Paradoxical Hormone Responses of KPL-1 Breast Cancer Cells in vivo: A Significant Role of Angiogenesis in Tumor Growth

Oncology ◽  
2000 ◽  
Vol 59 (2) ◽  
pp. 158-165 ◽  
Author(s):  
Junichi Kurebayashi ◽  
Hironori Kunisue ◽  
Shigeru Yamamoto ◽  
Masafumi Kurosumi ◽  
Takemi Otsuki ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Significant Role ◽  
Breast Cancer Cells ◽  
Hormone Responses

scholarly journals Antiproliferative Effect of Androgen Receptor Inhibition in Mesenchymal Stem-Like Triple-Negative Breast Cancer

2016 ◽  
Vol 38 (3) ◽  
pp. 1003-1014 ◽  
Author(s):  
Aiyu Zhu ◽  
Yan Li ◽  
Wei Song ◽  
Yumei Xu ◽  
Fang Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Androgen Receptor ◽  
Cyclin D1 ◽  
Cancer Cells ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative

Background/Aims: Androgen receptor (AR), a steroid hormone receptor, has recently emerged as prognostic and treatment-predictive marker in breast cancer. Previous studies have shown that AR is widely expressed in up to one-third of triple-negative breast cancer (TNBC). However, the role of AR in TNBC is still not fully understood, especially in mesenchymal stem-like (MSL) TNBC cells. Methods: MSL TNBC MDA-MB-231 and Hs578T breast cancer cells were exposed to various concentration of agonist 5-α-dihydrotestosterone (DHT) or nonsteroidal antagonist bicalutamide or untreated. The effects of AR on cell viability and apoptosis were determined by MTT assay, cell counting, flow cytometry analysis and protein expression of p53, p73, p21 and Cyclin D1 were analyzed by western blotting. The bindings of AR to p73 and p21 promoter were detected by ChIP assay. MDA-MB-231 cells were transplanted into nude mice and the tumor growth curves were determined and expression of AR, p73 and p21 were detected by Immunohistochemistry (IHC) staining after treatment of DHT or bicalutamide. Results: We demonstrate that AR agonist DHT induces MSL TNBC breast cancer cells proliferation and inhibits apoptosis in vitro. Similarly, activated AR significantly increases viability of MDA-MB-231 xenografts in vivo. On the contrary, AR antagonist, bicalutamide, causes apoptosis and exerts inhibitory effects on the growth of breast cancer. Moreover, DHT-dependent activation of AR involves regulation in the cell cycle related genes, including p73, p21 and Cyclin D1. Further investigations indicate the modulation of AR on p73 and p21 mediated by direct binding of AR to their promoters, and DHT could make these binding more effectively. Conclusions: Our study demonstrates the tumorigenesis role of AR and the inhibitory effect of bicalutamide in AR-positive MSL TNBC both in vitro and in vivo, suggesting that AR inhibition could be a potential therapeutic approach for AR-positive TNBC patients.

PEAK1 promotes invasion and metastasis and confers drug resistance in breast cancer

2021 ◽  
Author(s):  
xingang wang ◽  
YAN ZHENG ◽  
YU WANG
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cell Growth ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Multi Drug Resistance ◽  
Cancer Tissues

Abstract Background and AimsPseudopodium-enriched atypical kinase 1 (PEAK1) has reported to be upregulated in human malignancies and related with poor prognosis. Enhanced PEAK1 expression facilitates tumor cell survival, invasion, metastasis and chemoresistance. However, the role of PEAK1 in breast cancer is not clear. Here, we investigated the PEAK1 expression in breast cancer and analyzed its relation with clinicopathological status and chemotherapy resistance to the neoadjuvant chemotherapy (NAC). We also investigated the role of PEAK1 on breast cancer cells in vitro and in vivo. MethodsImmunohistochemistry (IHC) was performed in 112 surgical resected breast cancer tissues. The associations between clinicopathological status, multi-drug resistance and PEAK1 expression were determined. Effect of PEAK1 overexpression or down-expression on proliferation, colony formation, invasion, migration, metastasis and Doxorubicin sensitivity in the MCF-7 cells in vitro and in vivo was detected. ResultsPEAK1 was overexpressed in breast cancer tissues and NAC -resistant breast cancer tissues. High PEAK1 expression was related with tumor size, high tumor grade, T stage, LN metastasis, recurrence, Ki-67 expression, Her-2 expression and multi-drug resistance. Targeting PEAK1 inhibited cell growth, invasion, metastasis and reversed chemoresistance to Doxorubicin in breast cancer cells in vitro and in vivo. ConclusionHigh PEAK1 expression was associated with invasion, metastasis and chemoresistance of breast cancers. Furthermore, targeting PEAK1 could inhibit cell growth and metastasis, and reverse chemoresistance in breast cancer cells, which provides an effective treatment strategies for breast cancer.

LncRNA NEAT1 accelerates breast cancer progression through regulating miR-410-3p/ CCND1 axis

2020 ◽  
Vol 29 (2) ◽  
pp. 277-290
Author(s):  
Xuan Liu ◽  
Weirong Yao ◽  
Haiwei Xiong ◽  
Qiang Li ◽  
Yingliang Li
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Breast Cancer Progression ◽  
Cell Counting ◽  
Luciferase Reporter ◽  
Cancer Tissues

BACKGROUND: Breast cancer is the most common malignant tumor and usually occurs in women. Studies have shown that lncRNA nuclear enriched abundant transcript 1 (NEAT1) contributes to breast cancer progression. This study intends to further investigate the molecular mechanism of NEAT1 in breast cancer. METHODS: The expression levels of NEAT1, miR-410-3p and Cyclin D1 (CCND1) were detected by quantitative real-time PCR (qRT-PCR) in breast cancer tissues and cells. Kaplan-Meier analysis and the log-rank test were performed to determine the relationship between NEAT1 and overall survival. Cell Counting Kit-8 (CCK-8) assay analyzed cell proliferation. Transwell assay was performed to examine cell migration and invasion. The protein levels of CCND1 and epithelial-mesenchymal transition (EMT)-related proteins (E-cadherin, N-cadherin and Vimentin) were measured by western blot. The target relationship was predicted by bioinformatics analysis, and confirmed by luciferase reporter assay and RNA Immunoprecipitation (RIP) assay. Xenograft analysis was used to evaluate the tumor growth in vivo. RESULTS: NEAT1 and CCND1 were upregulated, while miR-410-3p was down-regulated in breast cancer tissues and cells. Higher NEAT1 expression level was associated with lower survival rate of breast cancer patients. Knockdown of miR-410-3p restored silenced NEAT1-mediated the inhibition of on proliferation, migration, invasion and EMT of breast cancer cells. In addition, NEAT1 regulated CCND1 expression by sponging miR-410-3p in breast cancer cells. NEAT1 knockdown blocked the tumor growth in vivo. CONCLUSION: NEAT1 induced breast cancer progression by regulating the miR-410-3p/CCND1 axis, indicating that NEAT1 may be a potential therapeutic target in breast cancer.

Safflower Yellow Prevents Pulmonary Metastasis of Breast Cancer by Inhibiting Tumor Cell Invadopodia

2016 ◽  
Vol 44 (07) ◽  
pp. 1491-1506 ◽  
Author(s):  
Huiying Fu ◽  
Renjie Wu ◽  
Yuanyuan Li ◽  
Lizong Zhang ◽  
Xiaofang Tang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Pulmonary Metastasis ◽  
Breast Cancer Cells ◽  
Dependent Cell ◽  
Response Profiles ◽  
Dose Dependent

Carthamus tinctorius L. is a traditional Chinese medicine that activates blood circulation and dissipates blood stasis, and has been extensively used as antitumor treatment in a clinical setting in single or in compound preparation form. However, empirical evidence and a better understanding of the possible mechanisms involved are still required. Here, we investigated the role of safflower yellow (SY), the active ingredient of C. tinctorius, in the pulmonary metastasis of breast cancer, and the underlying mechanism of action. EGF-meditated time- and dose-dependent cell response profiles were applied to screen for the activity of SY in vitro, while orthotopic lung metastasis and intravenous injection were used to evaluate the antimetastatic role of SY in vivo. SY could dose-dependently inhibit EGF-mediated time- and dose-dependent cell response profiles by inhibiting cytoskeletal rearrangement. We also found that SY significantly inhibited the migration of breast cancer cells in vitro and pulmonary metastasis of breast cancer cells in vivo. Consistent with these phenotypes, formation of invadopodia and the expression of MMP-9 and p-Src proteins were decreased after EGF stimulation in MBA-MD-231 cells treat with SY, as well as in lung metastatic foci. Additionally, circulating tumor cells retained in lung capillaries were also reduced. These results suggest that the antimetastatic effect of SY is due to its inhibition of invadopodia formation, which occurs mainly through Src-dependent cytoskeleton rearrangement. We suggest that SY should be considered as a potential novel therapeutic agent for the treatment of breast cancer.

Estrogen receptor β represses breast tumor growth and angiogenesis in vivo

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10101-10101
Author(s):  
J. Hartman ◽  
K. Lindberg ◽  
J. Inzunza ◽  
J. Wan ◽  
A. Ström ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Breast Tumor ◽  
Breast Cancer Cells ◽  
Cancer Cell Growth ◽  
Breast Cancer Cell Growth ◽  
Angiogenic Effect

10101 Background: Estrogens are well known stimulators of breast cancer cell growth in vitro as well as in vivo. Two different estrogen receptors exist, namely estrogen receptor (ER) α and β. ERα mediates the proliferative effect of estrogen in breast cancer cells and we have earlier shown that ERβ inhibits cell-cycle progression in vitro. Estrogens are well known stimulators of in vivo breast cancer cell growth as well as angiogenesis, and the effect is mediated through ERα. The function of ERβ in this context is not well understood. Methods: We have used ERα-positive T47D breast cancer cells stably transfected with a Tet/Off regulated ERβ expression vector system. The ERβ-inducible tumor cells are studied in vitro as well as in vivo. Results: By transplanting ERβ-inducible breast cancer cells into SCID-mice, we show that ERβ inhibits tumor growth and reduces the volume of established tumors. Furthermore, we show by immunohistochemistry, that the number of blood microvessels in the tumor periphery is decreased by ERβ expression, counteracting the well-known pro-angiogenic effect of ERα. By Western blot analysis on tumor extracts, we show that the concentration of the important pro-angiogenic growth factors VEGF and bFGF, normally expressed by breast tumor cells, is decreased in the ERβ-expressing tumors compared to the normal tumors. To exclude that the observed anti-angiogenic effect is just a result of reduced tumor growth, we incubated Tet/Off regulated ERβ expressing cells in vitro, during non-hypoxic conditions. We found that the expression of ERβ leads to decreased expression of VEGF and PDGFβ at the mRNA and protein-levels. In transient transfection assays, we found estrogen-ERα mediated up regulation of VEGF, PDGFβ and bFGF-promoter activities in T47D cells, and these activities were all suppressed following co-transfection with an ERβ-expression vector. Conclusions: We conclude that ERβ inhibits growth factor expression at transcriptional level in breast cancer cells; taken together, our data indicates that ERβ inhibits growth and angiogenesis of tumors formed by T47D breast cancer cells. This makes ERβ an interesting therapeutic target in breast cancer and perhaps treatment with the newly designed ERβ-selective ligands might work as a new anti-proliferative and anti-angiogenic therapy. No significant financial relationships to disclose.

Ras-Association Domain Family 1C Protein Enhances Breast Tumor Growth in Vivo

2012 ◽  
Vol 5 ◽  
pp. CGM.S9845 ◽  
Author(s):  
Mark E. Reeves ◽  
Robert J. Aragon ◽  
Mariana Alfakhouri ◽  
Shin-Tai Chen ◽  
Nancy Lowen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Growth Promoter ◽  
Domain Family ◽  
Over Expression ◽  
Immunohistochemical Analyses

The Ras association domain family 1 (RASSF1) gene is a Ras effector that plays an important role in carcinogenesis. We have previously shown that silencing of RASSF1C decreases and over-expression of RASSF1C increases cell proliferation, migration, and attenuates apoptosis of breast cancer cells in vitro. To further confirm our working hypothesis that RASSF1C may play a role as a growth promoter, we have tested the growth of human breast cancer cells stably over-expressing RASSF1A or RASSF1C in nude mice. Our studies show that breast cancer cells over-expressing HA-RASSF1A developed significantly smaller tumors and cells over-expressing HA-RASSF1C developed significantly larger tumors compared to control cells expressing the vector back bone. We have confirmed the expression of HA-RASSF1A and HA-RASSF1C in tumor tissue using RT-PCR, western blotting and immunohistochemical analyses using HA-antibody. Together, our previous in vitro and current in vivo findings further support our hypothesis that RASSF1C, unlike RASSF1A, is not a tumor suppressor and rather it appears to function as tumor growth promoter in breast cancer cells.

scholarly journals Exosomes Derived from Brain Metastatic Breast Cancer Cells Destroy the Blood-Brain Barrier by Carrying lncRNA GS1-600G8.5

2020 ◽  
Vol 2020 ◽  
pp. 1-10 ◽  
Author(s):  
Yunhe Lu ◽  
Lei Chen ◽  
Liangdong Li ◽  
Yiqun Cao
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Brain Metastasis ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Metastatic Breast ◽  
Metastatic Cells

Brain metastasis is a major cause of death in breast cancer patients. The greatest event for brain metastasis is the breaching of the blood-brain barrier (BBB) by cancer cells. The role of exosomes in cancer metastasis is clear, whereas the role of exosomes in the integrity of the BBB is unknown. Here, we established a highly brain metastatic breast cancer cell line by three cycles of in vivo selection. The effect of exosomes on the BBB was evaluated in vitro by tracking, transepithelial/transendothelial electrical resistance (TEER), and permeability assays. BBB-associated exosomal long noncoding RNA (lncRNA) was selected from the GEO dataset and verified by real-time PCR, TEER, permeability, and Transwell assays. The cells obtained by the in vivo selection showed higher brain metastatic capacity in vivo and higher migration and invasion in vitro compared to the parental cells. Exosomes from the highly brain metastatic cells were internalized by brain microvascular endothelial cells (BMECs), which reduced TEER and increased permeability of BBB. The exosomes derived from the highly metastatic cells promoted invasion of the breast cancer cells in the BBB model. lncRNA GS1-600G8.5 was highly expressed in the highly brain metastatic cells and their exosomes, as compared to the samples with reduced metastatic behavior. Silencing of GS1-600G8.5 significantly abrogated the BBB destructive effect of exosomes. GS1-600G8.5-deficient exosomes failed to promote the infiltration of cancer cells through the BBB. Furthermore, BMECs treated with GS1-600G8.5-deprived exosomes expressed higher tight junction proteins than those treated with the control exosomes. These data suggest the exosomes derived from highly brain metastatic breast cancer cells might destroy the BBB system and promote the passage of cancer cells across the BBB, by transferring lncRNA GS1-600G8.5.

Polymalic Acid–Based Nanobiopolymer Provides Efficient Systemic Breast Cancer Treatment by Inhibiting both HER2/neu Receptor Synthesis and Activity

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Breast Cancer ◽  
Cancer Therapy ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Tumor Growth Inhibition ◽  
Human Breast ◽  
Akt Phosphorylation

Biodegradable nanopolymers are believed to offer great potential in cancer therapy. Here, we report thecharacterization of a novel, targeted, nanobiopolymeric conjugate based on biodegradable, nontoxic, andnonimmunogenic PMLA [poly(b-L-malic acid)]. The PMLA nanoplatform was synthesized for repetitive systemictreatments of HER2/neu-positive human breast tumors in a xenogeneic mouse model. Various moieties werecovalently attached to PMLA, including a combination of morpholino antisense oligonucleotides (AON) directedagainst HER2/neu mRNA, to block new HER2/neu receptor synthesis; anti-HER2/neu antibody trastuzumab(Herceptin), to target breast cancer cells and inhibit receptor activity simultaneously; and transferrin receptorantibody, to target the tumor vasculature and mediate delivery of the nanobiopolymer through the hostendothelial system. The results of the study showed that the lead drug tested significantly inhibited the growth ofHER2/neu-positive breast cancer cells in vitro and in vivo by enhanced apoptosis and inhibition of HER2/neureceptor signaling with suppression of Akt phosphorylation. In vivo imaging analysis and confocal microscopydemonstrated selective accumulation of the nanodrug in tumor cells via an active delivery mechanism. Systemictreatment of human breast tumor-bearing nude mice resulted in more than 90% inhibition of tumor growth andtumor regression, as compared with partial (50%) tumor growth inhibition in mice treated with trastuzumab orAON, either free or attached to PMLA. Our findings offer a preclinical proof of concept for use of the PMLAnanoplatform for combination cancer therapy.

scholarly journals Human drug efflux transporter ABCC5 confers acquired resistance to pemetrexed in breast cancer

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jihui Chen ◽  
Zhipeng Wang ◽  
Shouhong Gao ◽  
Kejin Wu ◽  
Fang Bai ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Line ◽  
Abc Transporters ◽  
Breast Cancer Cells ◽  
Breast Cancer Treatment ◽  
Control Group ◽  
Mcf 7

Abstract Aim Pemetrexed, a new generation antifolate drug, has been approved for the treatment of locally advanced or metastatic breast cancer. However, factors affecting its efficacy and resistance have not been fully elucidated yet. ATP-binding cassette (ABC) transporters are predictors of prognosis as well as of adverse effects of several xenobiotics. This study was designed to explore whether ABC transporters affect pemetrexed resistance and can contribute to the optimization of breast cancer treatment regimen. Methods First, we measured the expression levels of ABC transporter family members in cell lines. Subsequently, we assessed the potential role of ABC transporters in conferring resistance to pemetrexed in primary breast cancer cells isolated from 34 breast cancer patients and the role of ABCC5 in mediating pemetrexed transport and apoptotic pathways in MCF-7 cells. Finally, the influence of ABCC5 expression on the therapeutic effect of pemetrexed was evaluated in an in vivo xenograft mouse model of breast cancer. Results The expression levels of ABCC2, ABCC4, ABCC5, and ABCG2 significantly increased in the pan-resistant cell line, and the ABCC5 level in the MCF-7-ADR cell line was 5.21 times higher than that in the control group. ABCC5 expression was inversely correlated with pemetrexed sensitivity (IC50, r = 0.741; p < 0.001) in breast cancer cells derived from 34 patients. Furthermore, we found that the expression level of ABCC5 influenced the efflux and cytotoxicity of pemetrexed in MCF-7 cells, with IC50 values of 0.06 and 0.20 μg/mL in ABCC5 knockout and over-expression cells, respectively. In the in vivo study, we observed that ABCC5 affected the sensitivity of pemetrexed in breast tumor-bearing mice, and the tumor volume was much larger in the ABCC5-overexpressing group than in the control group when compared with their own initial volumes (2.7-fold vs. 1.3-fold). Conclusions Our results indicated that ABCC5 expression was associated with pemetrexed resistance in vitro and in vivo, and it may serve as a target or biomarker for the optimization of pemetrexed regimen in breast cancer treatment.

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