Radiosensitivity of Cancer Cells Is Regulated by Translationally Controlled Tumor Protein

Translationally controlled tumor protein (TCTP) is a ubiquitous multifunctional protein that is essential for cell survival. This study reveals that the regulation of radiosensitivity of cancer cells is yet another function of TCTP. The relationship between endogenous TCTP levels and sensitivity to radiation was examined in breast cancer cell lines (T47D, MDA-MB-231, and MCF7) and lung cancer cells lines (A549, H1299, and H460). Cancer cells with high expression levels of TCTP were more resistant to radiation. TCTP overexpression inhibited radiation-induced cell death, while silencing TCTP led to an increase in radiosensitivity. DNA damage in the irradiated TCTP-silenced A549 cells was greater than in irradiated control shRNA-transfected A549 cells. p53, a well-known reciprocal regulator of TCTP, was increased in irradiated TCTP down-regulated A549 cells. Moreover, introduction of p53 siRNA in TCTP knocked-down A549 cells abrogated the increased radiosensitivity induced by TCTP knockdown. An in vivo xenograft study also confirmed enhanced radiosensitivity in TCTP down-regulated A549 cells. These findings suggest that TCTP has the potential to serve as a therapeutic target to overcome radiation resistance in cancer, a major problem for the effective treatment of cancers.

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A radiosensitizer, gallotannin-rich extract from Bouea macrophylla seeds, inhibits radiation-induced epithelial-mesenchymal transition in breast cancer cells

BMC Complementary Medicine and Therapies ◽

10.1186/s12906-021-03363-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Jiraporn Kantapan ◽

Siwaphon Paksee ◽

Aphidet Duangya ◽

Padchanee Sangthong ◽

Sittiruk Roytrakul ◽

...

Keyword(s):

Breast Cancer ◽

Dna Damage ◽

Cell Death ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Breast Cancer Cell Lines ◽

Mesenchymal Transition ◽

Mammosphere Formation ◽

Radiation Induced

Abstract Background Radioresistance can pose a significant obstacle to the effective treatment of breast cancers. Epithelial–mesenchymal transition (EMT) is a critical step in the acquisition of stem cell traits and radioresistance. Here, we investigated whether Maprang seed extract (MPSE), a gallotannin-rich extract of seed from Bouea macrophylla Griffith, could inhibit the radiation-induced EMT process and enhance the radiosensitivity of breast cancer cells. Methods Breast cancer cells were pre-treated with MPSE before irradiation (IR), the radiosensitizing activity of MPSE was assessed using the colony formation assay. Radiation-induced EMT and stemness phenotype were identified using breast cancer stem cells (CSCs) marker (CD24−/low/CD44+) and mammosphere formation assay. Cell motility was determined via the wound healing assay and transwell migration. Radiation-induced cell death was assessed via the apoptosis assay and SA-β-galactosidase staining for cellular senescence. CSCs- and EMT-related genes were confirmed by real-time PCR (qPCR) and Western blotting. Results Pre-treated with MPSE before irradiation could reduce the clonogenic activity and enhance radiosensitivity of breast cancer cell lines with sensitization enhancement ratios (SERs) of 2.33 and 1.35 for MCF7 and MDA-MB231cells, respectively. Pretreatment of breast cancer cells followed by IR resulted in an increased level of DNA damage maker (γ-H2A histone family member) and enhanced radiation-induced cell death. Irradiation induced EMT process, which displayed a significant EMT phenotype with a down-regulated epithelial marker E-cadherin and up-regulated mesenchymal marker vimentin in comparison with untreated breast cancer cells. Notably, we observed that pretreatment with MPSE attenuated the radiation-induced EMT process and decrease some stemness-like properties characterized by mammosphere formation and the CSC marker. Furthermore, pretreatment with MPSE attenuated the radiation-induced activation of the pro-survival pathway by decrease the expression of phosphorylation of ERK and AKT and sensitized breast cancer cells to radiation. Conclusion MPSE enhanced the radiosensitivity of breast cancer cells by enhancing IR-induced DNA damage and cell death, and attenuating the IR-induced EMT process and stemness phenotype via targeting survival pathways PI3K/AKT and MAPK in irradiated breast cancer cells. Our findings describe a novel strategy for increasing the efficacy of radiotherapy for breast cancer patients using a safer and low-cost natural product, MPSE.

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Electrochemically Reduced Water Delays Mammary Tumors Growth in Mice and Inhibits Breast Cancer Cells SurvivalIn Vitro

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/4753507 ◽

2018 ◽

Vol 2018 ◽

pp. 1-14 ◽

Cited By ~ 3

Author(s):

Giovanni Vanni Frajese ◽

Monica Benvenuto ◽

Rosanna Mattera ◽

Saverio Giampaoli ◽

Elena Ambrosin ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Mammary Tumors ◽

Experimental Models ◽

Breast Cancer Cell Lines ◽

Beneficial Effects ◽

Significant Prolongation ◽

Reduced Water

Electrochemical reduced water (ERW) has been proposed to have beneficial effects on human health due to its rich content of H2and the presence of platinum nanoparticles with antioxidant effects. Many studies have demonstrated that ERW scavenging properties are able to reduce the damage caused by oxidative stress in different experimental models. Although fewin vivostudies have been reported, it has been demonstrated that ERW may display anticancer effects by induction of tumor cells apoptosis and reduction of both angiogenesis and inflammation. In this study, we show that ERW treatment of MCF-7, MDA-MB-453, and mouse (TUBO) breast cancer cells inhibited cell survival in a time-dependent fashion. ERW decreased ErbB2/neuexpression and impaired pERK1/ERK2 and AKT phosphorylation in breast cancer cells. In addition, ERW treatment induced apoptosis of breast cancer cell lines independently of the status of p53 and ER and PR receptors. Ourin vivoresults showed that ERW treatment of transgenic BALB-neuT mice delayed the development of mammary tumors compared to the control. In addition, ERW induced a significant prolongation of tumor-free survival and a reduction in tumor multiplicity. Overall, these results suggest a potential beneficial role of ERW in inhibiting cancer cells growth.

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Loss of an Estrogen Receptor Isoform (ERαΔ3) in Breast Cancer and the Consequences of Its Reexpression: Interference with Estrogen-Stimulated Properties of Malignant Transformation

Molecular Endocrinology ◽

10.1210/mend.11.13.0031 ◽

1997 ◽

Vol 11 (13) ◽

pp. 2004-2015 ◽

Cited By ~ 1

Author(s):

I. Erenburg ◽

B. Schachter ◽

R. Mira y Lopez ◽

L. Ossowski

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Vector Control ◽

Cancer Cells ◽

Dominant Negative ◽

Breast Cancer Cell Lines ◽

Breast Cancers ◽

Normal Breast Epithelium ◽

Anchorage Independent Growth

Abstract Comparison of mRNA ratios of a non-DNA-binding estrogen receptor (ERα) isoform, missing exon 3 (ERαΔ3), to the full-length ERα, in normal breast epithelium to that in primary breast cancers and breast cancer cell lines revealed a 30-fold reduction of this ratio in cancer cells (P < 0.0001). To test what functions may have been affected by the loss of ERαΔ3, stable clones of MCF-7 cells expressing ectopic ERαΔ3 protein, at the range of physiological ERα, were generated. In vector-transfected controls the ERαΔ3-mRNA and protein were less than 10% while in the ERαΔ3-expressing clones, ERαΔ3-mRNA and protein ranged from 36–76% of the total ERα. Estrogen (E2) stimulated the expression of pS2-mRNA in pMV7 vector control cells, but the stimulation was reduced by up to 93% in ERαΔ3-expressing clones. In addition, several properties associated with the transformed phenotype were also strongly affected when ERαΔ3 protein was reexpressed. Compared with vector-transfected control cells, the saturation density of the ERαΔ3-expressing clones was reduced by 50–68%, while their exponential growth rate was only slightly (14.5 ± 5%) lower. The in vivo invasiveness of the ERαΔ3-expressing cells was significantly reduced (P = 0.007) by up to 79%. E2 stimulated anchorage-independent growth of the pMV7 vector control cells, but reduced it to below baseline levels in ERαΔ3 clones. The reduction of the pS2 response to E2 in the ERαΔ3-expressing clones and the E2 block of anchorage-independent growth to below baseline were more pronounced than expected from the dominant negative function of ERαΔ3. These observations suggest that E2 may activate an additional ERαΔ3-dependent inhibitory pathway. The drastic reduction of ERαΔ3 to ERα ratio in breast cancer, and the fact that when present in breast cancer cells this isoform leads to a suppression, rather than enhancement, of the transformed phenotype by E2 suggests that the regulation of ERα-mRNA splicing may need to be altered for the breast carcinogenesis to proceed.

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Matrix Metalloproteinase 8 (Collagenase 2) Induces the Expression of Interleukins 6 and 8 in Breast Cancer Cells

Journal of Biological Chemistry ◽

10.1074/jbc.m113.464230 ◽

2013 ◽

Vol 288 (23) ◽

pp. 16282-16294 ◽

Cited By ~ 37

Author(s):

Sally Thirkettle ◽

Julie Decock ◽

Hugh Arnold ◽

Caroline J. Pennington ◽

Diane M. Jaworski ◽

...

Keyword(s):

Breast Cancer ◽

Matrix Metalloproteinase ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Breast Cancer Cells ◽

Breast Cancer Cell Lines

Matrix metalloproteinase 8 (MMP-8) is a tumor-suppressive protease that cleaves numerous substrates, including matrix proteins and chemokines. In particular, MMP-8 proteolytically activates IL-8 and, thereby, regulates neutrophil chemotaxis in vivo. We explored the effects of expression of either a WT or catalytically inactive (E198A) mutant version of MMP-8 in human breast cancer cell lines. Analysis of serum-free conditioned media from three breast cancer cell lines (MCF-7, SK-BR-3, and MDA-MB-231) expressing WT MMP-8 revealed elevated levels of IL-6 and IL-8. This increase was mirrored at the mRNA level and was dependent on MMP-8 catalytic activity. However, sustained expression of WT MMP-8 by breast cancer cells was non-permissive for long-term growth, as shown by reduced colony formation compared with cells expressing either control vector or E198A mutant MMP-8. In long-term culture of transfected MDA-MB-231 cells, expression of WT but not E198A mutant MMP-8 was lost, with IL-6 and IL-8 levels returning to base line. Rare clonal isolates of MDA-MB-231 cells expressing WT MMP-8 were generated, and these showed constitutively high levels of IL-6 and IL-8, although production of the interleukins was no longer dependent upon MMP-8 activity. These studies support a causal connection between MMP-8 activity and the IL-6/IL-8 network, with an acute response to MMP-8 involving induction of the proinflammatory mediators, which may in part serve to compensate for the deleterious effects of MMP-8 on breast cancer cell growth. This axis may be relevant to the recognized ability of MMP-8 to orchestrate the innate immune system in inflammation in vivo.

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Transferrin-Conjugated Polymeric Nanoparticle for Receptor-Mediated Delivery of Doxorubicin in Doxorubicin-Resistant Breast Cancer Cells

Pharmaceutics ◽

10.3390/pharmaceutics11020063 ◽

2019 ◽

Vol 11 (2) ◽

pp. 63 ◽

Cited By ~ 15

Author(s):

Zar Chi Soe ◽

Jun Bum Kwon ◽

Raj Kumar Thapa ◽

Wenquan Ou ◽

Hanh Thuy Nguyen ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Targeted Delivery ◽

Poloxamer 407 ◽

Multi Drug Resistance ◽

Breast Cancer Cell Lines ◽

Polymeric Nanoparticle ◽

Cellular Apoptosis

In this study, a transferrin (Tf)-conjugated polymeric nanoparticle was developed for the targeted delivery of the chemotherapeutic agent doxorubicin (Dox) in order to overcome multi-drug resistance in cancer treatment. Our objective was to improve Dox delivery for producing significant antitumor efficacy in Dox-resistant (R) breast cancer cell lines with minimum toxicity to healthy cells. The results of our experiments revealed that Dox was successfully loaded inside a transferrin (Tf)-conjugated polymeric nanoparticle composed of poloxamer 407 (F127) and 123 (P123) (Dox/F127&P123-Tf), which produced nanosized particles (~90 nm) with a low polydispersity index (~0.23). The accelerated and controlled release profiles of Dox from the nanoparticles were characterized in acidic and physiological pH and Dox/F127&P123-Tf enhanced Dox cytotoxicity in OVCAR-3, MDA-MB-231, and MDA-MB-231(R) cell lines through induction of cellular apoptosis. Moreover, Dox/F127&P123-Tf inhibited cell migration and altered the cell cycle patterns of different cancer cells. In vivo study in MDA-MB-231(R) tumor-bearing mice demonstrated enhanced delivery of nanoparticles to the tumor site when coated in a targeting moiety. Therefore, Dox/F127&P123-Tf has been tailored, using the principles of nanotherapeutics, to overcome drug-resistant chemotherapy.

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The synergistic effect between celecoxib and luteolin and dependence on estrogen receptor in human breast cancer cells.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.28_suppl.135 ◽

2015 ◽

Vol 33 (28_suppl) ◽

pp. 135-135

Author(s):

Ye-Won Jeon ◽

Youngjin Suh

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Combination Treatment ◽

Breast Cancer Cells ◽

Synergistic Effects ◽

Breast Cancer Cell Lines ◽

Human Breast ◽

Mcf 7

135 Background: The anti-cancer effects of celecoxib and luteolin are well known. Although our previous study demonstrated that the combination of celecoxib and luteolin synergistically inhibits breast tumor growth compared with each of the treatments alone, we did not uncover the molecular mechanisms of these effects. The aims of our present study were to compare the effects of a celecoxib and luteolin combination treatment in four different human breast cell lines and to determine the mechanisms of action in vitro and in vivo. Methods: Using MCF-7, MCF7/HER18, MDA-MB-231 and SkBr3 human breast cancer cells, proliferation assay, apoptosis assay, inhibition assay with MEK and PI3K inhibitor in addition to western blotting and xenograft study after treatment with celecoxib and luteolin. Results: The synergistic effects of a celecoxib and luteolin combination treatment yielded significantly greater cell growth inhibition in all four breast cancer cell lines compared with the single agents alone. In particular, combined celecoxib and luteolin treatment significantly decreased the growth of MDA-MB-231 cancer cells in vivo compared with either agent alone. The celecoxib and luteolin combination treatment induced synergistic effects via Akt inactivation and extracellular signal-regulated kinase (ERK) signaling inhibition in MCF-7 and MCF7/HER18 cells and via Akt inactivation and ERK signaling activation in MDA-MB-231 and SkBr3 cells. Conclusions: These results demonstrate the synergistic anti-tumor effect of the celecoxib and luteolin combination treatment in different four breast cancer cell lines, thus introducing the possibility of this combination as a new treatment modality.

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The relationship of lncRNA NR2F1 and breast cancer angiogenesis via IL-8/lncRNA NR2F1/miR-200s/IL-8 loop.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e12573 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e12573-e12573

Author(s):

Qi Zhang ◽

Jin Zhang ◽

Sihong Lu ◽

Nan Shao ◽

Ying Lin

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Breast Cancer Cells ◽

Cancer Metastasis ◽

Tube Formation ◽

Breast Cancer Cell Lines ◽

Zebrafish Model ◽

The Relationship

e12573 Background: Angiogenesis is key for metastasis and predicts a poor prognosis in breast cancer. Among the pro-angiogenic factors, interleukin-8 (IL-8) could be secreted by tumor cells mediated by microRNA-200 family (miR-200s). Long non-coding RNA (LncRNA), was reported to absorb microRNA to play multiple roles in various diseases including breast cancer. Our preliminary results recognized lncRNA NR2F1 through Agilent Human LncRNA array from breast cancer cells overexpressing IL-8. However, the relationship between LncRNA NR2F1 and breast cancer angiogenesis remains unknown. Methods: Breast cancer cell migration, invasion, proliferation and angiogenesis were assessed by Transwell, CCK8, tube formation, and wound healing assays. The expression of LncRNA NR2F1, miR-200s and IL-8 were detected by qPCR, Western blotting and ELISA. Breast cancer metastasis and angiogenesis in vivo were measured in a zebrafish model. Results: We found that the basal expression of lncRNA NR2F1 is higher in breast cancer cell lines than it in normal cells. In vitro, lncRNA NR2F1 induced breast cancer migration, invasion, and proliferation. Meanwhile, lncRNA NR2F1 promoted human umbilical vascular endothelial cell (HUVEC) proliferation, tube formation, and migration both via breast cancer conditioned medium and via direct HUVEC transfection. In the zebrafish model, lncRNA NR2F1 promoted breast cancer cell metastasis and neo-angiogenesis. Further study disclosed that lncRNA NR2F1 downregulated the expression of miR-200s, which in turn upregulated the expression of IL-8 in breast cancer cells. Conclusions: Our findings suggest that LncRNA NR2F1, as a potential promoter of breast cancer, may induce breast cancer angiogenesis through IL-8/lncRNA NR2F1/miR-200s/IL-8 loop.

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MicroRNA-374b inhibits breast cancer progression through regulating CCND1 and TGFA genes

Carcinogenesis ◽

10.1093/carcin/bgab005 ◽

2021 ◽

Author(s):

Yan Liu ◽

Ai Zhang ◽

Ping-Ping Bao ◽

Li Lin ◽

Yina Wang ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Breast Cancer Cells ◽

Molecular Mechanisms ◽

Breast Cancer Progression ◽

Breast Cancer Cell Lines ◽

Malignant Behavior

Abstract Emerging evidence indicates that microRNAs (miRNAs) play a critical role in breast cancer development. We recently reported that a higher expression of miR-374b in tumor tissues was associated with a better disease-free survival of triple-negative breast cancer (TNBC). However, the functional significance and molecular mechanisms underlying the role of miR-374b in breast cancer are largely unknown. In this current study, we evaluated the biological functions and potential mechanisms of miR-374b in both TNBC and non-TNBC. We found that miR-374b was significantly downregulated in breast cancer tissues, compared to adjacent tissues. MiR-374b levels were also lower in breast cancer cell lines, as compared to breast epithelial cells. In vitro and in vivo studies demonstrated that miR-374b modulates the malignant behavior of breast cancer cells, such as cell proliferation in 2D and 3D, cell invasion ability, colony forming ability, and tumor growth in mice. By using bioinformatics tools, we predicted that miR-374b plays a role in breast cancer cells through negatively regulating cyclin D1 (CCND1) and transforming growth factor alpha (TGFA). We further confirmed that CCND1 and TGFA contribute to the malignant behavior of breast cancer cells in vitro and in vivo. Our rescue experiments showed that overexpressing CCND1 or TGFA reverses the phenotypes caused by miR-374b overexpression. Taken together, our studies suggest that miR-374b modulates malignant behavior of breast cancer cells by negatively regulating CCND1 and TGFA genes. The newly identified miR-374b-mediated CCND1 and TGFA gene silencing may facilitate a better understanding of the molecular mechanisms of breast cancer progression.

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Tumor Suppressor SMAR1 Regulates PKM Alternative Splicing by HDAC6 Mediated Deacetylation of PTBP1

10.21203/rs.3.rs-151525/v1 ◽

2021 ◽

Author(s):

Arpankumar Choksi ◽

Apoorva Parulekar ◽

Richa Pant ◽

Vibhuti Kumar Shah ◽

Ramakrishna Nimma ◽

...

Keyword(s):

Breast Cancer ◽

Alternative Splicing ◽

Tumor Suppressor ◽

Cancer Cells ◽

Warburg Effect ◽

Breast Cancer Cell Lines ◽

Alternative Splicing Events ◽

Isoform Expression ◽

The Warburg Effect

Abstract Background:Highly proliferating cancer cells exhibit the Warburg effect by regulation of PKM alternative splicing and promoting the expression of PKM2. Majority of the alternative splicing events are known to occur in the nuclear matrix where various MARBPs actively participate in the alternative splicing events. SMAR1, being a MARBP and an important tumor suppressor, is known to regulate the splicing of various cancer-associated genes. This study focuses on the regulation of PKM alternative splicing and inhibition of the Warburg effect by SMAR1.Methods:Immunohistochemistry was performed in breast cancer patient samples to establish the correlation between SMAR1 and PKM isoform expression. Further, expression of PKM isoforms upon modulation in SMAR1 expression in breast cancer cell lines was quantified by qRT-PCR and western blot. The acetylation status of PTBP1 was estimated by immunoprecipitation along with its enrichment on PKM pre-mRNA by CLIP in SMAR1 knockdown conditions. The role of SMAR1 in tumor metabolism and tumorigenesis was explored by in vitro enzymatic assays and functional assays upon SMAR1 knockdown. Besides, in vivo tumor formation by injecting adeno-SMAR1 transduced MDA-MB-231 cells in NOD/SCID mice was performed. Results:The expression profile of SMAR1 and PKM isoforms in breast cancer patients revealed that SMAR1 has an inverse correlation with PKM2 and a positive correlation with PKM1. Further quantitative PKM isoform expression upon modulation in SMAR1 expression also reflects that SMAR1 promotes the expression of PKM1 over tumorigenic isoform PKM2. SMAR1 deacetylates PTBP1 via recruitment of HDAC6 resulting in reduced enrichment of PTBP1 on PKM pre-mRNA. SMAR1 inhibits the Warburg effect, tumorigenic potential of cancer cells and in vivo tumor generation in PKM2 dependent manner.Conclusions:SMAR1 regulates PKM alternative splicing by causing HDAC6 dependent deacetylation of PTBP1, resulting in reduced enrichment of PTBP1 on PKM pre-mRNA. Additionally, SMAR1 suppresses glucose utilization and lactate production via repression of PKM2 expression. This suggests that tumor suppressor SMAR1 inhibits tumor cell metabolism and tumorigenic properties of cancer cells via regulation of PKM alternative splicing.

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2-hexyl-4-pentynoic acid (HPTA), a novel radiosensitizer to breast cancer cells through increasing the instability of DNA repair proteins

10.21203/rs.3.rs-80703/v1 ◽

2020 ◽

Author(s):

Zuchao Cai ◽

David Lim ◽

Guochao Liu ◽

Wenwen Ding ◽

Zhendong Wang ◽

...

Keyword(s):

Breast Cancer ◽

Dna Damage ◽

Homologous Recombination ◽

Western Blot ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Breast Cancer Cell Lines ◽

Homologous Recombination Pathway ◽

Recombination Pathway

Abstract Background Breast cancer is one of the most common malignant tumors in the world which is the main cause of cancer death for women. Radiotherapy is the main treatment. Although some drugs have been found to enhance the effect of radiotherapy, there are also obvious deficiencies. Therefore, recent applied clinical research has been focusing on locating a suitable radiosensitizer to breast cancer radiotherapy. Methods MTT, clonogenic survival assays, comet assays, immunofluorescence and western blot analyses were used to detect the effect of VPA / HPTA on DNA damage induced by radiotherapy for breast cancer through a variety of cell models( MCF7, EUFA423, HCC1937, DMBA-induced rat breast cancer-derived primary culture cell and DMBA-induced transformed human normal breast cell line). At the same time, flow cytometry, immunofluorescence and western blot analyses were used to investigate the effect of VPA / HPTA on DNA damage repair induced by radiation. In vivo experiment, the effect of HPTA as radiosensitizer was investigated by DMBA-induced breast cancer in rats. Finally, the possible mechanism of HPTA acting on target protein was proved by cycloheximide chase experiment. Results In this study, a derivative of valproic acid (VPA), 2-hexyl-4-pentynoic acid (HPTA), was demonstrated for the first time that low concentration of HPTA (15 µM) has radiosensitizing properties to breast cancer cells by multiple working models of breast cancer cell lines (in vivo), equivalent to a high concentration of VPA (500 µM). Mechanistic investigations revealed that HPTA induced radiosensitivity through inhibiting the BRCA1-Rad51-mediated homologous recombination pathway. These results were further manifested in breast cancer animal model (in vitro). Most importantly, our study found that HPTA influenced the stability of BRCA1 and Rad51 proteins via shorting their half-life. Conclusions Our findings support the proposition HPTA as an alternate, safe and effective radiosensitizer to tumor cells. Targeting BRCA1-Rad51-mediated homologous recombination pathway through HPTA may be a rational strategy to improve the radiotherapeutic efficacy of breast cancer.

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