Inhibition of EGFR autophosphorylation plays an important role in the anti-breast cancer efficacy of the dithiocarbamate derivative TM208

Aim： To investigate the effects of a novel dithiocarbamate derivative TM208 on human breast cancer cells as well as the pharmacoki- netic characteristics of TM208 in human breast cancer xenograft mice. Methods： Human breast cancer MCF-7 and MDA-MB-231 cells were treated with TM208 or a positive control drug tamoxifen. Cell pro- liferation was examined using SRB and colony formation assays. Cell apoptosis was analyzed with Annexin V-FITC/PI staining assay. Protein expression was examined with Western blot, ELISA and immunohistochemical analyses. MCF-7 breast cancer xenograft nude mice were orally administered TM208 （50 or 150 mg.k$1〈1-1） or tamoxifen （50 mg.kgl〈t-~） for 18 d. On d 19, the tumors were collected for analyses. Blood samples were collected from the mice treated with the high dose of TM208, and plasma concentrations of TM208 were measured using LC-MS/MS. Results： Treatment of MCF-7 and MDA-MB-231 cells with TM208 dose-dependently inhibited the cell proliferation and colony formation in vitro （the IC~o values were 36.38＋3.77 and 18.13＋0.76 pmol/L, respectively）. TM208 （20-150pmol/L） dose-dependently induced apoptosis of both the breast cancer cells in vitro. In MCF-7 breast cancer xenograft nude mice, TM208 administration dose-depend- ently reduced the tumor growth, but did not result in the accumulation of TM208 or weight loss. TM208 dose-dependently inhibited the phosphorylation of EGFR and ERK1/2 in both the breast cancer cells in vitro as well as in the MCF-7 xenograft tumor. Conclusion： Inhibition of EGFR autophosphorylation plays an important role in the anticancer effect of TM208 against human breast cancer.     

Quercetin exerts bidirectional regulation effects on the efficacy of tamoxifen in estrogen receptor‐positive breast cancer therapy: An in vitro study

Tamoxifen was widely applied in the therapy of estrogen receptor (ER)‐positive breast cancer. With the purpose of determining the potential impacts of quercetin on its effectiveness, MCF‐7 cells were selected as the in vitro model and several cellular biological behaviors (ie, cell proliferation, migration, invasion, cycle, apoptosis, and oxidative stress) were investigated. As results, quercetin showed contrasting dose‐response to cellular behaviors dependent on the ROS‐regulated p53 signaling pathways. In detail, quercetin promoted cell proliferation and inhibited cell apoptosis at low concentrations, whereas high‐concentration resulted in apoptosis induction. Moreover, quercetin at a low concentration significantly inhibited tamoxifen‐induced antiproliferation in MCF‐7 cells, whereas high concentrations enhanced cell apoptosis in a synergetic manner. The real‐time quantitative polymerase chain reaction analysis further implied that quercetin exerted its dual roles in tamoxifen‐induced antiproliferative effects by regulated the gene expression involved in cell metastasis, cycle, and apoptosis through the ER pathways. Our present study provides a considerable support to the combination of quercetin and tamoxifen on human ER‐positive breast carcinoma management.     

Pharmacokinetic-pharmacodynamic modeling of the anticancer effect of TM208 on non-small cell lung cancer xenograft

In the present study, we aimed to investigate the anticancer effect of TM208 (4-methylpiperazine-1-carbodithioc-acid-3-cyano-3,3-diphenylpropyl ester hydrochloride) on non-small cell lung cancer (NSCLC). Moreover, pharmacokinetic-pharmacodynamic (PK-PD) model was developed to describe and simulate the time-course of the drug response in A549 xenograft model. The inhibition rates of two treatment groups (TM208 100 mg/kg group and TM208 150 mg/kg group) in A549 xenograft model were first compared with both vehicle and positive control groups. Subsequently, natural tumor growth model was built and finally PK-PD model was established based on the PD data of the vehicle control group and TM208 treatment groups. In addition, the model was further evaluated, and the anti-cancer efficacy under different regimens was simulated. Our results showed that NSCLC was one potential indication of TM208 and TM208 150 mg/kg QD would be an effective regimen. For parameters about tumor growth, the initial volume was 0.134 cm³ and the growth rate was 0.0869 day^–1. For parameters about drug efficacy, the killing factor was 0.174 mL/μg/dand average transit rate among transit compartments was 0.173 day^–1. Among various regimens in the step of simulation, TM208 900 mg/kg QW, which was a hypothetical regimen without experimental data support yet, showed similar anticancer effect compared with TM208 150 mg/kg QD. In conclusion, the anti-cancer effect of TM208 on NSCLC was demonstrated by the pre-clinical experiment and confirmed by the developed PK-PD model. Moreoever, results from model simulation would be helpful for further translational research of TM208.     

The potential role of estrogen receptors and the SRC family as targets for the treatment of breast cancer

Background: Breast cancer has a number of subtypes, the main ones are estrogen-receptor (ER)-positive, luminal type A and B. Treatment selection, with respect to hormonal therapy, is based upon ER expression. Whilst for ER-positive cancers, endocrine therapy is highly successful in the adjuvant setting, a significant proportion of cancers exhibit hormone resistance, often associated with altered growth factor receptor or ER signalling. Modulation of steroid receptor function by receptor co-activators or repressors is a potential mechanism of resistance. The p160 or SRC proto-oncogene family of co-activators are important in breast cancer response to endocrine therapy and can act as a paradigm of co-activator function. Objective/methods: This review focuses on the role of ER and ER co-activators in breast cancer and current approaches to targeting SRC co-factors for treatment of hormone-receptor-positive breast cancer. Results/conclusions: There is a drive to selectively apply aromatase inhibitors on the basis of either risk or biological evidence of resistance to tamoxifen treatment. Both strategies may yield improved treatment to benefit ratios.     

GPER-1/GPR30 a novel estrogen receptor sited in the cell membrane: therapeutic coupling to breast cancer

Introduction: Breast cancer is clinically classified as ‘estrogen-positive’ when at least 1% of cancer cells stain for the estrogen receptor alpha (ERα). However, recent research on both basic and clinical aspects of breast cancer suggests that GPER-1 (G protein-coupled estrogen receptor-1) may have an important role in breast cancer.

Areas covered: This review provides a comprehensive and systematic literature search on GPER-1. We have focused on the role of GPER-1 in breast cancer and on resistance to endocrine therapy, an unsolved clinical issue still under discussion.

Expert opinion: The discovery of GPER-1 as a novel estrogen receptor is unique and the signaling pathways activated by its stimulation, when compared to the classical nuclear ERα, indicate a potential role of GPER-1 in the genesis and mechanisms of drug resistance in breast cancer. Tumors expressing ERα represent the largest group of breast cancer patients indicating that more women eventually die from ERα-positive breast tumors than from other more malignant breast cancer subtypes such as HER2-positive and the triple negative groups. It is important to develop new strategies on endocrine therapy with regard to ERα and GPER-1 receptors to achieve innovative successful therapeutic tools.     

Antitumor effects of deguelin on H460 human lung cancer cells in vitro and in vivo: Roles of apoptotic cell death and H460 tumor xenografts model

Deguelin, a naturally occurring rotenoid of the flavonoid family, is known to be an Akt inhibitor, to have chemopreventive activities and anti‐tumor effect on several cancers. In this study, investigation to elucidate the effect of deguelin on apoptotic pathways in human lung cancer cells and on the anti‐tumor effect in lung cancer xenograft nu/nu mice was performed. In vitro studies, found that deguelin induced cell morphological changes, and decreased the percentage of viability through the induction of apoptosis in H460 lung cancer cells. Deguelin triggered apoptosis in H460 cells was also confirmed by DAPI staining, DNA gel electrophoresis, and Annexin V‐FITC staining and these effects are dose‐dependent manners. It was also found that deguelin promoted the Ca²⁺ production and activation of caspase‐3 but decreased the level of ΔΨ _m in H460 cells. Western blots indicated that the protein levels of cytochrome c , AIF, and pro‐apoptotic Bax and Bak protein were increased, but the anti‐apoptotic Bcl‐2 and Bcl‐x were decreased that may have led to apoptosis in H460 cells after exposure to deguelin. It was also confirmed by confocal laser microscope examination that deguelin promoted the release of AIF from mitochondria to cytosol. In vivo studies, found that in immunodeficient nu/nu mice bearing H460 tumor xenografts showed that the deguelin significantly suppressed tumor growth. Deguelin might be a potential therapeutic agent for the treatment of lung cancer in the future. This finding might fully support a critical event for deguelin via induction of apoptotic cell death and H460 tumor xenografts model against human lung cancer. © 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 84–98, 2017.     

Pharmacokinetic-pharmacodynamic modeling of the anticancer effect of erlotinib in a human non-small cell lung cancer xenograft mouse model

Aim： Erlotinib is used to treat non-small-cell lung cancer （NSCLC）, which targets epidermal growth factor receptor （EGFR） tyrosine kinase. The aim of this study was to investigate the relationship between erlotinib plasma concentrations and phosphorylated EGFR （pEGFR） levels, as well as the relationship between pEGFR levels and tumor growth inhibition in a human non-small-cell lung cancer xenograft mouse model. Methods： Female BALB/c nude mice were implanted with the human NSCLC cell line SPC-A-1. The animals were given via gavage a single dose of erlotinib （4, 12.5, or 50 mg/kg）. Pharmacokinetics of erlotinib was determined using LC-MS/MS. Tumor volume and pEGFR levels in tumor tissues were measured at different time points after erlotinib administration, The levels of pEGFR in tumor tissues was detected using Western blotting and ELISA assays. Results： The pharmacokinetics of erlotinib was described by a two-compartment model with first order extravascular absorption kinetics. There was a time delay of approximately 2 h between erlotinib plasma concentrations and pEGFR degradation. The time course of pEGFR degradation was reasonably fit by the indirect response model with a calculated IC~o value of 1.80 pg/mL. The relationship between pEGFR levels and tumor volume was characterized by the integrated model with a Kbio value of 0.507 cm3/week which described the impact of pEGFR degradation on tumor growth. Conclusion： The pharmacokinetic/pharmacodynamic properties of erlotinib in a human tumor xenograft model were described by the indirect response model and integrated model, which will be helpful in understanding the detailed processes of erlotinib activity and determining an appropriate dosing regimen in clinical studies.     

哇巴因抑制乳腺癌细胞增殖与雌激素受体亚型介导的信号通路有关

目的在确定哇巴因是否经雌激素受体(estrogen re-ceptor,ER)途径发挥抗乳腺癌细胞增殖作用的基础上,进一步探讨ER亚型在哇巴因介导的增殖抑制中的作用。方法选择兼有两种ER亚型表达的人乳腺癌细胞株MCF-7为研究对象,采用MTT法、RNA干扰技术及蛋白印迹检测技术,观察ER亚型对哇巴因介导的细胞增殖抑制作用的影响。结果在0.1～1 000 nmol.L-1浓度范围内,哇巴因以剂量依赖性方式明显抑制MCF-7细胞的增殖活性,该抑制作用可被ER阻断剂ICI 182,780部分阻断。应用RNA干扰技术沉默ERα或ERβ基因表达,进一步证实哇巴因对MCF-7细胞的增殖抑制作用主要由ERα介导。结论哇巴因可通过ERα信号通路对乳腺癌发挥抗肿瘤效应。NKA结合ER可能是未来开发抗乳癌药物的潜在重要靶点。     

A new bisphosphonate derivative,CP, induces gastric cancer cell apoptosis via activation of the ERK1/2 signaling pathway

Aim： To investigate the effects of a new derivative of bisphosphonates, [2-（6-aminopurine-9-yl）-l-hydroxy-phosphine acyl ethyl] phosphonic acid （CP）, on human gastric cancer. Methods： Human gastric cancer cell lines （SGC-7901, BGC-823, MKN-45, and MKN-28） and human colon carcinoma cell lines （LoVo and HT-29） were tested. Cell growth was determined using the MTT assay. Flow cytometry, Western blot, caspase activity assay and siRNA transfection were used to examine the mechanisms of anticancer action. Female BALB/c nude mice were implanted with SGC- 7901 cells. From d6 after inoculation, the animals were injected with CP （200 pg/kg, ip） or vehicle daily for 24 d. Results： CP suppressed the growth of the 6 human cancer cell lines with similar IC5o values （3239 pmol/L）. In SGC-7901 cells, CP arrested cell cycle progression at the G2/M phase. The compound activated caspase-9, increased the expression of pro-apoptotic proteins Bax and Bad, decreased the expression of anti-apoptotic protein Bcl-2. Furthermore, the compound selectively activated ERK1/2 without affecting JNK and p38 in SGC-7901 cells. Treatment of SGC-7901 cells with the specific ERK1/2 inhibitor PD98059 or ERK1/2 siRNA hampered CP-mediated apoptosis. In the human gastric cancer xenograft nude mouse model, chronic administration of CP significantly retarded the tumor growth. Conclusion： CP is a broad-spectrum inhibitor of human carcinoma cells in vitro, and it also exerts significant inhibition on gastric cancer cell growth in vivo. CP induces human gastric cancer apoptosis via activation of the ERK1/2 signaling pathway.     

A new bisphosphonate derivative,CP, induces gastric cancer cell apoptosis via activation of the ERK1/2 signaling pathway

Aim:

To investigate the effects of a new derivative of bisphosphonates, [2-(6-aminopurine-9-yl)-1-hydroxy-phosphine acyl ethyl] phosphonic acid (CP), on human gastric cancer.

Methods:

Human gastric cancer cell lines (SGC-7901, BGC-823, MKN-45, and MKN-28) and human colon carcinoma cell lines (LoVo and HT-29) were tested. Cell growth was determined using the MTT assay. Flow cytometry, Western blot, caspase activity assay and siRNA transfection were used to examine the mechanisms of anticancer action. Female BALB/c nude mice were implanted with SGC-7901 cells. From d6 after inoculation, the animals were injected with CP (200 μg/kg, ip) or vehicle daily for 24 d.

Results:

CP suppressed the growth of the 6 human cancer cell lines with similar IC₅₀ values (3239 μmol/L). In SGC-7901 cells, CP arrested cell cycle progression at the G₂/M phase. The compound activated caspase-9, increased the expression of pro-apoptotic proteins Bax and Bad, decreased the expression of anti-apoptotic protein Bcl-2. Furthermore, the compound selectively activated ERK1/2 without affecting JNK and p38 in SGC-7901 cells. Treatment of SGC-7901 cells with the specific ERK1/2 inhibitor PD98059 or ERK1/2 siRNA hampered CP-mediated apoptosis. In the human gastric cancer xenograft nude mouse model, chronic administration of CP significantly retarded the tumor growth.

Conclusion:

CP is a broad-spectrum inhibitor of human carcinoma cells in vitro, and it also exerts significant inhibition on gastric cancer cell growth in vivo. CP induces human gastric cancer apoptosis via activation of the ERK1/2 signaling pathway.     

药动学/药效学模型研究抗CD3/EpCAM双特异性抗体M701在人结肠癌异种移植小鼠中的抗肿瘤作用

M701 为抗分化簇3/表面上皮细胞黏附因子(cluster of differentiation 3/epithelial cell adhesion molecule,CD3/EpCAM)的双特异性抗体,拟用于治疗癌细胞腹腔转移引起的恶性腹水.本研究应用群体模型方法,构建M701在人结肠癌异种移植小鼠中的药动学/药...     

Physiologically based pharmacokinetic and pharmacodynamic modeling of an antagonist (SM‐406/AT‐406) of multiple inhibitor of apoptosis proteins (IAPs) in a mouse xenograft model of human breast cancer

The inhibitors of apoptosis proteins (IAPs) are a class of key apoptosis regulators overexpressed or dysregulated in cancer. SM‐406/AT‐406 is a potent and selective small molecule mimetic of Smac that antagonizes the inhibitor of apoptosis proteins (IAPs). A physiologically based pharmacokinetic and pharmacodynamic (PBPK‐PD) model was developed to predict the tissue concentration–time profiles of SM‐406, the related onco‐protein levels in tumor, and the tumor growth inhibition in a mouse model bearing human breast cancer xenograft. In the whole body physiologically based pharmacokinetic (PBPK) model for pharmacokinetics characterization, a well stirred (perfusion rate‐limited) model was used to describe SM‐406 pharmacokinetics in the lung, heart, kidney, intestine, liver and spleen, and a diffusion rate‐limited (permeability limited) model was used for tumor. Pharmacodynamic (PD) models were developed to correlate the SM‐406 concentration in tumor to the cIAP1 degradation, pro‐caspase 8 decrease, CL‐PARP accumulation and tumor growth inhibition. The PBPK‐PD model well described the experimental pharmacokinetic data, the pharmacodynamic biomarker responses and tumor growth. This model may be helpful to predict tumor and plasma SM‐406 concentrations in the clinic. Copyright © 2013 John Wiley & Sons, Ltd.     

Chemopreventive and anti‐angiogenic effects of dietary phenethyl isothiocyanate in an N‐methyl nitrosourea‐induced breast cancer animal model

The effect of phenethyl isothiocyanate (PEITC), a component of cruciferous vegetables, on the initiation and progression of cancer was investigated in a chemically induced estrogen‐dependent breast cancer model. Breast cancer was induced in female Sprague Dawley rats (8 weeks old) by the administration of N‐methyl nitrosourea (NMU). Animals were administered 50 or 150 µmol/kg oral PEITC and monitored for tumor appearance for 18 weeks. The PEITC treatment prolonged the tumor‐free survival time and decreased the tumor incidence and multiplicity. The time to the first palpable tumor was prolonged from 69 days in the control, to 84 and 88 days in the 50 and 150 µmol/kg PEITC‐treated groups. The tumor incidence in the control, 50 µmol/kg, and 150 µmol/kg PEITC‐treated groups was 56.6%, 25.0% and 17.2%, while the tumor multiplicity was 1.03, 0.25 and 0.21, respectively. Differences were statistically significant (p < 0.05) from the control, but there were no significant differences between the two dose levels. The intratumoral capillary density decreased from 4.21 ± 0.30 vessels per field in the controls to 2.46 ± 0.25 in the 50 µmol/kg and 2.36 ± 0.23 in the 150 µmol/kg PEITC‐treated animals. These studies indicate that supplementation with PEITC prolongs the tumor‐free survival, reduces tumor incidence and burden, and is chemoprotective in NMU‐induced estrogen‐dependent breast cancer in rats. For the first time, it is reported that PEITC has anti‐angiogenic effects in a chemically induced breast cancer animal model, representing a potentially significant mechanism contributing to its chemopreventive activity. Copyright © 2012 John Wiley & Sons, Ltd.     

肿瘤微环境对乳腺癌发生发展的影响

摘要： 肿瘤微环境 （TME） 在局部耐药性、 免疫逃脱和远端转移等多个肿瘤发生、 发展的步骤中起关键作用。依据 不同个体的 TME, 准确评估和选择临床用药, 可有效控制原位癌和转移癌的恶性转化。目前, 治疗癌症的主要方法 是化疗, 由于 TME 中良性细胞可调节癌细胞对标准化疗和靶向药物治疗的反应, 因此, 结合靶向 TME 治疗会取得更 理想的临床疗效。本文就乳腺癌 TME 中细胞外基质 （ECM）、 肿瘤相关成纤维细胞、 肿瘤相关巨噬细胞、 调节性 T 细 胞和骨髓间质干细胞对肿瘤发生、 发展的作用机制进行综述。     

Hypothesis: prolactin is tumorigenic to human breast: dispelling the myth that prolactin-induced mammary tumors are rodent-specific

The commonly held assumption that rodent mammary tumors resulting from elevated prolactin are species-specific, or not biologically relevant to humans, is incorrect. Substantial epidemiological, clinical, and biological evidence now exists confirming the role of prolactin in human breast cancer. This evidence is evaluated and the argument presented that the tumorigenic risk from prolactin is therefore not species-specific to rodents but directly applies to humans. Further, as the mechanisms of prolactin-induced mammary tumor promotion and development appear analogous between rodents and humans, mammary tumorigenic findings in rodent carcinogenicity bioassays are both predictive and biologically relevant to the human response. Toxicologists and regulators need to consider this in carcinogenicity risk assessments.     

GnRH激动剂对人卵巢癌裸鼠移植瘤抑制作用及不良反应的研究

目的 研究GnRH激动剂对人卵巢癌裸鼠移植瘤抑制作用及副作用.方法 将人卵巢癌细胞OVCAR3注射入裸鼠腹腔内,构建移植瘤模型.将裸鼠随机分为3组,OVCAR3对照组、低剂量曲普瑞林组(75μg)和高剂量曲普瑞林组(150 μg).镜下观察曲普瑞林对全身及腹腔各脏器的毒副作用并测定对内分泌的影响.结果 高剂量曲普瑞林组...     

Perfluorinated chemicals,PFOS and PFOA,enhance the estrogenic effects of 17β‐estradiol in T47D human breast cancer cells

Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are the two most popular surfactants among perfluorinated compounds (PFCs), with a wide range of uses. Growing evidence suggests that PFCs have the potential to interfere with estrogen homeostasis, posing a risk of endocrine‐disrupting effects. This in vitro study aimed to investigate the estrogenic effect of these compounds on T47D hormone‐dependent breast cancer cells. PFOS and PFOA (10^?12 to 10^?4 M) were not able to induce estrogen response element (ERE) activation in the ERE luciferase reporter assay. The ERE activation was induced when the cells were co‐incubated with PFOS (10^?10 to 10^?7 M) or PFOA (10^?9 to 10^?7 M) and 1 nM of 17β‐estradiol (E2). PFOS and PFOA did not modulate the expression of estrogen‐responsive genes, including progesterone (PR) and trefoil factor (pS2), but these compounds enhanced the effect of E2‐induced pS2 gene expression. Neither PFOS nor PFOA affected T47D cell viability at any of the tested concentrations. In contrast, co‐exposure with PFOS or PFOA and E2 resulted in an increase of E2‐induced cell viability, but no effect was found with 10 ng ml^?1 EGF co‐exposure. Both compounds also intensified E2‐dependent growth in the proliferation assay. ERK1/2 phosphorylation was increased by co‐exposure with PFOS or PFOA and E2, but not with EGF. Collectively, this study shows that PFOS and PFOA did not possess estrogenic activity, but they enhanced the effects of E2 on estrogen‐responsive gene expression, ERK1/2 activation and the growth of the hormone‐deprived T47D cells. Copyright © 2015 John Wiley & Sons, Ltd.     

Induction of apoptosis in estrogen dependent and independent breast cancer cells by the marine terpenoid dehydrothyrsiferol

Breast cancer (BCA) represents the highest incidence of death in 35- to 60-year-old women. Above all, hormone unresponsive BCA is still associated with poorer prognosis than hormone receptor expressing malign, mammary tumors. There is a consistent need for effective compounds to treat especially the first variant of this disease. Therefore, we investigated the cytotoxic effects of the marine polyether triterpenoid dehydrothyrsiferol (DT) in four BCA cell lines. Annexin V labeling revealed higher rates of DT-induced apoptosis in hormone insensitive than in estrogen receptor expressing cells. Flow cytometric analysis of combined DNA fragmentation and total DNA labeling allowed us to ascribe apoptotic cells to their cell cycle stage. Although, high cell mortality was detected in mitogen dependent G(1)-phase, time, concentration, and cell line dependent populations of apoptotic cells were also found to be of S-phase and G(2)/M-phase origin. These results suggest that the induction of apoptosis by DT might be transduced through more than one effector pathway. Cell cycle distributions and 5-bromo-2'-deoxyuridine incorporation varied in a treatment dependent manner and differed from control experiments with colchicine and doxorubicin which exclude that DT functions as a mitosis inhibitor. In summary, we propose that DT might be an interesting candidate for an antitumor drug development regimen.     

Reduced camptothecin sensitivity of estrogen receptor‐positive human breast cancer cells following exposure to di(2‐ethylhexyl)phthalate (DEHP) is associated with DNA methylation changes

Di(2‐ethylhexyl)phthalate (DEHP) has been considered as an estrogen receptor alpha (ERα) agonist due to its ability to interact with ERα and promote the cell proliferation of ERα‐positive breast cancer cells. The impact of DEHP on the chemical therapy in breast cancer is little known. Two breast cancer cell lines, MCF‐7 (ERα‐dependent) and MDA‐MB‐231 (ERα‐independent) were examined. We found that DEHP impaired the effectiveness of camptothecin (CPT) and alleviated the CPT‐induced formation of reactive oxygen species in ERα‐positive MCF‐7 cells, but not in ERα‐negative MDA‐MB‐231 cells. DEHP also significantly protected MCF‐7 cells against the genotoxicity of CPT. Genome‐wide DNA methylation profiling revealed that after 48 hours of exposure to 100 μM DEHP, MCF‐7 cells exhibited a significant change in their DNA methylation pattern, including hypermethylation of 700 genes and hypomethylation of 221 genes. The impaired therapeutic response to CPT in DEHP‐exposed MCF‐7 cells is probably mediated by epigenetic changes, especially through Wnt/β‐catenin signaling. A zebrafish xenograft model confirmed the disruptive effect of DEHP on CPT‐induced anti‐growth of MCF‐7 cells. In summary, DEHP exposure induces acquired CPT‐resistance in breast cancer cells and epigenetic changes associated with Wnt/β‐catenin signaling activation are probably depending on an ER‐positive status.