不同新辅助化疗方案治疗三阴乳腺癌临床对比研究

目的对比研究不同新辅助化疗方案治疗三阴乳腺癌(TNBC)的临床效果。方法 TNBC患者62例随机分组,各31例。TP组给予多西他赛+卡铂化疗方案,TAC组给予多西他赛+多柔比星+环磷酰胺化疗方案。比较两组总有效率、临床完全缓解(cCR)率、病理完全缓解(pCR)率、不良反应发生率;随访1年,比较两组无病生存率、总生存率。结果TP组总有效率与TAC组比较差异无统计学意义(P>0.05);TP组cCR率、pCR率高于TAC组,差异有统计学意义(P<0.05);TP组不良反应发生率与TAC组比较,3~4级脱发发生率、白细胞减少发生率、肝功能损害发生率,差异有统计学意义(P<0.05);随访1年,TP组总生存率、无病生存率与TAC组相比差异无统计学意义(P>0.05)。结论新辅助化疗方案中,TP方案(多西他赛+卡铂)治疗TNBC总疗效、生存情况与TAC方案(多西他赛+多柔比星+环磷酰胺)相当,可提高cCR率、pCR率,降低不良反应发生率,用于三阴性乳腺癌新辅助化疗的效果肯定。     

circSLCO1B3在三阴乳腺癌脑转移中的作用及其调控机制

目的 探讨circSLCO1B3在三阴乳腺癌（TNBC）脑转移中的作用及其可能的调控机制。方法 采用qRT-PCR实验检测circSLCO1B3在乳腺癌细胞系中的表达。采用过表达质粒上调TNBC子代脑转移细胞231Br中circSLCO1B3的表达,设为circSLCOB3-OE组（转染对照质粒的为circCTR-OE组）,采用Transwell侵袭实验检测circSLCO1B3对231Br细胞侵袭能力的影响。经小鼠左心室注射231Br细胞,构建体内脑转移模型,检测circSLCO1B3对TNBC脑转移能力的影响。通过CircInteractome及TargetScan在线软件分别预测与circSLCO1B3结合的miRNA及miRNA下游靶基因,并使用双荧光素酶报告基因和qRT-PCR、Western blotting实验验证其调控关系。结果 相对正常乳腺上皮细胞,circSLCO1B3在TNBC细胞系中均显著下调,且在TNBC子代脑转移细胞231Br中下调最为显著（P<0.05）。与circCTR-OE组比较,circSLCOB3-OE组231Br细胞的侵袭能力、脑转移结节数...     

三阴乳腺癌组织中p27、survivin的表达及临床意义

目的探讨p27、survivin在三阴乳腺癌(TNBC)发生、发展中的作用。方法选择我院手术切除的TNBC(肿瘤组)、非特殊类型乳腺浸润性导管癌(浸润组)、良性乳腺增生症(增生组)组织标本各56份,采用免疫组化SP二部法检测各组p27、survivin的表达情况,并分析p27、survivin的表达与TNBC临床病理参数的相关性。结果肿瘤组、浸润组、增生组p27阳性表达率分别为41.1%、67.8%、91.1%,肿瘤组明显低于其余两组,浸润组明显低于增生组(P均<0.01);survivin阳性率分别为69.6%、60.7%、5.3%,肿瘤组及浸润组明显高于增生组(P均<0.01)。p27表达与TNBC的患者年龄、肿瘤直径、临床分期及淋巴结转移有关,survivin与TNBC的患者年龄、肿瘤直径有关。p27与survivin在TNBC中表达呈负相关。结论 p27、survivin异常表达可能与TNBC的发生、发展及预后密切相关。     

三阴乳腺癌中Notch1和Wnt1的表达及其临床意义

目的检测三阴乳腺癌组织(TNBC)中Notch1、Wnt1的表达并探讨其临床意义。方法采用免疫组织化学SP法检测56例TNBC组织和30例癌旁正常乳腺组织Notch1、Wnt1的表达情况。结果 TNBC组织中Notch1、Wnt1的阳性表达率分别为62.5%(35/56)、53.6%(30/56),高于癌旁正常组织(P<0.01);Notch1、Wnt1的阳性率在病理分期、肿瘤的大小、病理分级、cTNM和淋巴结转移方面比较,差异均有统计学意义(P<0.05)。Notch1与Wnt1的表达呈正相关(r=0.671,P=0.000)。结论 Notch1和Wnt1在TNBC中高表达,与TNBC的发生、发展和转移密切相关。     

miR-185通过靶向BRCA1抑制三阴乳腺癌细胞的增殖与侵袭

目的探讨miR-185是否通过靶向人类乳腺癌易感基因(BRCA)1抑制三阴乳腺癌细胞的生长与侵袭及其抗肿瘤机制。方法采用Target Scan软件预测miR-185靶基因、将野生型或突变型E2F6的3'-UTR区域克隆到荧光素酶报告基因的下游(E2F6-wt或E2F6-mut)并分别与miR-185模拟物(miR-185 mimics)及其无关对照寡核苷酸序列(scramble)、抗miR-185寡核苷酸序列(miR-185-LNA)及其无关对照寡核苷酸序列(control)共转染,荧光素酶报告基因实验验证所预测的靶基因E2F6、qRT-PCR检测转染后靶基因的mRNA表达水平、Western印迹检测转染后靶基因的蛋白表达水平。MTS和Transwell验证不同转染后,三阴乳腺癌细胞MDA-MB-231的细胞生长增殖活性和侵袭能力。结果在共转染miR-185mimics和E2F6-wt、scramble和E2F6-wt两组中,miR-185组荧光素酶活性强度降低了约41.3%(P<0.05)。转染miR-185后,E2F6的蛋白和mRNA水平均显著下调,BRCA1的蛋白和mRNA水平均显著上调(P<0.05)。在细胞增殖试验中,转染miR-185后,三阴乳腺癌细胞MDA-MB-231的生长速度显著低于scramble组(P<0.05);与vector组比,BRCA1组可显著抑制三阴乳腺癌细胞MDA-MB-231的生长(P<0.05),且miR-185+BRCA1组比BRCA1组对细胞生长的抑制作用更加明显(P<0.05)。Transwell侵袭实验中,转染miR-185和BRCA1组在36 h后穿过基底膜的细胞数分别为(100±6)和(100±9),而对照组即转染scramble和转染vector组穿膜细胞数分别为(210±13)和(180±14),即miR-185和BRCA1能明显抑制三阴乳腺癌细胞MDA-MB-231的穿膜能力,差异有统计学意义(P<0.05)。结论 miR-185通过靶向调控BRCA1表达而抑制三阴乳腺癌细胞的生长与侵袭。     

老年三阴乳腺癌组织中MMP-9和CD147的表达及意义

目的探讨基质金属蛋白酶(MMP)-9和CD147在老年三阴乳腺癌(TNBC)中的表达及对预后的影响。方法行手术切除治疗的年龄≥60岁TNBC患者组织标本63例,51例老年乳腺纤维瘤组织,采用免疫组化方法,检测MMP-9和CD147的表达情况,并分析其与临床病理特征的相关性,通过Kaplan-Meier生存曲线法计算不同组别的老年TNBC的生存率。结果 MMP-9和CD147在老年TNBC中的表达明显高于老年乳腺纤维瘤(P<0.05);MMP-9和CD147的表达与老年TNBC肿瘤直径、病理学分级、组织学分级、淋巴转移情况以及Ki67高表达(>30%)有关(均P<0.05),而与P53的表达无关(P>0.05);34例MMP-9阳性的老年TNBC中位生存时间(OS)为28.0个月,95%CI为10.0~41.3个月,29例MMP-9阴性的老年TNBC OS为34.0个月,95%CI(12.0~49.6个月),MMP-9阳性生存率明显低于MMP-9阴性(P=0.015);37例CD147阳性的老年TNBC OS为26.0个月,95%CI为10.0~35.2个月,26例CD147阴性的老年TNBC OS为35.0个月,95%CI为11.0~51.7个月,CD147阳性生存率明显低于CD147阴性(P=0.007)。结论 MMP-9和CD147在老年TNBC中表达显著增高,且与TNBC的恶性进展密切相关,有可能成为老年TNBC临床治疗新靶点。     

Ki-67在基底细胞样型三阴乳腺癌中的表达及意义

目的探讨基底或非基底细胞样型三阴乳腺癌组织中Ki-67的表达及意义。方法选取沈阳医学院附属中心医院病理科诊断三阴乳腺癌病例42例,其中基底细胞样型24例为实验组,非基底细胞样型18例为对照组。结果 Ki-67阳性表达定位于肿瘤细胞核,实验组Ki-67阳性表达率为95.8%(23/24),较对照组50.0%(9/18)明显增高(P0.01),且其表达阳性率与组织学分级相关(P0.01),与年龄、淋巴结是否转移、肿瘤大小无关(P0.05)。结论在三阴乳腺癌中,基底细胞样型较非基底细胞样型的Ki-67阳性率高,其阳性提示预后较差。Ki-67有可能成为判断基底细胞样型三阴乳腺癌的一种独立肿瘤标志物,对其预后评价有重要意义。     

三阴乳腺癌原发灶和转移灶中ER-α36、EpCAM、Sox2的表达及临床意义

目的探讨雌激素受体(ER)-α36、上皮细胞黏附分子(Ep CAM)、性别决定区Y框蛋白(Sox)2在三阴乳腺癌(TNBC)原发灶和转移灶中的表达及临床意义。方法 TNBC患者的石蜡标本62例,其中48例有对应的术后转移灶石蜡标本,采用免疫组织化学法检测ER-α36、Ep CAM、Sox2在48例TNBC原发灶和相应转移灶中的表达情况,分析ER-α36、Ep CAM、Sox2蛋白表达与TNBC患者临床病理特征的关系,并且分析TNBC组织中ER-α36、Ep CAM、Sox2蛋白之间的关系。结果在TNBC原发灶和转移灶中ER-α36、Sox2的高表达率差异有统计学意义(P<0.05),Ep CAM的高表达率差异无统计学意义(P>0.05)。TNBC组织中,ER-α36的高表达与淋巴结转移有关(P<0.05),Ep CAM的高表达与肿瘤的组织学分期有关(P<0.05),而Sox2的高表达与淋巴结转移和肿瘤TNM分期有关(P<0.05),Ep CAM与Sox2的表达存在正相关性(r=0.790,P<0.05)。结论 ER-α36和Sox2的高表达提示着TNBC的高侵袭性,且Ep CAM与Sox2在TNBC的侵袭转移中发挥着协同作用,ER-α36、Ep CAM、Sox2均可作为TNBC侵袭转移的潜在分子治疗靶标。     

重组人血管内皮抑素与化疗联合治疗转移性三阴乳腺癌11例

三阴乳腺癌(TNBC)肿瘤侵袭性强,易发生局部复发及远处转移,内分泌治疗和曲妥珠单抗治疗无效。尽管对化疗有较高的总反应率,但患者总体的临床预后仍极差。当前,抗肿瘤血管生成治疗已成为恶性肿瘤新的重要治疗模式和研究热点。重组人血管内皮抑素不仅抑制肿瘤血管的生成、诱导肿瘤细胞凋亡,而且不易耐药,毒副作用轻。因此,我科开展重组人血管内皮抑素与化疗(多西紫杉醇及卡培他滨方案)联合治疗转移性TNBC观察其疗效。     

三阴性乳腺癌中c-myc蛋白的表达及其与术后复发转移的关系

目的探讨三阴性乳腺癌(TNBC)中c-myc蛋白的表达及其与术后复发转移的关系。方法选取60例TNBC患者(TNBC组)及60例同期非TNBC患者(非TNBC组),另选取同期乳腺增生患者30例为对照组,比较三组乳腺组织中c-myc蛋白的表达情况。分析c-myc蛋白的阳性表达与临床病理指标的关系,采用无病生存期(DFS)分析患者术后3年复发转移的情况。结果 TNBC组乳腺组织中c-myc蛋白的阳性表达率显著高于非TNBC组及对照组,非TNBC组亦高于对照组(P<0.05);c-myc的表达与TNM分期、组织学分级、淋巴结转移有明显的关系(P<0.05)。c-myc阳性表达者术后3年DFS的比例显著低于c-myc阴性表达者(P<0.05)。结论 c-myc在TNBC患者中高表达,且和TNM分期、组织学分级、淋巴结转移和术后复发及转移相关,c-myc过度表达的患者术后出现复发与转移的风险更高,可能参与术后癌症复发与远处转移的分子过程。     

Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer

Inherited predisposition to breast cancer is known to be caused by loss-of-function mutations in BRCA1, BRCA2, PALB2, CHEK2, and other genes involved in DNA repair. However, most families severely affected by breast cancer do not harbor mutations in any of these genes. In Finland, founder mutations have been observed in each of these genes, suggesting that the Finnish population may be an excellent resource for the identification of other such genes. To this end, we carried out exome sequencing of constitutional genomic DNA from 24 breast cancer patients from 11 Finnish breast cancer families. From all rare damaging variants, 22 variants in 21 DNA repair genes were genotyped in 3,166 breast cancer patients, 569 ovarian cancer patients, and 2,090 controls, all from the Helsinki or Tampere regions of Finland. In Fanconi anemia complementation gene M (FANCM), nonsense mutation c.5101C>T (p.Q1701X) was significantly more frequent among breast cancer patients than among controls [odds ratio (OR) = 1.86, 95% CI = 1.26–2.75; P = 0.0018], with particular enrichment among patients with triple-negative breast cancer (TNBC; OR = 3.56, 95% CI = 1.81–6.98, P = 0.0002). In the Helsinki and Tampere regions, respectively, carrier frequencies of FANCM p.Q1701X were 2.9% and 4.0% of breast cancer patients, 5.6% and 6.6% of TNBC patients, 2.2% of ovarian cancer patients (from Helsinki), and 1.4% and 2.5% of controls. These findings identify FANCM as a breast cancer susceptibility gene, mutations in which confer a particularly strong predisposition for TNBC.Breast cancer is the most common cancer affecting women worldwide. It is also the principal cause of death from cancer among women globally, accounting for 14% of all cancer deaths (1). The etiology of breast cancer is multifactorial, and the risk depends on various factors like age, family history, and reproductive, hormonal, or dietary factors. The majority of breast cancers are sporadic, but approximately 15% of cases show familial aggregation (2, 3). Since the identification of the first breast and ovarian cancer susceptibility genes breast cancer 1 and 2 (BRCA1 and BRCA2, respectively) by linkage analysis and positional cloning, several breast cancer susceptibility genes and alleles with different levels of risk and prevalence in the population have been recognized. BRCA1 and BRCA2 mutation carriers have more than 10-fold increased risk of breast cancer compared with women in the general population, and mutations in TP53, PTEN, STK11, and CDH1 have also been associated with a high lifetime risk of breast cancer in the context of rare inherited cancer syndromes (4). In addition, rare variants in genes such as checkpoint kinase 2 (CHEK2), ataxia telangiectasia mutated (ATM), and BRCA1 interacting helicase BRIP1, that confer a two- to fourfold increased risk, and in partner and localizer of BRCA2 (PALB2), with even higher risk estimates, have been found with candidate gene approaches (5, 6), and an increasing number of common low-risk loci with modest odds ratios (ORs; as much as 1.26-fold increased risk for heterozygous carriers) have been identified by genome-wide association studies (7).However, the major portion of hereditary breast cancer still remains unexplained, and many susceptibility loci are yet to be found. Exome sequencing combined with genotyping of the identified variants in case-control analysis is an effective method to recognize novel risk alleles, based on the assumption that disease-causing variants are rare and often accumulate in the protein-coding areas of the genome (8–10).Since the discovery that proteins encoded by the BRCA1 and BRCA2 breast/ovarian cancer susceptibility genes are directly involved in homologous recombination repair of DNA double-strand breaks, it has been evident that other genes involved in DNA repair are attractive breast cancer susceptibility candidates (4). Biallelic mutations in ATM gene cause rare ataxia telangiectasia disease and are associated with an increased risk for breast cancer as a result of improper DNA damage response (11). Fanconi anemia (FA) is a rare genetic disorder caused by biallelic mutations in FA genes that also participate in DNA repair. At least 15 FA genes have been identified (12). Patients with heterozygous mutations in certain FA genes have an elevated risk for various cancers, and monoallelic mutations in at least four of these genes [BRCA2, BRIP1, PALB2, and RAD51 paralog C (RAD51C)] are associated with an increased risk of breast or ovarian cancer (12, 13). Recurrent founder mutations in several cancer susceptibility genes, including the BRCA2, PALB2, and RAD51C FA genes, have been identified in the Finnish population (14–16). The PALB2 and RAD51C founder mutations have been detected at 2% frequency in Finnish breast or ovarian cancer families (15–17), whereas, in other populations, mutations in these genes are rare and often unique for each family. Founder effects in the isolated populations such as Finland or Iceland may enrich certain mutations and thus explain a significant proportion of all mutations in certain genes (18, 19). This provides an advantage in the search for novel susceptibility genes and alleles.In this study, we used exome sequencing to uncover previously unidentified recurrent breast or ovarian cancer predisposing variants in the Finnish population with a focus on DNA repair genes. Selected variants were further genotyped in a large case-control sample set. Our investigation revealed an association of a nonsense mutation (rs147021911) in an FA complementation gene, FANCM, with breast cancer, especially with triple-negative (TN) breast cancer (TNBC).     

D-mannose facilitates immunotherapy and radiotherapy of triple-negative breast cancer via degradation of PD-L1

Breast cancer is the most frequent malignancy in women worldwide, and triple-negative breast cancer (TNBC) patients have the worst prognosis and highest risk of recurrence. The therapeutic strategies for TNBC are limited. It is urgent to develop new methods to enhance the efficacy of TNBC treatment. Previous studies demonstrated that D-mannose, a hexose, can enhance chemotherapy in cancer and suppress the immunopathology of autoimmune diseases. Here, we show that D-mannose can significantly facilitate TNBC treatment via degradation of PD-L1. Specifically, D-mannose can activate AMP-activated protein kinase (AMPK) to phosphorylate PD-L1 at S195, which leads to abnormal glycosylation and proteasomal degradation of PD-L1. D-mannose–mediated PD-L1 degradation promotes T cell activation and T cell killing of tumor cells. The combination of D-mannose and PD-1 blockade therapy dramatically inhibits TNBC growth and extends the lifespan of tumor-bearing mice. Moreover, D-mannose–induced PD-L1 degradation also results in messenger RNA destabilization of DNA damage repair–related genes, thereby sensitizing breast cancer cells to ionizing radiation (IR) treatment and facilitating radiotherapy of TNBC in mice. Of note, the effective level of D-mannose can be easily achieved by oral administration in mice. Our study unveils a mechanism by which D-mannose targets PD-L1 for degradation and provides methods to facilitate immunotherapy and radiotherapy in TNBC. This function of D-mannose may be useful for clinical treatment of TNBC.

Breast cancer is the most common type of cancer in women all over the world and is curable in most early-stage, nonmetastatic patients (∼70 to 80%) (1). Triple-negative breast cancer (TNBC), which is characterized by absence of the molecular markers estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) and accounts for ∼15 to 20% of all breast cancer cases (2, 3), has the worst prognosis compared to other subtypes, and the 5-y survival rate for these women if they do not present with metastatic disease is 65 to 90% depending on the disease stage at diagnosis. TNBC is highly invasive and has the highest risk of distant metastasis (∼46%) (1, 4). Notably, the median survival time of patients after metastasis is only 13.3 mo (4). The therapeutic strategies for TNBC are very limited. Until 2019, TNBC treatment was still restricted to chemotherapy (2). Over the past 2 y, immunotherapy, in combination with chemotherapy, has been applied in TNBC treatment and has shown promising results, but a large number of TNBC patients are nonresponsive or resistant to immunotherapy. In addition, radiotherapy can also improve locoregional control of breast cancer. However, TNBC shows resistance to radiotherapy, and radiotherapy did not change the local recurrence rate of TNBC (5). Overall, TNBC treatment is still a challenge, and exploring appropriate systematic treatments and improving the efficacy of immunotherapy and radiotherapy are important goals of breast cancer research.Programmed death ligand 1 (PD-L1, also called B7-H1) is a 33-kDa protein located either on the cell membrane or in the cytoplasm. Membrane-localized PD-L1 can inhibit the proliferation and cytolytic activity of T cells to help cancer cells escape from immune surveillance via interaction with its receptor programmed cell death protein 1 (PD-1) on immune cells (6, 7). Immune checkpoint blockade therapy has been a focus of cancer research and treatment in recent years (8). Immunotherapies targeting PD-1/PD-L1 have shown substantial clinical benefits in different tumor types (9, 10). In addition to its well-established role as an immune checkpoint molecule, intracellular PD-L1 also acts as an RNA-binding protein and competes with RNA exosomes to increase RNA stability globally. Specifically, PD-L1 in the cytoplasm binds with messenger RNAs (mRNAs) of several DNA damage repair (DDR)-related genes and protects them from degradation, which facilitates the DDR and enhances tumor resistance to DNA-damaging therapy (11).Glycosylation is one of the most important posttranslational modifications (PTMs) (12). Glycans have been shown to play different biological roles in glycoproteins, such as assisting correct folding, targeting proteins to specific receptors, controlling the residence time in the bloodstream, and regulating the function of proteins (13). N-glycosylation is one of the most common glycosylation forms on proteins. N-linked glycans are covalently attached to proteins at the asparagine residue of the NXT motif (Asn-X-Ser/Thr) when the new proteins are being translated and transported into the endoplasmic reticulum. All N-glycans share a common core sequence and are further classified into three types: high D-mannose, hybrid, and complex glycans (14, 15). It has been reported that complex N-glycan exists on the extracellular domain of PD-L1 and that PD-L1 is N-glycosylated at N35, N192, N200, and N219 in cancer cells (16), which promotes its stability and suppresses T cell activity. Glycosylation of PD-L1 is also essential for the PD-L1/PD-1 interaction and immunosuppression in TNBC (17). Interestingly, metformin, a drug widely used for the treatment of type 2 diabetes, was reported to induce abnormal glycosylation and degradation of PD-L1 (18).D-mannose, a C-2 epimer of glucose, is the major monosaccharide component of N-glycans and is internalized into mammalian cells via membrane glucose transporters (19). Once taken into cells, D-mannose is phosphorylated by hexokinase (HK) and produces mannose-6-phosphate (M6P), which can be directed into glycolysis or glycosylation pathway (20). Previous studies demonstrated that a supraphysiological level of D-mannose could enhance the sensitivity of cancer cells to chemotherapy (21) and suppress the immunopathology of autoimmune diabetes and airway inflammation (22). D-mannose has also been shown to oppose macrophage activation by impairing IL-1-β production (23). More recently, D-mannose was reported to suppresses oxidative response and block phagocytosis in experimental neuroinflammation (24). However, the function of D-mannose in immunotherapy and radiotherapy in cancer remains unknown. Here, we demonstrated that D-mannose can target PD-L1 for degradation by impairing its glycosylation via AMPK activation. Importantly, oral administration of D-mannose decreased PD-L1 levels in mice, which promoted antitumor immunity and sensitized TNBC to radiotherapy.     

Identify the triple-negative and non-triple-negative breast cancer by using texture features of medicale ultrasonic image: A STROBE-compliant study

The study aimed to explore the value of ultrasound (US) texture analysis in the differential diagnosis of triple-negative breast cancer (TNBC) and non-TNBC.Retrospective analysis was done on 93 patients with breast cancer (35 patients with TNBC and 38 patients with non-TNBC) who were admitted to Taizhou people''s hospital from July 2015 to June 2019. All lesions were pathologically proven at surgery. US images of all patients were collected. Texture analysis of US images was performed using MaZda software package. The differences between textural features in TNBC and non-TNBC were assessed. Receiver operating characteristic curve analysis was used to compare the diagnostic performance of textural parameters showing significant difference.Five optimal texture feature parameters were extracted from gray level run-length matrix, including gray level non-uniformity (GLNU) in horizontal direction, vertical gray level non-uniformity, GLNU in the 45 degree direction, run length non-uniformity in 135 degree direction, GLNU in the 135 degree direction. All these texture parameters were statistically higher in TNBC than in non-TNBC (P <.05). Receiver operating characteristic curve analysis indicated that at a threshold of 268.9068, GLNU in horizontal direction exhibited best diagnostic performance for differentiating TNBC from non-TNBC. Logistic regression model established based on all these parameters showed a sensitivity of 69.3%, specificity of 91.4% and area under the curve of 0.834.US texture features were significantly different between TNBC and non-TNBC, US texture analysis can be used for preliminary differentiation of TNBC from non-TNBC.     

Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy,induces complete responses in triple-negative breast cancer models

Triple-negative breast cancers (TNBCs) are defined by a lack of expression of estrogen, progesterone, and HER2 receptors. Because of the absence of identified targets and targeted therapies, and due to a heterogeneous molecular presentation, treatment guidelines for patients with TNBC include only conventional chemotherapy. Such treatment, while effective for some, leaves others with high rates of early relapse and is not curative for any patient with metastatic disease. Here, we demonstrate that these tumors are sensitive to the heat shock protein 90 (Hsp90) inhibitor PU-H71. Potent and durable anti-tumor effects in TNBC xenografts, including complete response and tumor regression, without toxicity to the host are achieved with this agent. Notably, TNBC tumors respond to retreatment with PU-H71 for several cycles extending for over 5 months without evidence of resistance or toxicity. Through a proteomics approach, we show that multiple oncoproteins involved in tumor proliferation, survival, and invasive potential are in complex with PU-H71-bound Hsp90 in TNBC. PU-H71 induces efficient and sustained downregulation and inactivation, both in vitro and in vivo, of these proteins. Among them, we identify downregulation of components of the Ras/Raf/MAPK pathway and G₂-M phase to contribute to its anti-proliferative effect, degradation of activated Akt and Bcl-xL to induce apoptosis, and inhibition of activated NF-κB, Akt, ERK2, Tyk2, and PKC to reduce TNBC invasive potential. The results identify Hsp90 as a critical and multimodal target in this most difficult to treat breast cancer subtype and support the use of the Hsp90 inhibitor PU-H71 for clinical trials involving patients with TNBC.     

三阴性乳腺癌的临床病理特点及预后因素分析

目的总结三阴性乳腺癌的临床病理学特点及其影响预后的因素。方法回顾性分析111例三阴性乳腺癌患者临床病理特点、复发和生存情况以及影响预后的因素。结果111例三阴性乳腺癌占同期确诊乳腺癌患者人数的9．6％。三阴性乳腺癌患者发病年龄较轻,中位年龄为46．9岁;瘤体较大,肿瘤直径〉5cm的占21．6％（24／111）;临床分期以Ⅱ、Ⅲ期为主,其中Ⅱ期59．5％（66／111）,Ⅲ期29．7％（33／111）。67例（60．4％）患者伴腋窝淋巴结转移,40例（36．0％）患者出现复发或转移。单因素分析结果显示,肿瘤大小、TNM分期、淋巴结状态对患者的总生存率的影响有统计学意义。Cox多因素分析显示,肿瘤大小和腋窝淋巴结N分期是影响预后的独立危险因素。结论三阴性乳腺癌为一种独特的乳腺癌亚型,发病年龄轻,临床分期较晚,复发转移率高,预后较差。     

三阴性乳腺癌的超声影像学研究进展

三阴性乳腺癌(triple negative breast cancer,TNBC)系雌激素受体(estrogen receptor,ER)、孕激素受体(progesterone receptor,PR)和人类表皮生长因子受体-2(human epidermal growth factor receptor-2,HER-2)表达均为阴性的乳腺癌,具有特殊生物学行为及临床病理特征,预后差。该文对三阴性乳腺癌的超声影像学研究进展作一综述。     

Hypoxia-inducible factor 1-dependent expression of platelet-derived growth factor B promotes lymphatic metastasis of hypoxic breast cancer cells

Lymphatic dissemination from the primary tumor is a major mechanism by which breast cancer cells access the systemic circulation, resulting in distant metastasis and mortality. Numerous studies link activation of hypoxia-inducible factor 1 (HIF-1) with tumor angiogenesis, metastasis, and patient mortality. However, the role of HIF-1 in lymphatic dissemination is poorly understood. In this study, we show that HIF-1 promotes lymphatic metastasis of breast cancer by direct transactivation of the gene encoding platelet-derived growth factor B (PDGF-B), which has proliferative and chemotactic effects on lymphatic endothelial cells. Lymphangiogenesis and lymphatic metastasis in mice bearing human breast cancer orthografts were blocked by administration of the HIF-1 inhibitor digoxin or the tyrosine kinase inhibitor imatinib. Immunohistochemical analysis of human breast cancer biopsies demonstrated colocalization of HIF-1α and PDGF-B, which were correlated with lymphatic vessel area and histological grade. Taken together, these data provide experimental support for breast cancer clinical trials targeting HIF-1 and PDGF-B.