現(xiàn)導(dǎo)致乳腺癌耐藥的新標(biāo)志物[N];科技日?qǐng)?bào);2011年

10 劉霞;一種天然分子能阻止乳腺癌惡化[N];科技日?qǐng)?bào);2011年

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2 李凱;ID(inhibitor of DNA binding)家族蛋白調(diào)控乳腺細(xì)胞的分化并影響乳腺癌的預(yù)后[D];復(fù)旦大學(xué);2014年

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5 姚若斯;精氨酸甲基轉(zhuǎn)移酶PRMT7誘導(dǎo)乳腺癌細(xì)胞發(fā)生表皮—間質(zhì)轉(zhuǎn)換及轉(zhuǎn)移的作用機(jī)制研究[D];東北師范大學(xué);2015年

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10 汪[?如;染色體6q25.1區(qū)域基因多態(tài)性與乳腺癌遺傳易感性的關(guān)聯(lián)研究[D];南方醫(yī)科大學(xué);2015年

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5 葛廣哲;樹(shù)，

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