Electric charge conversable drug liposomes enable to enhance treatment efficacy of breast cancer

Intrinsic drug resistance has been demonstrated in different types of breast cancer cells, leading to the recurrence of disease after treatment. Here, we report a functional drug liposome that enables electric charge conversion in the weak acidic milieu of cancer to enhance the treatment efficacy of different breast cancers. The functional drug liposomes were developed by encapsulating daunorubicin and rofecoxib, and modified with new functional material, D-alpha tocopherol acid succinate-polyethylene glycol-glutarate (TPGS1000-glutarate). The results demonstrated that the liposomes promoted the effects of cellular uptake and lysosomal escape, followed by targeting the mitochondria. Consequently, the electric charge conversable drug liposomes significantly enhanced the treatment efficacy by initiating a cascade of reactions through inducing autophagy and apoptosis in different breast cancer cells. In conclusion, the electric charge conversable drug liposomes enable to enhance treatment efficacy of different breast cancers, and hence the study could offer a broadly applicable strategy to enhance efficacy against heterogeneous and refractory cancer cells.

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Transcriptional coregualtor NUPR1 maintains tamoxifen resistance in breast cancer cells

Cell Death and Disease ◽

10.1038/s41419-021-03442-z ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Lingling Wang ◽

Jiashen Sun ◽

Yueyuan Yin ◽

Yanan Sun ◽

Jinyi Ma ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Critical Role ◽

Endocrine Resistance ◽

Autophagic Flux ◽

Physical Interaction ◽

Premature Senescence ◽

Breast Cancers ◽

Transcriptional Coregulator

AbstractTo support cellular homeostasis and mitigate chemotherapeutic stress, cancer cells must gain a series of adaptive intracellular processes. Here we identify that NUPR1, a tamoxifen (Tam)-induced transcriptional coregulator, is necessary for the maintenance of Tam resistance through physical interaction with ESR1 in breast cancers. Mechanistically, NUPR1 binds to the promoter regions of several genes involved in autophagy process and drug resistance such as BECN1, GREB1, RAB31, PGR, CYP1B1, and regulates their transcription. In Tam-resistant ESR1 breast cancer cells, NUPR1 depletion results in premature senescence in vitro and tumor suppression in vivo. Moreover, enforced-autophagic flux augments cytoplasmic vacuolization in NUPR1-depleted Tam resistant cells, which facilitates the transition from autophagic survival to premature senescence. Collectively, these findings suggest a critical role for NUPR1 as a transcriptional coregulator in enabling endocrine persistence of breast cancers, thus providing a vulnerable diagnostic and/or therapeutic target for endocrine resistance.

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Transcriptome profiles of stem-like cells from primary breast cancers allow identification of ITGA7 as a predictive marker of chemotherapy response

British Journal of Cancer ◽

10.1038/s41416-021-01484-w ◽

2021 ◽

Author(s):

Noha Gwili ◽

Stacey J. Jones ◽

Waleed Al Amri ◽

Ian M. Carr ◽

Sarah Harris ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Predictive Marker ◽

Therapy Resistance ◽

Differentially Expressed ◽

Molecular Profile ◽

Chemotherapy Response ◽

Breast Cancers

Abstract Background Breast cancer stem cells (BCSCs) are drivers of therapy-resistance, therefore are responsible for poor survival. Molecular signatures of BCSCs from primary cancers remain undefined. Here, we identify the consistent transcriptome of primary BCSCs shared across breast cancer subtypes, and we examine the clinical relevance of ITGA7, one of the genes differentially expressed in BCSCs. Methods Primary BCSCs were assessed using immunohistochemistry and fluorescently labelled using Aldefluor (n = 17). Transcriptomes of fluorescently sorted BCSCs and matched non-stem cancer cells were determined using RNA-seq (n = 6). ITGA7 expression was examined in breast cancers using immunohistochemistry (n = 305), and its functional role was tested using siRNA in breast cancer cells. Results Proportions of BCSCs varied from 0 to 9.4%. 38 genes were significantly differentially expressed in BCSCs; genes were enriched for functions in vessel morphogenesis, motility, and metabolism. ITGA7 was found to be significantly downregulated in BCSCs, and low expression significantly correlated with reduced survival in patients treated with chemotherapy, and with chemoresistance in breast cancer cells in vitro. Conclusions This study is the first to define the molecular profile of BCSCs from a range of primary breast cancers. ITGA7 acts as a predictive marker for chemotherapy response, in accordance with its downregulation in BCSCs.

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Spot 14: A Marker of Aggressive Breast Cancer and a Potential Therapeutic Target

Endocrinology ◽

10.1210/en.2006-0463 ◽

2006 ◽

Vol 147 (9) ◽

pp. 4048-4055 ◽

Cited By ~ 31

Author(s):

William B. Kinlaw ◽

Jennifer L. Quinn ◽

Wendy A. Wells ◽

Christopher Roser-Jones ◽

Joel T. Moncur

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Therapeutic Target ◽

Milk Fat ◽

Breast Cancer Cells ◽

De Novo ◽

Lipid Synthesis ◽

Breast Cancers ◽

Spot 14 ◽

Aggressive Breast Cancer

Spot 14 (S14) is a nuclear protein that communicates the status of dietary fuels and fuel-related hormones to genes required for long-chain fatty acid synthesis. In mammary gland, S14 is important for both epithelial proliferation and milk fat production. The S14 gene is amplified in some breast cancers and is strongly expressed in most. High expression of S14 in primary invasive breast cancer is conspicuously predictive of recurrence. S14 mediates the induction of lipogenesis by progestin in breast cancer cells and accelerates their growth. Conversely, S14 knockdown impairs de novo lipid synthesis and causes apoptosis. We found that breast cancer cells do not express lipoprotein lipase (LPL) and hypothesize that they do not have access to circulating lipids unless the local environment supplies it. This may explain why primary breast cancers with low S14 do not survive transit from the LPL-rich mammary fat pad to areas devoid of LPL, such as lymph nodes, and thus do not appear as distant metastases. Thus, S14 is a marker for aggressive breast cancer and a potential target as well. Future effort will center on validation of S14 as a therapeutic target and producing antagonists of its action.

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Selective Effects of Thioridazine on Self-Renewal of Basal-Like Breast Cancer Cells

Scientific Reports ◽

10.1038/s41598-019-55145-3 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Matthew Tegowski ◽

Cheng Fan ◽

Albert S. Baldwin

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Breast Cancer Cells ◽

Cell Types ◽

Breast Cancer Cell Lines ◽

Breast Cancers ◽

Self Renewal ◽

Basal Like Breast Cancer

AbstractSeveral recent publications demonstrated that DRD2-targeting antipsychotics such as thioridazine induce proliferation arrest and apoptosis in diverse cancer cell types including those derived from brain, lung, colon, and breast. While most studies show that 10–20 µM thioridazine leads to reduced proliferation or increased apoptosis, here we show that lower doses of thioridazine (1–2 µM) target the self-renewal of basal-like breast cancer cells, but not breast cancer cells of other subtypes. We also show that all breast cancer cell lines tested express DRD2 mRNA and protein, regardless of thioridazine sensitivity. Further, DRD2 stimulation with quinpirole, a DRD2 agonist, promotes self-renewal, even in cell lines in which thioridazine does not inhibit self-renewal. This suggests that DRD2 is capable of promoting self-renewal in these cell lines, but that it is not active. Further, we show that dopamine can be detected in human and mouse breast tumor samples. This observation suggests that dopamine receptors may be activated in breast cancers, and is the first time to our knowledge that dopamine has been directly detected in human breast tumors, which could inform future investigation into DRD2 as a therapeutic target for breast cancer.

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Review of: Tamoxifen and TRAIL synergistically induce apoptosis in breast cancer cells

Breast Cancer Online ◽

10.1017/s1470903108006676 ◽

2008 ◽

Vol 11 (2) ◽

Cited By ~ 1

Author(s):

Alison J. Butt

Keyword(s):

Breast Cancer ◽

Tumor Growth ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Single Agent ◽

Xenograft Model ◽

Estrogen Receptor Α ◽

Tumor Xenograft ◽

Breast Cancers ◽

Induced Apoptosis

Citation of original article:C. Lagadec, E. Adriaenssens, R. A. Toillon, V. Chopin, R. Romon, F. Van Coppenolle, H. Hondermarck, X. Le Bourhis. Oncogene advance online publication, 3 September 2007; doi:10.1038/sj.onc.1210749.Abstract of the original article:Tamoxifen (TAM), is widely used as a single agent in adjuvant treatment of breast cancer. Here, we investigated the effects of TAM in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in estrogen receptor-α (ER-α)-positive and -negative breast cancer cells. We showed that cotreatment with TAM and TRAIL synergistically induced apoptosis regardless of ER-α status. By contrast, cotreatment did not affect the viability of normal breast epithelial cells. Cotreatment with TAM and TRAIL in breast cancer cells decreased the levels of antiapoptotic proteins including FLIPs and Bcl-2, and enhanced the levels of proapoptotic proteins such as FADD, caspase 8, tBid, Bax and caspase 9. Furthermore, cotreatment-induced apoptosis was efficiently reduced by FADD- or Bid-siRNA, indicating the implication of both extrinsic and intrinsic pathways in synergistic apoptosis induction. Importantly, cotreatment totally arrested tumor growth in an ER-α-negative MDA-MB-231 tumor xenograft model. The abrogation of tumor growth correlated with enhanced apoptosis in tumor tissues. Our findings raise the possibility to use TAM in combination with TRAIL for breast cancers, regardless of ER-α status.

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The Role of Aryl Hydrocarbon Receptor and Crosstalk with Estrogen Receptor in Response of Breast Cancer Cells to the Novel Antitumor Agents Benzothiazoles and Aminoflavone

International Journal of Breast Cancer ◽

10.4061/2011/923250 ◽

2011 ◽

Vol 2011 ◽

pp. 1-9 ◽

Cited By ~ 23

Author(s):

Mariana A. Callero ◽

Andrea I. Loaiza-Pérez

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Aryl Hydrocarbon Receptor ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Antitumor Agents ◽

Breast Cancers ◽

Nude Mouse Model ◽

Aryl Hydrocarbon ◽

Mcf 7

Many estrogen-receptor- (ER-) expressing breast cancers become refractory to ER-based therapies. New antitumor drugs like aminoflavone (AF) and benzothiazoles (Bzs) have been developed and have exquisite antitumor activity in ER+MCF-7 and T47D cells and in a MCF-7 nude mouse model. ER(−) breast cancer cells like MDA-MB-231 are less susceptible. We previously found in MCF-7 cells that these drugs activate the aryl hydrocarbon receptor (AhR) via translocation to the nucleus, induction of AhR-specific DNA binding activity, and expression of CYP1A1, whose transcription is controlled by the AhR-ARNT transcription factor. CYP1A1 metabolizes AF and Bz to a species which directly or after further metabolism damages DNA. In contrast an AhR-deficient variant of MCF-7 or cells with predominantly nuclear AhR expression, such as MDA-MB 231, are resistant. Thus, these drugs, unlike other neoplastic agents, require AhR-mediated signaling to cause DNA damage. This is a new treatment strategy for breast cancers with intact AhR signaling.

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Evidence of lateral transmission of aggressive features between different types of breast cancer cells

International Journal of Oncology ◽

10.3892/ijo.2017.4128 ◽

2017 ◽

Vol 51 (5) ◽

pp. 1482-1496 ◽

Cited By ~ 8

Author(s):

Nancy Adriana Espinoza-Sánchez ◽

Eduardo Vadillo ◽

Juan Carlos Balandrán ◽

Alberto Monroy-García ◽

Rosana Pelayo ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Different Types ◽

Lateral Transmission

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Inhibiting PAD2 enhances the anti-tumor effect of docetaxel in tamoxifen-resistant breast cancer cells

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-019-1404-8 ◽

2019 ◽

Vol 38 (1) ◽

Cited By ~ 4

Author(s):

Fujun Li ◽

Lixia Miao ◽

Teng Xue ◽

Hao Qin ◽

Santanu Mondal ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Combination Treatment ◽

Breast Cancer Cells ◽

Tamoxifen Resistance ◽

Nuclear Accumulation ◽

Breast Cancers ◽

Inhibition Of Proliferation ◽

Tamoxifen Resistant

Abstract Background Tamoxifen resistance presents a huge clinical challenge for breast cancer patients. An understanding of the mechanisms of tamoxifen resistance can guide development of efficient therapies to prevent drug resistance. Methods We first tested whether peptidylarginine deiminase 2 (PAD2) may be involved in tamoxifen-resistance in breast cancer cells. The effect of depleting or inhibiting PAD2 in tamoxifen-resistant MCF-7 (MCF7/TamR) cells was evaluated both in vitro and in vivo. We then investigated the potential of Cl-amidine, a PAD inhibitor, to be used in combination with tamoxifen or docetaxel, and further explored the mechanism of the synergistic and effective drug regimen of PADs inhibitor and docetaxel on tamoxifen-resistant breast cancer cells. Results We report that PAD2 is dramatically upregulated in tamoxifen-resistant breast cancer. Depletion of PAD2 in MCF7/TamR cells facilitated the sensitivity of MCF7/TamR cells to tamoxifen. Moreover, miRNA-125b-5p negatively regulated PAD2 expression in MCF7/TamR cells, therefore overexpression of miR-125b-5p also increased the cell sensitivity to tamoxifen. Furthermore, inhibiting PAD2 with Cl-amidine not only partially restored the sensitivity of MCF7/TamR cells to tamoxifen, but also more efficiently enhanced the efficacy of docetaxel on MCF7/TamR cells with lower doses of Cl-amidine and docetaxel both in vivo and in vivo. We then showed that combination treatment with Cl-amidine and docetaxel enhanced p53 nuclear accumulation, which synergistically induced cell cycle arrest and apoptosis. Meanwhile, p53 activation in the combination treatment also accelerated autophagy processes by synergistically decreasing the activation of Akt/mTOR signaling, thus enhancing the inhibition of proliferation. Conclusion Our results suggest that PAD2 functions as an important new biomarker for tamoxifen-resistant breast cancers and that inhibiting PAD2 combined with docetaxel may offer a new approach to treatment of tamoxifen-resistant breast cancers.

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Using epigenetic reprogramming to target triple-negative breast cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e14565 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e14565-e14565

Author(s):

D. Sharma ◽

B. B. Knight ◽

R. Yacoub ◽

T. Liu ◽

L. Taliaferro-Smith ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Hormone Receptors ◽

Triple Negative ◽

Combined Treatment ◽

Brdu Incorporation ◽

Breast Cancers

e14565 Background: The outcome for patients with breast cancer has been significantly improved by the use of targeted agents. The prognosis of triple negative (TN) breast cancers, which do not express hormone receptors (ER, PR) or Her2, is poor, because of an aggressive clinical course and lack of targeted therapeutic agents. Epigenetic silencing of specific genes has been observed in breast cancer and some of these genes are more important due to available targeted therapies such as ER. Since all endocrine therapies are designed to block ER function in some way, the identification of new therapies or strategies that could sensitize TN breast cancers to existing endocrine therapy could provide a revolutionary means of treating this aggressive subtype of cancer Methods: We examined the efficacy of combined treatment of HDAC inhibitor LBH589 and DNMT inhibitor decitabine to regenerate ER and PR in TN breast cancer cells using RT-PCR and immunoblotting. Changes in growth and proliferation of TN breast cancer cells in response to LBH589 and decitabine treatment were determined by XTT, BrdU incorporation and colony formation assay. Changes in apoptotic proteins were determined by western blotting. Athymic nude mice were used to establish pre-clinical models for TN breast cancer cells and effectiveness of combined treatment of LBH589 and decitabine was determined. Tumors biopsies were analyzed for ER and PR re-expression by western blot analysis and immunohistochemistry at the end of the treatment. Results: Combined treatment of LBH589 and decitabine resulted in re-expression of ER and PR in TN breast cancers in vitro and in vivo. Although re-expression of ER and PR were noted following LBH589 treatment alone, re-expression was more robust with the combination. TN breast cancer cells showing re-expressed ER can be targeted with tamoxifen. Tamoxifen inhibits growth of TN breast cancer cells re- expressing ER by triggering apoptosis. Conclusions: The importance of epigenetic events such as DNA methylation and HDAC inhibition in tumor progression is becoming increasingly evident. A trial evaluating the ability of LBH589 and decitabine to re- express ER, which can then be targeted by tamoxifen, is planned in patients with metastatic TN breast cancer. No significant financial relationships to disclose.

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Variations in Cell Surfaces of Estrogen Treated Breast Cancer Cells Detected by A Combined Instrument for Far-Field and Near-Field Microscopy

Analytical Cellular Pathology ◽

10.1155/2002/132504 ◽

2002 ◽

Vol 24 (2-3) ◽

pp. 89-100 ◽

Cited By ~ 7

Author(s):

P. Perner ◽

A. Rapp ◽

C. Dressler ◽

L. Wollweber ◽

J. Beuthan ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Surface Topography ◽

Breast Cancer Cells ◽

Light Transmission ◽

Single Cells ◽

Near Field ◽

Far Field ◽

Breast Cancers ◽

General Behaviour

The response of single breast cancer cells (cell line T‐47D) to 17β‐estradiol (E2) under different concentrations was studied by using an instrument that allows to combine far‐field light microscopy with high resolution scanning near‐field (AFM/SNOM) microscopy on the same cell. Different concentrations of E2induce clearly different effects as well on cellular shape (in classical bright‐field imaging) as on surface topography (atomic force imaging) and absorbance (near‐field light transmission imaging). The differences range from a polygonal shape at zero via a roughly spherical shape at physiological up to a spindle‐like shape at un‐physiologically high concentrations. The surface topography of untreated control cells was found to be regular and smooth with small overall height modulations. At physiological E2concentrations the surfaces became increasingly jagged as detected by an increase in membrane height. After application of the un‐physiological high E2concentration the cell surface structures appeared to be smoother again with an irregular fine structure. The general behaviour of dose dependent differences was also found in the near‐field light transmission images. In order to quantify the treatment effects, line scans through the normalised topography images were drawn and a rate of co‐localisation between high topography and high transmission areas was calculated. The cell biological aspects of these observations are, so far, not studied in detail but measurements on single cells offer new perspectives to be empirically used in diagnosis and therapy control of breast cancers.

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