PTP1B和ER-α36在乳腺癌转移中的作用及其临床病理学意义
发布时间：2018-07-26 08:44
【摘要】：乳腺癌是女性最常见的恶性肿瘤之一,其高度异质性是导致乳腺癌患者在临床表现、治疗反应性和预后等方面存在显著差异的主要原因。近年来,乳腺癌分子亚型概念的提出,对于指导临床个体化治疗和判断预后起到重要作用。因此,明确乳腺癌患者分子亚型不仅为乳腺癌个体化治疗方案提供支持,也为深入研究乳腺癌分子机制提供依据。肿瘤侵袭和转移特征是导致乳腺癌患者复发和不良预后的主要原因,也是肿瘤治疗难以克服的瓶颈问题。新近研究发现提示,肿瘤干细胞(CSCs)可能是导致侵袭转移的主要根源,此群细胞在肿瘤细胞全体中含量甚少,但独具自我更新、无限增殖、多向分化潜能及肿瘤重建的能力。本课题组前期研究发现,ER-α36阳性乳腺癌细胞ALDH1表达阳性并具有干细胞样表型,提示ER-α36在乳腺癌中具有重要意义。与肿瘤干细胞产生密切相关的重要机制上皮间质转化(EMT)也被认为是在肿瘤转移过程中重要的细胞生物学事件。除此之外,肿瘤细胞转移需要降解间质的细胞外基质,而基质金属蛋白酶(MMPs)是降解细胞外基质的关键酶。已有研究提示,不同分子亚型的乳腺癌侵袭转移能力具有差异,然而调控不同亚型乳腺癌患者侵袭转移的分子机制尚不清楚。蛋白酪氨酸磷酸酶1B(PTP1B)是一种非跨膜蛋白酪氨酸激酶,已被发现在胃癌、结直肠癌及前列腺癌等多种肿瘤中高表达,并参与了肿瘤的发生发展。而在乳腺癌中,PTP1B虽在肿瘤中高表达,但其在各种亚型乳腺癌中表达如何,是否及如何影响乳腺癌细胞的侵袭转移能力尚不清楚。基于此,我们首先对328例乳腺癌进行分子分型,检测PTP1B在乳腺癌中的表达规律,通过敲低或过表达PTP1B的表达,观察PTP1B是否可以影响乳腺癌细胞侵袭迁移能力。然后,探讨了PTP1B影响乳腺癌细胞侵袭迁移的作用机制。最后,观察PTP1B与乳腺癌分子亚型的关系,分析其与乳腺癌患者临床病理学参数的关系及能否依据不同乳腺癌亚型进而指导乳腺癌患者个体化治疗。主要结果和结论如下:1、乳腺癌分子亚型鉴定结果。(1)通过细胞免疫组化(ICC)联合RT-PCR检测ER、PR和HER2蛋白及m RNA表达,将12种正常及乳腺癌细胞系分为四种亚型。MCF7和T47D为Luminal A型(ER+和/或pr+,her2-);bt-474和uacc-732为luminalb型(er+和/或pr+,her2+);mcf10a、mda-mb-231、mda-mb-453、bt549、sum159和bcap37为basal-like型(er-,pr-,her2-);skbr3和jimt1为her2过表达型(er-,pr-,her2+)。(2)应用ihc的方法检测328例浸润性乳腺癌组织中er、pr、her2和ki67蛋白表达水平情况,并对其进行分子分型。其中四种亚型分布状态为:151例为luminala型,54例为luminalb型,94例为basal-like型,29例为her2过表达型。不同亚型乳腺癌患者总生存(overallsurvival,os)及无病生存(disease-freesurvival,dfs)均具有显著性差异(p0.001,p0.001)。其中luminala型乳腺癌患者预后显著好于其它任何亚型乳腺癌患者(p0.001)。2、ptp1b在乳腺癌中高表达并可以显著促进乳腺癌细胞的侵袭和迁移能力。(1)ptp1b蛋白在乳腺癌组织中的表达显著高于癌旁正常组织(p0.001)。蛋白表达主要分布在肿瘤组织或癌旁正常组织胞浆中。(2)ptp1b与乳腺癌淋巴结转移显著正相关,其高表达患者淋巴结更易发生转移(p0.01)。(3)在细胞系mcf7中,敲低ptp1b的表达后可以显著抑制乳腺癌细胞系的侵袭和迁移能力(p0.01)。(4)在细胞系mda-mb-231中,过表达ptp1b的表达后可以显著促进乳腺癌细胞系的侵袭和迁移能力(p0.01)。3、ptp1b通过调控pten和mmps调控乳腺癌细胞侵袭转移能力。(1)敲低mcf7细胞ptp1b表达可以有效抑制akt磷酸化,这一改变主要是通过上调pi3k/akt上游通路中pten蛋白来实现的。相反,过表达ptp1b表达可以抑制pten的变化进而促进akt磷酸化。(2)敲低mcf7细胞ptp1b表达可以有效抑制基质蛋白酶(mmp2和mmp7)mrna和蛋白水平的改变。然而,过表达ptp1b表达可以有效促进mmp2和mmp7mrna和蛋白水平的表达。(3)敲低或过表达ptp1b对细胞系mcf7和mda-mb-231中相关干性因子表达无显著影响(oct4、nanog、sox2和aldh1,p0.05)。此外,通过成球培养法富集mcf7和mda-mb-231细胞中的乳腺癌干细胞,发现ptp1b的表达与乳腺癌干细胞无显著相关性。(4)敲低或过表达ptp1b后不影响emt相关基因(e-cadherin、n-cadherin和vimentin,p0.05)mrna和蛋白表达。4、PTP1B在Luminal型乳腺癌中高表达且与不良预后正相关。(1)PTP1B蛋白在不同亚型乳腺癌组织中差异表达,在Luminal型和HER2阳性型中高表达,在Basal-like型中低表达(P0.05)。PTP1B蛋白在不同亚型乳腺及乳腺癌细胞系中亦呈现差异表达,在Luminal型和HER2过表达型细胞系中高表达,在Basal-like型细胞系中低表达。(2)PTP1B高表达与患者ER状态显著正相关(P0.05)。(3)PTP1B高表达与Luminal型乳腺癌患者不良预后相关(P0.05,DFS),而与其它亚型乳腺癌患者预后无显著相关性(P0.05)。5、ER-α36在乳腺癌组织中的临床意义。(1)ER-α36与乳腺癌患者淋巴结转移正相关,ER-α36高表达提示患者不良预后(P0.05)。(2)ER-α36蛋白在不同亚型乳腺癌组织中差异表达,在Luminal型和HER2阳性型中高表达,在Basal-like型中低表达(P0.05)。综上所述,乳腺癌细胞系的亚型鉴定为乳腺癌科研工作者提供了良好的研究基础,对于乳腺癌患者个体化治疗和机制深入研究提供依据。同时,乳腺癌分子亚型与患者预后显著相关,我们应该推进和完善乳腺癌亚型的鉴定,以期更好的指导患者诊治及判断临床预后。PTP1B在乳腺癌中高表达并与LNM相关,其促进乳腺癌细胞的侵袭转移的潜在机制主要是与PI3K/AKT通路和MMPs有关,而非CSCs和EMT依赖的调控通路。ER-α36与乳腺癌患者淋巴结转移正相关,其高表达显示患者不良预后。以上研究为认识不同分子亚型乳腺癌生物学特点、阐明其转移机制提供了理论与实验依据。
[Abstract]:Breast cancer is one of the most common malignant tumors in women. Its high heterogeneity is the main reason that causes significant differences in clinical manifestations, reactivity and prognosis in breast cancer patients. In recent years, the concept of the molecular subtypes of breast cancer has played an important role in guiding clinical individualized treatment and judging prognosis. The molecular subtypes of breast cancer patients not only provide support for the individualized treatment of breast cancer, but also provide a basis for the in-depth study of the molecular mechanism of breast cancer. The characteristics of tumor invasion and metastasis are the main causes leading to the recurrence and poor prognosis of breast cancer patients. Stem cells (CSCs) may be the main source of invasion and metastasis, and this group of cells has little content in all tumor cells, but it has a unique self renewal, unlimited proliferation, multidirectional differentiation potential and the ability to reconstruct the tumor. Previous studies in our group have found that ER- alpha 36 positive breast cancer cells are positive for ALDH1 expression and have stem cell like phenotypes, suggesting ER- Alpha 36 is of great significance in breast cancer. The important mechanism of epithelial mesenchymal transition (EMT), which is closely related to tumor stem cells, is also considered to be an important cell biological event in the process of tumor metastasis. In addition, tumor cell metastasis requires the degradation of extracellular matrix, and matrix metalloproteinase (MMPs) is the degradation of extracellular matrix. The key enzymes in the matrix have been suggested that the invasion and metastasis of different subtypes of breast cancer are different. However, the molecular mechanism of the invasion and metastasis of different subtypes of breast cancer is unclear. Protein tyrosine phosphatase 1B (PTP1B) is a non transmembrane protein tyrosine irritable enzyme, which has been found in gastric cancer, colorectal cancer and prostate cancer. The high expression of cancer and other cancers is involved in the development of the tumor. In breast cancer, although PTP1B is highly expressed in the tumor, it is not clear whether it is expressed in various subtypes of breast cancer and how and how it affects the invasion and metastasis of breast cancer cells. Based on this, we first made molecular typing for 328 cases of breast cancer and detected PTP1 The expression of B in breast cancer, by knocking down or overexpressing PTP1B expression, observed whether PTP1B could affect the invasion and migration of breast cancer cells. Then, the mechanism of the effect of PTP1B on the invasion and migration of breast cancer cells was explored. Finally, the relationship between PTP1B and the molecular subtypes of breast cancer was observed and the clinical pathology of breast cancer patients was analyzed. The relationship between the parameters and the individual breast cancer subtypes can be used to guide the individual treatment of breast cancer. The main results and conclusions are as follows: 1, the identification results of the molecular subtypes of breast cancer. (1) the expression of ER, PR and HER2 protein and m RNA by cellular immunization (ICC) combined with the expression of PR and HER2 protein and m RNA, and to divide 12 normal and breast cancer cell lines into four subtypes.MCF7 And T47D is Luminal A type (ER+ and / or pr+, her2-); BT-474 and uacc-732 are luminal B type (er+ and pr+, her2+). And the expression level of Ki67 protein and its molecular typing. The four subtypes were luminala, 54 luminal B, 94 basal-like and 29 HER2 overexpressed. The total survival (overallsurvival, OS) and disease-free survival (disease-freesurvival, DFS) in different subtypes of breast cancer were significant. The difference (p0.001, p0.001). The prognosis of luminala type breast cancer patients is significantly better than any other subtype of breast cancer (p0.001).2, PTP1B is highly expressed in breast cancer and can significantly promote the invasion and migration of breast cancer cells. (1) the expression of PTP1B protein in breast cancer tissues is significantly higher than that of normal paracancerous tissue (p0.001). (2) PTP1B was significantly correlated with lymph node metastasis in breast cancer, and the lymph node metastasis of the patients with high expression was more likely to metastasize (P0.01). (3) in cell line MCF7, the invasion and migration ability of breast cancer cell lines could be significantly inhibited after the expression of low PTP1B (P0.01). (4) in cell line mda-m In b-231, overexpression of PTP1B can significantly promote the invasion and migration capacity of breast cancer cell lines (P0.01).3. PTP1B regulates the invasion and metastasis of breast cancer cells by regulating PTEN and MMPs. (1) PTP1B expression in low MCF7 cells can effectively inhibit Akt phosphorylation. This change is mainly by up regulation of PTEN eggs in the pi3k/akt upstream pathway. On the contrary, overexpression of PTP1B expression can inhibit changes in PTEN and thus promote Akt phosphorylation. (2) the expression of PTP1B in low MCF7 cells can effectively inhibit the change of mRNA and protein levels of matrix protease (MMP2 and MMP7). However, overexpression of PTP1B expression can effectively promote the expression of MMP2 and mmp7mrna and protein levels. (3) knock low or over. The expression of PTP1B had no significant effect on the expression of related dry factors in cell lines MCF7 and MDA-MB-231 (Oct4, Nanog, Sox2 and ALDH1, P0.05). In addition, the enrichment of breast cancer stem cells in MCF7 and MDA-MB-231 cells was enriched by spheroid culture, and there was no significant correlation between PTP1B expression and breast cancer stem cells. (4) low or overexpressed PTP1B was not affected. The related genes (E-cadherin, N-cadherin and vimentin, P0.05) mRNA and protein expressed.4. PTP1B was highly expressed in Luminal type breast cancer and was positively related to poor prognosis. (1) the expression of PTP1B protein in different subtypes of breast cancer tissues was expressed in the Luminal type and HER2 positive type, and the low expression of the protein in the Basal-like type was different. Subtype breast and breast cancer cell lines also showed differential expression, high expression in type Luminal and HER2 overexpressed cell lines, low expression in Basal-like type cell lines. (2) high expression of PTP1B was significantly positively correlated with patients' ER state (P0.05). (3) high expression of PTP1B was associated with poor prognosis of Luminal type breast cancer patients (P0.05, DFS), and other subtypes. There was no significant correlation between the prognosis of patients with breast cancer (P0.05).5, ER- alpha 36 in breast cancer tissue. (1) ER- alpha 36 was positively correlated with lymph node metastasis in breast cancer patients, and high expression of ER- alpha 36 indicated poor prognosis (P0.05). (2) ER- alpha 36 protein was expressed differently in different subtype breast cancer tissues, and high table in Luminal and HER2 positive types The subtype identification of the breast cancer cell lines provides a good basis for breast cancer research workers and provides a basis for the individual treatment and mechanism of breast cancer patients. At the same time, the subtypes of breast cancer molecules are significantly related to the prognosis of the patients. We should promote and improve the prognosis of the breast cancer molecules. We should promote and improve the Basal-like. Identification of the subtypes of breast cancer in order to better guide the diagnosis and treatment of patients and determine the clinical prognosis of.PTP1B in breast cancer high expression and related to LNM. The potential mechanism for promoting invasion and metastasis of breast cancer cells is mainly related to the PI3K/AKT pathway and MMPs, not CSCs and EMT dependent modulation pathway.ER- alpha 36 and lymph node metastasis of breast cancer patients The above study shows the biological characteristics of different molecular subtypes of breast cancer and the theoretical and experimental basis for elucidating the mechanism of metastasis of different molecular subtypes of breast cancer.
【学位授予单位】：第三军医大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R737.9
[Abstract]:Breast cancer is one of the most common malignant tumors in women. Its high heterogeneity is the main reason that causes significant differences in clinical manifestations, reactivity and prognosis in breast cancer patients. In recent years, the concept of the molecular subtypes of breast cancer has played an important role in guiding clinical individualized treatment and judging prognosis. The molecular subtypes of breast cancer patients not only provide support for the individualized treatment of breast cancer, but also provide a basis for the in-depth study of the molecular mechanism of breast cancer. The characteristics of tumor invasion and metastasis are the main causes leading to the recurrence and poor prognosis of breast cancer patients. Stem cells (CSCs) may be the main source of invasion and metastasis, and this group of cells has little content in all tumor cells, but it has a unique self renewal, unlimited proliferation, multidirectional differentiation potential and the ability to reconstruct the tumor. Previous studies in our group have found that ER- alpha 36 positive breast cancer cells are positive for ALDH1 expression and have stem cell like phenotypes, suggesting ER- Alpha 36 is of great significance in breast cancer. The important mechanism of epithelial mesenchymal transition (EMT), which is closely related to tumor stem cells, is also considered to be an important cell biological event in the process of tumor metastasis. In addition, tumor cell metastasis requires the degradation of extracellular matrix, and matrix metalloproteinase (MMPs) is the degradation of extracellular matrix. The key enzymes in the matrix have been suggested that the invasion and metastasis of different subtypes of breast cancer are different. However, the molecular mechanism of the invasion and metastasis of different subtypes of breast cancer is unclear. Protein tyrosine phosphatase 1B (PTP1B) is a non transmembrane protein tyrosine irritable enzyme, which has been found in gastric cancer, colorectal cancer and prostate cancer. The high expression of cancer and other cancers is involved in the development of the tumor. In breast cancer, although PTP1B is highly expressed in the tumor, it is not clear whether it is expressed in various subtypes of breast cancer and how and how it affects the invasion and metastasis of breast cancer cells. Based on this, we first made molecular typing for 328 cases of breast cancer and detected PTP1 The expression of B in breast cancer, by knocking down or overexpressing PTP1B expression, observed whether PTP1B could affect the invasion and migration of breast cancer cells. Then, the mechanism of the effect of PTP1B on the invasion and migration of breast cancer cells was explored. Finally, the relationship between PTP1B and the molecular subtypes of breast cancer was observed and the clinical pathology of breast cancer patients was analyzed. The relationship between the parameters and the individual breast cancer subtypes can be used to guide the individual treatment of breast cancer. The main results and conclusions are as follows: 1, the identification results of the molecular subtypes of breast cancer. (1) the expression of ER, PR and HER2 protein and m RNA by cellular immunization (ICC) combined with the expression of PR and HER2 protein and m RNA, and to divide 12 normal and breast cancer cell lines into four subtypes.MCF7 And T47D is Luminal A type (ER+ and / or pr+, her2-); BT-474 and uacc-732 are luminal B type (er+ and pr+, her2+). And the expression level of Ki67 protein and its molecular typing. The four subtypes were luminala, 54 luminal B, 94 basal-like and 29 HER2 overexpressed. The total survival (overallsurvival, OS) and disease-free survival (disease-freesurvival, DFS) in different subtypes of breast cancer were significant. The difference (p0.001, p0.001). The prognosis of luminala type breast cancer patients is significantly better than any other subtype of breast cancer (p0.001).2, PTP1B is highly expressed in breast cancer and can significantly promote the invasion and migration of breast cancer cells. (1) the expression of PTP1B protein in breast cancer tissues is significantly higher than that of normal paracancerous tissue (p0.001). (2) PTP1B was significantly correlated with lymph node metastasis in breast cancer, and the lymph node metastasis of the patients with high expression was more likely to metastasize (P0.01). (3) in cell line MCF7, the invasion and migration ability of breast cancer cell lines could be significantly inhibited after the expression of low PTP1B (P0.01). (4) in cell line mda-m In b-231, overexpression of PTP1B can significantly promote the invasion and migration capacity of breast cancer cell lines (P0.01).3. PTP1B regulates the invasion and metastasis of breast cancer cells by regulating PTEN and MMPs. (1) PTP1B expression in low MCF7 cells can effectively inhibit Akt phosphorylation. This change is mainly by up regulation of PTEN eggs in the pi3k/akt upstream pathway. On the contrary, overexpression of PTP1B expression can inhibit changes in PTEN and thus promote Akt phosphorylation. (2) the expression of PTP1B in low MCF7 cells can effectively inhibit the change of mRNA and protein levels of matrix protease (MMP2 and MMP7). However, overexpression of PTP1B expression can effectively promote the expression of MMP2 and mmp7mrna and protein levels. (3) knock low or over. The expression of PTP1B had no significant effect on the expression of related dry factors in cell lines MCF7 and MDA-MB-231 (Oct4, Nanog, Sox2 and ALDH1, P0.05). In addition, the enrichment of breast cancer stem cells in MCF7 and MDA-MB-231 cells was enriched by spheroid culture, and there was no significant correlation between PTP1B expression and breast cancer stem cells. (4) low or overexpressed PTP1B was not affected. The related genes (E-cadherin, N-cadherin and vimentin, P0.05) mRNA and protein expressed.4. PTP1B was highly expressed in Luminal type breast cancer and was positively related to poor prognosis. (1) the expression of PTP1B protein in different subtypes of breast cancer tissues was expressed in the Luminal type and HER2 positive type, and the low expression of the protein in the Basal-like type was different. Subtype breast and breast cancer cell lines also showed differential expression, high expression in type Luminal and HER2 overexpressed cell lines, low expression in Basal-like type cell lines. (2) high expression of PTP1B was significantly positively correlated with patients' ER state (P0.05). (3) high expression of PTP1B was associated with poor prognosis of Luminal type breast cancer patients (P0.05, DFS), and other subtypes. There was no significant correlation between the prognosis of patients with breast cancer (P0.05).5, ER- alpha 36 in breast cancer tissue. (1) ER- alpha 36 was positively correlated with lymph node metastasis in breast cancer patients, and high expression of ER- alpha 36 indicated poor prognosis (P0.05). (2) ER- alpha 36 protein was expressed differently in different subtype breast cancer tissues, and high table in Luminal and HER2 positive types The subtype identification of the breast cancer cell lines provides a good basis for breast cancer research workers and provides a basis for the individual treatment and mechanism of breast cancer patients. At the same time, the subtypes of breast cancer molecules are significantly related to the prognosis of the patients. We should promote and improve the prognosis of the breast cancer molecules. We should promote and improve the Basal-like. Identification of the subtypes of breast cancer in order to better guide the diagnosis and treatment of patients and determine the clinical prognosis of.PTP1B in breast cancer high expression and related to LNM. The potential mechanism for promoting invasion and metastasis of breast cancer cells is mainly related to the PI3K/AKT pathway and MMPs, not CSCs and EMT dependent modulation pathway.ER- alpha 36 and lymph node metastasis of breast cancer patients The above study shows the biological characteristics of different molecular subtypes of breast cancer and the theoretical and experimental basis for elucidating the mechanism of metastasis of different molecular subtypes of breast cancer.
【学位授予单位】：第三军医大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R737.9
【相似文献】
中国期刊全文数据库 前10条
1 黄啸原;用“印度阅兵”形容乳腺癌合适吗?[J];诊断病理学杂志;2001年02期
2 张嘉庆,王殊,乔新民;乳腺癌的现状和远景[J];中华外科杂志;2002年03期
3 张维彬,汪波,石灵春;中医药在现代乳腺癌治疗中的运用[J];中国中西医结合急救杂志;2002年01期
4 薛志勇;食物与乳腺癌[J];山东食品科技;2002年04期
5 王旬果,王建军,郑国华;乳腺癌相关标志物的研究进展[J];山东医药;2002年33期
6 陆尚闻;;男人也患乳腺癌[J];环境;2003年12期
7 ;新技术清晰拍摄早期乳腺癌细胞[J];上海生物医学工程;2005年04期
8 田富国;郭向阳;张华一;;乳腺癌诊治研究新进展[J];肿瘤研究与临床;2005年S1期
9 马涛,谷俊朝;血管内皮生长因子与乳腺癌的临床研究进展[J];国外医学(外科学分册);2005年01期
10 郭庆良,谷俊朝;乳腺癌和瘦素相关性研究进展[J];国外医学.外科学分册;2005年03期
中国重要会议论文全文数据库 前10条
1 于永利;;抗乳腺癌免疫治疗融合蛋白[A];中国免疫学会第四届学术大会会议议程及论文摘要集[C];2002年
2 郭红飞;;中医治疗乳腺癌的策略[A];江西省中医、中西医结合肿瘤学术交流会论文集[C];2012年
3 庞朋沙;伍会健;;乳腺癌治疗靶标的研究进展[A];北方遗传资源的保护与利用研讨会论文汇编[C];2010年
4 陆劲松;邵志敏;吴炅;韩企夏;沈镇宙;;新型维甲酸抑制乳腺癌细胞的生长及诱导凋亡的机制研究[A];2000全国肿瘤学术大会论文集[C];2000年
5 刘爱国;胡冰;;乳腺癌临床治疗进展[A];安徽省抗癌协会第四次代表大会暨乳腺癌、肺癌专业委员会成立会议、安徽省肿瘤防治进展学术研讨会论文汇编[C];2001年
6 张嘉庆;王殊;乔新民;;乳腺癌的现状和远景[A];第一届全国中西医结合乳腺疾病学术会议论文汇编[C];2002年
7 刘清俊;;乳腺癌综合治疗的新进展[A];山西省抗癌协会第六届肿瘤学术交流会论文汇编[C];2003年
8 邵志敏;;21世纪乳腺癌治疗的展望[A];第三届中国肿瘤学术大会教育论文集[C];2004年
9 陈松旺;张明;;乳腺癌治疗的回顾与展望[A];西部地区肿瘤学学术会议论文汇编[C];2004年
10 白霞;傅建新;丁凯阳;王兆钺;阮长耿;;组织因子途径抑制物-2在乳腺癌细胞中的表达研究[A];第10届全国实验血液学会议论文摘要汇编[C];2005年
中国重要报纸全文数据库 前10条
1 ;血检有望揭示乳腺癌治疗效果[N];医药经济报;2004年
2 记者 郑晓春;乳腺癌细胞扩散基因被找到[N];科技日报;2007年
3 中国军事医学科学院肿瘤中心主任 宋三泰;乳腺癌有了新疗法[N];中国妇女报;2002年
4 王艳红;抑制ＤＮＡ修补可消灭乳腺癌细胞[N];医药经济报;2005年
5 詹建;乳腺癌饮食 两个时期不一样[N];中国中医药报;2006年
6 辛君;乳腺癌扩散基因“浮出水面”[N];大众卫生报;2009年
7 记者 毛黎;美发现有效抑制乳腺癌细胞生长的分子[N];科技日报;2010年
8 记者 吴春燕 通讯员 王丽霞;乳腺癌治疗将有新途径[N];光明日报;2011年
9 王乐 沈基飞;我科学家发现导致乳腺癌耐药的新标志物[N];科技日报;2011年
10 刘霞;一种天然分子能阻止乳腺癌恶化[N];科技日报;2011年
中国博士学位论文全文数据库 前10条
1 柴红燕;疾病状态下CYP4Z1和4A的生物学行为及其药物干预研究[D];武汉大学;2012年
2 李凯;ID(inhibitor of DNA binding)家族蛋白调控乳腺细胞的分化并影响乳腺癌的预后[D];复旦大学;2014年
3 江一舟;乳腺癌新辅助化疗前后基因变异检测及其功能论证[D];复旦大学;2014年
4 马邵;酪氨酸去磷酸化增强表皮生长因子受体在乳腺癌治疗中靶向性的研究[D];山东大学;2015年
5 姚若斯;精氨酸甲基转移酶PRMT7诱导乳腺癌细胞发生表皮—间质转换及转移的作用机制研究[D];东北师范大学;2015年
6 侯培锋;α-酮戊二酸二甲酯(DM-2KG)上调缺氧诱导因子-1α(HIF-1α)诱发高致瘤性干细胞样乳腺癌细胞机制研究[D];福建医科大学;2014年
7 李丽丽;分泌蛋白SHON调控乳腺癌细胞EMT的分子机制研究[D];东北师范大学;2015年
8 陈丽艳;PI3K抑制剂联合组蛋白去乙酰化酶抑制剂对乳腺癌协同杀伤作用的分子机制研究[D];延边大学;2015年
9 朴俊杰;乳腺癌差异基因筛选及PAIP1对其生物学行为的影响[D];延边大学;2015年
10 汪[?如;染色体6q25.1区域基因多态性与乳腺癌遗传易感性的关联研究[D];南方医科大学;2015年
中国硕士学位论文全文数据库 前10条
1 杜文英;乳腺癌分子亚型的临床与病理特点[D];郑州大学;2011年
2 贾晓菲;彩色多普勒超声与乳腺癌病理及免疫组化指标的相关性研究[D];内蒙古大学;2015年
3 靳文;乳腺癌全基因组DNA甲基化修饰的研究[D];内蒙古大学;2015年
4 吴坤琳;TLR4/MyD88信号通路对乳腺癌侵袭性影响的实验研究[D];福建医科大学;2015年
5 葛广哲;树，
本文编号：2145472
本文链接：https://www.wllwen.com/yixuelunwen/zlx/2145472.html
