Activation of PI3K/Akt/mTOR signaling in the tumor stroma drives endocrine therapy-dependent breast tumor regression

Improved efficacy of neoadjuvant endocrine-targeting therapies in luminal breast carcinomas could be achieved with optimal use of pathway targeting agents. In a mouse model of ductal breast carcinoma we identify a tumor regressive stromal reaction that is induced by neoadjuvant endocrine therapy. This reparative reaction is characterized by tumor neovascularization accompanied by infiltration of immune cells and carcinoma-associated fibroblasts that stain for phosphorylated ribosomal protein S6 (pS6), downstream the PI3K/Akt/mTOR pathway. While tumor variants with higher PI3K/Akt/mTOR activity respond well to a combination of endocrine and PI3K/Akt/mTOR inhibitors, tumor variants with lower PI3K/Akt/mTOR activity respond more poorly to the combination therapy than to the endocrine therapy alone, associated with inhibition of stromal pS6 and the reparative reaction. In human breast cancer xenografts we confirm that such differential sensitivity to therapy is primarily determined by the level of PI3K/Akt/mTOR in tumor cells. We further show that the clinical response of breast cancer patients undergoing neoadjuvant endocrine therapy is associated with the reparative stromal reaction. We conclude that tumor level and localization of pS6 are associated with therapeutic response in breast cancer and represent biomarkers to distinguish which tumors will benefit from the incorporation of PI3K/Akt/mTOR inhibitors with neoadjuvant endocrine therapy.     

CUEDC2通过活化 PI3K／Akt 信号通路促进乳腺癌细胞的生长

目的：探讨 CUE 结构域2（CUE domain －containing 2,CUEDC2）蛋白在人乳腺癌细胞中的生物学作用。方法：人乳腺肿瘤细胞 MCF －7转染的 Myc －CUEDC2真核表达载体,提取转染细胞的总蛋白检测磷酸化 Akt 和总 Akt 的表达变化。利用 CCK －8检测过表达 CUEDC2后 MCF －7细胞的生长。结果：CUEDC2能够活化 Akt,使磷酸化 Akt 表达增加,能够促进人乳腺癌细胞生长。结论：当乳腺癌中 CUEDC2表达增高时,能够引起 PI3K／Akt 信号通路活化,促进肿瘤细胞生长。     

Chemoresistance in breast cancer: PI3K/Akt pathway inhibitors vs the current chemotherapy

Breast cancer is the most prevalent type of cancer among women. Several types of drugs, targeting the specific proteins expressed on the breast cancer cell surface (such as receptor tyrosine kinases and immune checkpoint regulators) and proteins involved in cell cycle and motility (including cyclin-dependent kinases, DNA stabilisers, and cytoskeleton modulators) are approved for different subtypes of breast cancer. However, breast cancer also has a poor response to conventional chemotherapy due to intrinsic and acquired resistance, and an Akt fingerprint is detectable in most drug-resistant cases. Overactivation of Akt and its upstream and downstream regulators in resistant breast cancer cells is considered a major potential target for novel anti-cancer therapies, suggesting that Akt signalling acts as a cellular mechanism against chemotherapy. The present review has shown that sustained activation of Akt results in resistance to different types of chemotherapy. Akt signalling plays a cellular defence role against chemotherapy and (1) enhances multi-drug resistance, (2) increases reactive oxygen species at breast tumor microenvironment, (3) enhances anaerobic metabolism, (4) inhibits the tricarboxylic cycle, (5) promotes PD-L1 upregulation, (6) inhibits apoptosis, (7) increases glucose uptake, and more importantly (8) recruits and interconnects the plasma membrane, nucleus, endoplasmic reticulum, and mitochondria to hijack breast cancer cells and rescue these cells from chemotherapy. Therefore, Akt signalling is considered a cellular defence mechanism employed against chemotherapeutic effects. In addition, interfering roles of PI3K/Akt signalling on the current cytotoxic and molecularly targeted therapy as well as immunotherapy of breast cancer are discussed with a clinical approach. Although, alpelisib, a PIK3CA inhibitor, is the only PI3K/Akt pathway inhibitor approved for breast cancer, we also highlight well-evaluated inhibitors of PI3K/Akt signalling based on different subtypes of breast cancer, which are under clinical trials whether as monotherapy or in combination with other types of chemotherapy.     

PI3K/Akt/mTOR信号通路抑制剂在乳腺癌中的研究进展

目的:总结PI3K/Akt/mTOR信号通路靶向治疗在乳腺癌中的研究进展.方法:以“PI3K/Akt/mTOR、信号通路和乳腺癌”等为关键词,检索2000-01-2011-06 PubMed、Ovid和Springer等数据库的相关文献.纳入标准:1)关于PI3K/Akt/mTOR信号通路的组成、功能特点;2)PI3K/Akt/mTOR信号通路与乳腺癌的关系研究;3)以PI3K/Akt/mTOR信号通路中关键分子为靶点的乳腺癌治疗.根据纳入标准,符合分析的文献40篇.结果:信号转导通路的异常是肿瘤发生、发展的重要步骤,PI3K/Akt/mTOR信号通路与人类多种肿瘤密切相关,其在肿瘤细胞的增殖、存活、抵抗凋亡、血管发生和转移以及对放化疗抵抗中发挥了重要作用.乳腺癌中常见PI3K/Akt/mTOR信号通路的异常激活,以此通路为靶点的药物已成为乳腺癌治疗的研究热点.结论:靶向PI3K/Akt/mTOR通路中关键分子的众多药物在乳腺癌开展了一系列相关的临床试验研究,一部分显示出较好的安全性和有效性.随着对PI3K/Akt/mTOR通路的分子生物学机制的深入研究,期待靶向此通路的抑制剂将会在乳腺癌治疗中发挥巨大的作用,进一步提高乳腺癌患者的疗效和改善预后.     

ＰＩ３Ｋ／Ａｋｔ信号传导通路及其在结直肠癌中的研究进展

结直肠癌是常见的恶性肿瘤之一,近十年来,结直肠癌在我国的发病率呈逐年上升的趋势。已有研究表明,ＰＩ３Ｋ／Ａｋｔ信号传导通路是与细胞增殖和细胞凋亡关系最密切的信号传导通路之一。随着ＰＩ３Ｋ／ＡＫｔ信号通路在结直肠癌发生、发展中的研究不断深入,该通路对结直肠癌发生、发展及治疗药物的研发具有十分重要的价值。本文就ＰＩ３Ｋ／Ａｋｔ信号传导通路在结直肠癌发生、发展和治疗中的作用以及机制的研究进展作一综述。     

Endocrine resistance associated with activated ErbB system in breast cancer cells is reversed by inhibiting MAPK or PI3K/Akt signaling pathways

Endocrine therapy resistance is one of the main challenges in the treatment of estrogen receptor positive (ER+) breast cancer patients. This study showed that two ER+ human breast carcinoma cell lines derived from MCF‐7 (MVLN cells) that have acquired under OH‐Tamoxifen selection two distinct phenotypes of endocrine resistance both displayed constitutive activation of the PI3K/Akt and MAPK pathways. Aberrant expression and activation of the ErbB system (phospho‐EGFR, phospho‐ErbB2, phospho‐ErbB3, over‐expression of ErbB4 and over‐expression of several ErbB ligands) were also observed in the two resistant cell lines, suggesting the existence of an autocrine loop leading to constitutive activation of MAPK and PI3K/Akt survival pathways. The recent clinical use of specific signal transduction inhibitors is one of the most promising therapeutic approaches in breast cancers. The MEK inhibitor PD98059 and the PI3K inhibitor LY294002 were both able to enhance the cytostatic effect of OH‐Tamoxifen or fulvestrant on MVLN sensitive cells. In the two resistant cell lines, inhibition of the MAPK or the PI3K/Akt pathways associated with endocrine therapy was sufficient to reverse OH‐Tamoxifen or fulvestrant resistance. Investigating the effect of a combination of both inhibitors on the reversion of OH‐Tamoxifen and fulvestrant resistance in the two resistant cell lines suggested that, in clinical practice, a strategy combining the two inhibitors would be the best approach to target the different endocrine resistance phenotypes possibly present in a tumor. In conclusion, the combination of MAPK and PI3K inhibitors represents a promising strategy to overcome endocrine therapy resistance in ER+ breast cancer patients.     

贝母素乙通过调控PI3K/Akt信号通路诱导乳腺癌MCF-7细胞凋亡

目的：探究贝母素乙（Peiminine）对乳腺癌细胞MCF-7细胞凋亡的影响及其可能作用机制。方法：采用不同浓度贝母素乙或联合PI3K抑制剂LY294002干预MCF-7细胞,MTT法检测细胞增殖能力;Hoechst33258染色和Annexin V-FITC/PI流式细胞术检测细胞凋亡情况;JC-1染色法检测细胞线粒体膜电位变化;Western blotting检测细胞中PI3K(p110α)、Akt、p-Akt(ser473)、Bad、Bax、Bcl-2、cleaved-Caspase-3以及线粒体和胞浆中细胞色素C(Cyt C)等蛋白表达水平。结果：贝母素乙可呈时间-浓度依赖性抑制MCF-7细胞增殖,诱导细胞出现凋亡形态改变,促进细胞凋亡,并降低线粒体膜电位,上调细胞中Bad、Bax、cleaved-Caspase-3及胞浆中Cyt C蛋白表达水平,下调PI3K(p110α)、p-Akt、Bcl-2和线粒体中Cyt C蛋白表达水平,而Akt蛋白表达水平无显著变化。然而,联合LY294002干预可增强贝母素乙对MCF-7细胞凋亡的促进作用。结论：贝母素乙可诱导乳腺癌MCF-7细胞凋...     

Prevalence of hormone receptors and HER2/neu in breast cancer cases in Jordan

The management and prognosis of breast cancer nowadays require the evaluation of Estrogen (ER), Progesterone Receptors (PR) and HER2/neu. Ethnic variation in the expression of these receptors is well documented. The aim of this study is to determine the prevalence of ER, PR and HER2/neu among Jordanian women with breast cancer of ductal and lobular types. A retrospective analysis was performed on 267 cases of breast cancer referred for treatment at King Hussein Cancer Center, Jordan between the period of June 2003 and June 2004. Standard immune stains were used for evaluation of hormone receptors and HER2/neu. In addition, evaluation of HER2/neu was done by FISH in selected cases. Of these 267 cases, 240 (89.9%) were ductal carcinomas of various histological grades, 122 (50.8%) of which were ER-positive, 138 (57.5%) PRpositive and 42 (17.5%) HER2/neu-positive. Twentytwo (8.2%) of all cases were lobular carcinomas, 15 (68%) of which were ER-positive, 20 (90.9%) PRpositive and 3 (13.6%) HER2/neu-positive. Five (1.9%) of the total cases were of mixed lobular and ductal types, 4 (80%) of which were ER-positive, 3 (60%) PR-positive and none were positive for HER2/neu. The prevalence of hormone receptor positivity in breast cancer of Jordanian women is lower than that of the western populations and close to other populations such as the Chinese and the minor ethnic groups of Northern America (African Americans).     

Increased signalling of EGFR and IGF1R, and deregulation of PTEN/PI3K/Akt pathway are related with trastuzumab resistance in HER2 breast carcinomas

Background:

Trastuzumab resistance hampers its well-known efficacy to control HER2-positive breast cancer. The involvement of PI3K/Akt pathway in this mechanism is still not definitively confirmed.

Methods:

We selected 155 patients treated with trastuzumab after development of metastasis or as adjuvant/neoadjuvant therapy. We performed immunohistochemistry for HER2, ER/PR, epidermal growth factor 1-receptor (EGFR), α-insulin-like growth factor 1-receptor (IGF1R), phosphatase and tensin homologue (PTEN), p110α, pAkt, pBad, pmTOR, pMAPK, MUC1, Ki67, p53 and p27; mutational analysis of PIK3CA and PTEN, and PTEN promoter hypermethylation.

Results:

We found 46% ER/PR-positive tumours, overexpression of EGFR (15%), α-IGF1R (25%), p110α (19%), pAkt (28%), pBad (22%), pmTOR (23%), pMAPK (24%), MUC1 (80%), PTEN loss (20%), and PTEN promoter hypermethylation (20%). PIK3CA and PTEN mutations were detected in 17% and 26% tumours, respectively. Patients receiving adjuvant trastuzumab with α-IGF1R or pBad overexpressing tumours presented shorter progression-free survival (PFS) (all P⩽0.043). Also, p110α and mTOR overexpression, liver and brain relapses implied poor overall survival (OS) (all P⩽0.041). In patients with metastatic disease, decreased PFS correlated with p110α expression (P=0.024), whereas for OS were the presence of vascular invasion and EGFR expression (P⩽0.019; Cox analysis).

Conclusion:

Our results support that trastuzumab resistance mechanisms are related with deregulation of PTEN/PI3K/Akt/mTOR pathway, and/or EGFR and IGF1R overexpression in a subset of HER2-positive breast carcinomas.     

Akt is frequently activated in HER2/neu-positive breast cancers and associated with poor prognosis among hormone-treated patients

Akt/PKB is a serine/threonine kinase that plays an important role in survival when cells are exposed to different apoptotic stimuli. Aberrant activation of Akt/PKB in breast carcinoma is associated with poor prognosis and resistance to endocrine therapy and chemotherapy. The Akt signaling pathway currently attracts considerable attention as a new target for effective therapeutic strategies. We therefore investigated the relationship between activation of Akt and clinicopathologic variables including hormone receptor and HER2/neu status. Breast cancer tissues obtained from 252 patients were utilized for this study. We evaluated Akt activation by immunohistochemical assessment of the expression of phosphorylated Akt (pAkt) at Ser-473. Eighty-four cases (33.3%) were diagnosed as positive for pAkt expression. pAkt was significantly associated with HER2/neu overexpression (p < 0.0001). There was an inverse correlation between pAkt and PR expression (p = 0.0321); however, there was no association between pAkt and ER expression. Survival analysis showed that pAkt positivity was associated with poor disease-free survival in cases with postoperative hormone therapy; however, there was no association in cases without hormone therapy. Our results indicate that Akt activation induced poor prognosis in patients who received adjuvant hormone therapy. This finding suggests that inhibition of the Akt signaling pathway may increase the efficacy of hormone therapy and improve the prognosis of patients who receive adjuvant hormone therapy.     

PI3K/Akt途径在朊蛋白介导胃癌耐药中的作用研究

目的:探讨PI3K/Akt途径在朊蛋白(PrPc)介导胃癌耐药中的作用.方法:脂质体基因转染法建立高表达PrPc的胃癌细胞亚系.Western印迹检测转染细胞中Akt蛋白的表达.噻唑蓝(MTT) 比色法测定单独或联用PI3K抑制剂LY294002时转染细胞对化疗药物的敏感性.流式细胞仪检测单独或联用LY294002时转染细胞内阿霉素蓄积和潴留.结果:将PrPc正义载体pcDNA-PrP转入SGC7901,成功建立PrPc高表达胃癌细胞亚系并命名为PS;空载体转染细胞命名为BS.Western-Blot显示磷酸化Akt在PS中的表达较BS及SGC7901增高,而三者的总Akt则无差别.未经LY294002处理时,在阿霉素或长春新碱的作用下,PS的存活率分别为91.4%±3.4%和89.4%±3.8%,较BS(79.2%±4.3%和75.9%±2.1%)明显增高(均 ),PS细胞内阿霉素蓄积量和潴留量分别为4.4±0.3和4.2±0.4,明显低于BS(8.2±0.5和8.0±0.3)(均 );当联合LY294002处理后,PS在两种药物作用下的存活率均随着LY294002浓度的增加逐渐降低,并均在LY294002为30μmol/L时接近BS(均 ),PS细胞内阿霉素蓄积量和潴留量逐渐增高,并均在LY294002为30μmol/L时接近BS(均 ).结论:PrPc介导的胃癌耐药与PI3K/ Akt途径活性密切相关,抑制PI3K/ Akt途径活性可逆转PrPc介导的胃癌耐药.     

Proliferation,migration and invasion of triple negative breast cancer cells are suppressed by berbamine via the PI3K/Akt/MDM2/p53 and PI3K/Akt/mTOR signaling pathways

Breast cancer is the second most common cause of cancer-associated mortality among women worldwide, and triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Berbamine (BBM) is a traditional Chinese medicine used for the treatment of leukopenia without any obvious side effects. Recent reports found that BBM has anti-cancer effects. The present study aimed to investigate the effects of BBM on TNBC cell lines and the underlying molecular mechanism. MDA-MB-231 cells and MCF-7 cells, two TNBC cell lines, were treated with various concentrations of BBM. A series of bioassays including MTT, colony formation, EdU staining, apoptosis, trypan blue dye, wound healing, transwell, ELISA and western blotting assays were performed. The results showed that BBM significantly inhibited cell proliferation of MDA-MB-231 cells (P<0.05; IC₅₀=22.72 µM) and MCF-7 cells (P<0.05; IC₅₀=20.92 µM). BBM (20 µM) decreased the apoptosis ratio (percentage of absorbance compared with the control group) by 28.4±3.3% (P<0.05) in MDA-MB-231 cells, and 62.4±24.6% (P<0.05) in MCF-7 cells. In addition, BBM inhibited cell migration and invasion of TNBC cells. Furthermore, the expression levels of PI3K, phosphorylated-Akt/Akt, COX-2, LOX, MDM2 and mTOR were downregulated by BBM, and the expression of p53 was upregulated by BBM. These results indicated that BBM may suppress the development of TNBC via regulation of the PI3K/Akt/MDM2/p53 and PI3K/Akt/mTOR signal pathways. Therefore, BBM might be used as a drug candidate for the treatment of TNBC in the future.     

Antibody targeting of HER2/HER3 signaling overcomes heregulin‐induced resistance to PI3K inhibition in prostate cancer

Dysregulated expression and/or mutations of the various components of the phosphoinositide 3‐kinase (PI3K)/Akt pathway occur with high frequency in prostate cancer and are associated with the development and progression of castration resistant tumors. However, small molecule kinase inhibitors that target this signaling pathway have limited efficacy in inhibiting tumor growth, primarily due to compensatory survival signals through receptor tyrosine kinases (RTKs). Although members of the epidermal growth factor receptor (EGFR), or HER, family of RTKs are strongly implicated in the development and progression of prostate cancer, targeting individual members of this family such as EGFR or HER2 has resulted in limited success in clinical trials. Multiple studies indicate a critical role for HER3 in the development of resistance against both HER‐targeted therapies and PI3K/Akt pathway inhibitors. In this study, we found that the growth inhibitory effect of GDC‐0941, a class I PI3K inhibitor, is markedly reduced in the presence of heregulin. Interestingly, this effect is more pronounced in cells lacking phosphatase and tensin homolog function. Heregulin‐mediated resistance to GDC‐0941 is associated with reactivation of Akt downstream of HER3 phosphorylation. Importantly, combined blockade of HER2 and HER3 signaling by an anti‐HER2/HER3 bispecific antibody or a mixture of anti‐HER2 and anti‐HER3 antibodies restores sensitivity to GDC‐0941 in heregulin‐treated androgen‐dependent and ‐independent prostate cancer cells. These studies indicate that the combination of PI3K inhibitors with HER2/HER3 targeting antibodies may constitute a promising therapeutic strategy for prostate cancer.     

Anti-HER-3 MAbs inhibit HER-3-mediated signaling in breast cancer cell lines resistant to anti-HER-2 antibodies

Two members of the EGF receptor family, HER2 and HER3, act as key oncogenes in breast cancer cells. A MAb against HER2, trastuzumab, interferes with HER2 signaling and istherapeutically effective in humans. Here, we explored the biologic effects of an antibody against HER3 (alpha-HER3ECD) in the invasive breast cancer cell lines MCF-7ADR and MDA-MB-468. Pretreating the breast cancer cells with alpha-HER3ECD prior to Heregulin stimulation caused significant reduction of the migratory and proliferative properties. This reduction is due to a substantial decrease in the tyrosine phosphorylation content of HER2 and to a modification of the HER2/HER3 association, which ultimately inhibits the activity of the downstream effectors phosphatidyinositol-3-OH-kinase and c-jun-terminal kinase. Furthermore, HER3 is internalized and not activated by HRG after pretreatment with alpha-HER3ECD. Our data reinforce the notion that HER3 could be a key target in cancer drug design and show the great potential of anti-HER3 antibodies for the therapy of breast cancer and other malignancies characterized by overexpression of HER3.     

Therapy after cyclin-dependent kinase inhibition in metastatic hormone receptor-positive breast cancer: Resistance mechanisms and novel treatment strategies

Endocrine therapy has been the standard of care for patients with metastatic hormone receptor (HR)-positive, HER2-negative breast cancer since the 1970s, improving survival while avoiding the toxicities associated with cytotoxic chemotherapy. However, all HR-positive tumors ultimately develop resistance to endocrine therapy. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have more recently become an important component of the management of this breast cancer subtype, significantly delaying time to the disease progression and improving survival when combined with endocrine therapy. However, as with endocrine therapy alone, treatment resistance remains a universal phenomenon. As more women receive CDK4/6 inhibitors as part of their treatment, the management of de novo and acquired resistance to combined CDK4/CDK6 inhibitor plus endocrine therapy regimens has emerged as an important clinical challenge. Several resistance mechanisms have been described, including alterations in the CDK4/6/cyclin D complex or its major effector retinoblastoma protein (pRb), bypass signaling through other cyclin/CDK complexes and activation of upstream signaling pathways, in particular the PI3K/mTOR pathway, but robust biomarkers to predict resistance remain elusive, and the role for continuing CDK4/6 inhibitors after progression remains under investigation. Novel strategies being evaluated in clinical trials include the continuation of CDK4/6 inhibitors through progression, as well as triplet therapy combinations with PI3K inhibitors or immune checkpoint inhibitors.     

PI3K／Akt途径在朊蛋白介导胃癌耐药中的作用研究

目的：探讨P13K／Akt途径在朊蛋白（PrPc）介导胃癌耐药中的作用。方法：脂质体基因转染法建立高表达PrPc的胃癌细胞亚系。Western印迹检测转染细胞中Akt蛋白的表达。噻唑蓝（MTT）比色法测定单独或联用P13K抑制剂LY294002时转染细胞对化疗药物的敏感性。流式细胞仪检测单独或联用LY294002时转染细胞内阿霉素蓄积和潴留。结果：将PrPc正义载体pcDNA—PrP转入SGC7901,成功建立PrPc高表达胃癌细胞亚系并命名为PS;空载体转染细胞命名为BS。Western—Blot显示磷酸化Akt在PS中的表达较Bs及SGC7901增高,而三者的总Akt则无差别。未经LY294002处理时,在阿霉素或长春新碱的作用下,PS的存活率分别为91．4％±3．4％和89．4％±3．8％,较BS（79．2％±4．3％和75．9％±2．1％）明显增高（均）,PS细胞内阿霉素蓄积量和潴留量分别为4．4±0．3和4．2±0．4,明显低于BS（8．2±0．5和8．0±0．3）（均）;当联合LY294002处理后,PS在两种药物作用下的存活率均随着LY294002浓度的增加逐渐降低,并均在LY294002为30tLmol／L时接近BS（均）,PS细胞内阿霉素蓄积量和潴留量逐渐增高,并均在LY294002为30μmol／L时接近BS（均）。结论：PrPc介导的胃癌耐药与P13K／Akt途径活性密切相关,抑制P13K／Akt途径活性可逆转PrPc介导的胃癌耐药。     

PI3K/Akt信号通路在RANKL诱导的MCF-7乳腺癌细胞迁移中的作用

目的：核因子-κB受体活化因子配体（RANKL）能促进表达RANK的上皮癌细胞迁移至骨,与乳腺癌骨转移密切相关。本文探讨磷脂酰肌醇-3-激酶/丝苏氨酸蛋白激酶（phosphoinositide3-kinase/serine/threonine protein kinase PI3K/Akt）信号通路在RANKL诱导的乳腺癌MCF-7细胞迁移中的作用。方法：流式细胞仪检测MCF-7细胞表面RANK蛋白的表达;Transwell法测定RANKL刺激后MCF-7细胞迁移能力的改变;Western-blot检测MCF-7细胞RANKL刺激后p-Akt及Akt的表达。SPSS 16.0软件分析实验数据。结果：MCF-7细胞表达RANK蛋白,RANKL诱导MCF-7细胞迁移能力显著增强,RANKL的圈套受体OPG可阻断RANKL诱导的细胞迁移。RANKL刺激后MCF-7细胞p-Akt表达在1、5分钟时一过性升高,PI3K抑制剂LY294002显著抑制RANKL诱导的细胞迁移。结论：PI3K/Akt信号通路参与RANKL诱导的乳腺癌细胞系MCF-7迁移。     

Fascin is involved in the chemotherapeutic resistance of breast cancer cells predominantly via the PI3K/Akt pathway

Background:

A major therapeutic challenge for breast cancer is the ability of cancer cells to evade killing of conventional chemotherapeutic agents. We have recently reported the actin-bundling protein (fascin) as a major regulator of breast cancer metastasis and survival.

Methods:

Survival of breast cancer patients that received chemotherapy and xenograft tumour model was used to assess the effect of chemotherapy on fascin-positive and -negative breast cancer cells. Molecular and cellular assays were used to gain in-depth understanding of the relationship between fascin and chemoresistance.

Results:

We showed a significant correlation between fascin expression and shorter survival in breast cancer patients who received chemotherapy. In xenograft experiments, fascin-positive cancer cells displayed significantly more resistance to chemotherapy-mediated apoptotic cell death than fascin-negative counterparts. This increased chemoresistance was at least partially mediated through PI3K/Akt signalling, and was paralleled by increased FAK phosphorylation, enhanced expression of the inhibitor of apoptosis proteins (XIAP and Livin) and suppression of the proapoptotic markers (caspase 9, caspase 3 and PARP).

Conclusions:

This is the first report to demonstrate fascin involvement in breast cancer chemotherapeutic resistance, supporting the development of fascin-targeting drugs for better treatment of chemoresistance breast cancer.