Combined p53- and PTEN-deficiency activates expression of mesenchyme homeobox 1 (MEOX1) required for growth of triple-negative breast cancer

Triple-negative breast cancer (TNBC) is an aggressive cancer subtype for which effective therapies are unavailable. TNBC has a high frequency of tumor protein p53 (Tp53/p53)- and phosphatase and tensin homolog (PTEN) deficiencies, and combined p53- and PTEN-deficiency is associated with poor prognosis and poor response to anticancer therapies. In this study, we discovered that combined p53- and PTEN-deficiency in TNBC activates expression of the transcription factor mesenchyme homeobox 1 (MEOX1). We found that MEOX1 is expressed only in TNBC cells with frequent deficiencies in p53 and PTEN, and that its expression is undetectable in luminal A, luminal B, and HER2+ subtypes, as well as in normal breast cells with wild-type (WT) p53 and PTEN. Notably, siRNA knockdown of both p53 and PTEN activated MEOX1 expression in breast cancer cells, whereas individual knockdowns of either p53 or PTEN had only minimal effects on MEOX1 expression. MEOX1 knockdown abolished cell proliferation of p53- and PTEN-deficient TNBC in vitro and inhibited tumor growth in vivo, but had no effect on the proliferation of luminal and HER2+ cancer cells and normal breast cells. RNA-Seq and immunoblotting analyses showed that MEOX1 knockdown decreased expression of tyrosine kinase 2 (TYK2), signal transducer and activator of transcription 5B (STAT5B), and STAT6 in p53- and PTEN-deficient TNBC cells. These results reveal the effects of combined p53- and PTEN-deficiency on MEOX1 expression and TNBC cell proliferation, suggesting that MEOX1 may serve as a potential therapeutic target for managing p53- and PTEN-deficient TNBC.

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Abstract 2141: The differential apoptotic responses of normal breast cells versus luminal and triple negative breast cancer cells to chemotherapeutic agents

10.1158/1538-7445.am2011-2141 ◽

2011 ◽

Author(s):

Jamie L. King ◽

Kashenya M. Gurley ◽

Checo J. Rorie

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Triple Negative Breast Cancer ◽

Breast Cancer Cells ◽

Triple Negative ◽

Chemotherapeutic Agents ◽

Normal Breast ◽

Breast Cells

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Vascular endothelial growth factor encoded by Parapoxviruses can regulate metabolism and survival of triple negative breast cancer cells

Cell Death and Disease ◽

10.1038/s41419-020-03203-4 ◽

2020 ◽

Vol 11 (11) ◽

Author(s):

Dipayan Bose ◽

Sagarika Banerjee ◽

Rajnish Kumar Singh ◽

Lyn M. Wise ◽

Erle S. Robertson

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Triple Negative Breast Cancer ◽

Breast Cancer Cells ◽

Triple Negative ◽

Normal Breast ◽

Cancer Breast ◽

Human Genes ◽

Metabolic Gene Expression ◽

Breast Cells

AbstractDysbiotic microbiomes are linked to many pathological outcomes including different metabolic disorders like diabetes, atherosclerosis and even cancer. Breast cancer is the second leading cause of cancer associated death in women, and triple negative breast cancer (TNBC) is the most aggressive type with major challenges for intervention. Previous reports suggested that Parapoxvirus signatures are one of the predominant dysbiotic viral signatures in TNBC. These viruses encode several genes that are homologs of human genes. In this study, we show that the VEGF homolog encoded by Parapoxviruses, can induce cell proliferation, and alter metabolism of breast cancer and normal breast cells, through alteration of MAPK-ERK and PI3K-AKT signaling. In addition, the activity of the transcription factor FoxO1 was altered by viral-encoded VEGF through activation of the PI3K-AKT pathway, leading to reprogramming of cellular metabolic gene expression. Therefore, this study provides new insights into the function of viral-encoded VEGFs, which promoted the growth of the breast cancer cells and imparted proliferative phenotype with altered metabolism in normal breast cells.

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Effects of Sambucus Ebulus Extract on Cell Proliferation and Viability of Triple-Negative Breast Cancer: An In Vitro and In Vivo Study

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520621666210412113944 ◽

2021 ◽

Vol 21 ◽

Author(s):

Vahid F. Omrani ◽

Ameneh Koochaki ◽

Sahar Behzad ◽

Vahid Kia ◽

Peyman Ghasemi ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Cell Cycle ◽

Cell Proliferation ◽

Triple Negative ◽

Normal Breast ◽

Sambucus Ebulus ◽

Breast Cells

Background: Triple-negative breast cancer (TNBC) accounts for 15% of all breast cancer (BC) cases and is a severe type of BC. Since medicinal herbs containing biocompatible substances that are accepted by patient more than chemical therapeutics, they can be considered a safe option for treating BC. Objective: This study evaluated the effect of Sambucus Ebulus (S. ebulus) extract on a model of TNBC. Methods: S. ebulus extract was prepared using petroleum ether, ethyl acetate, and methanol. The petroleum ether extract was fractionated and analyzed using vacuum liquid chromatography and GC-MS, respectively. MDA-MB-231 and MCF-10A were used as TNBC and normal breast cells, respectively. Flowcytometry and MTT assays were performed to evaluate cell cycle, apoptosis, and viability of the cells. Gene expression analysis was performed using RT-qPCR. Nude mouse allograft tumor models were used, and pathological sections were evaluated. Results: The findings indicated that S. ebulus extract remarkably decreased cell proliferation and viability. The extract had no toxicity to the normal breast cells but efficiently killed the cancer cells. Cell cycle- and apoptosis-related gene expression showed that fraction 4 of S. ebulus extract significantly increased the expression of Bax, Bak, P53, and c-MYC. Conclusion: This study showed satisfactory results of the effect of S. ebulus extract on clearing BC cells both in vitro and in vivo. Thus, S. ebulus extract may be a safe herbal compound for eliminating BC cells without toxicity to host cells.

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CD44 Targeted Nanomaterials for Treatment of Triple-Negative Breast Cancer

Cancers ◽

10.3390/cancers13040898 ◽

2021 ◽

Vol 13 (4) ◽

pp. 898

Author(s):

Ghazal Nabil ◽

Rami Alzhrani ◽

Hashem Alsaab ◽

Mohammed Atef ◽

Samaresh Sau ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

In Vivo Studies ◽

High Dose ◽

Luminal A ◽

Combination Strategy ◽

Ongoing Research

Identified as the second leading cause of cancer-related deaths among American women after lung cancer, breast cancer of all types has been the focus of numerous research studies. Even though triple-negative breast cancer (TNBC) represents 15–20% of the number of breast cancer cases worldwide, its existing therapeutic options are fairly limited. Due to the pivotal role of the presence/absence of specific receptors to luminal A, luminal B, HER-2+, and TNBC in the molecular classification of breast cancer, the lack of these receptors has accounted for the aforementioned limitation. Thereupon, in an attempt to participate in the ongoing research endeavors to overcome such a limitation, the conducted study adopts a combination strategy as a therapeutic paradigm for TNBC, which has proven notable results with respect to both: improving patient outcomes and survivability rates. The study hinges upon an investigation of a promising NPs platform for CD44 mediated theranostic that can be combined with JAK/STAT inhibitors for the treatment of TNBC. The ability of momelotinib (MMB), which is a JAK/STAT inhibitor, to sensitize the TNBC to apoptosis inducer (CFM-4.16) has been evaluated in MDA-MB-231 and MDA-MB-468. MMB + CFM-4.16 combination with a combination index (CI) ≤0.5, has been selected for in vitro and in vivo studies. MMB has been combined with CD44 directed polymeric nanoparticles (PNPs) loaded with CFM-4.16, namely CD44-T-PNPs, which selectively delivered the payload to CD44 overexpressing TNBC with a significant decrease in cell viability associated with a high dose reduction index (DRI). The mechanism underlying their synergism is based on the simultaneous downregulation of P-STAT3 and the up-regulation of CARP-1, which has induced ROS-dependent apoptosis leading to caspase 3/7 elevation, cell shrinkage, DNA damage, and suppressed migration. CD44-T-PNPs showed a remarkable cellular internalization, demonstrated by uptake of a Rhodamine B dye in vitro and S0456 (NIR dye) in vivo. S0456 was conjugated to PNPs to form CD44-T-PNPs/S0456 that simultaneously delivered CFM-4.16 and S0456 parenterally with selective tumor targeting, prolonged circulation, minimized off-target distribution.

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

Cellular Physiology and Biochemistry ◽

10.1159/000443052 ◽

2016 ◽

Vol 38 (3) ◽

pp. 1003-1014 ◽

Cited By ~ 24

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.

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Agonists and knockdown of estrogen receptor β differentially affect invasion of triple-negative breast cancer cells in vitro

BMC Cancer ◽

10.1186/s12885-016-2973-y ◽

2016 ◽

Vol 16 (1) ◽

Cited By ~ 21

Author(s):

Susanne Schüler-Toprak ◽

Julia Häring ◽

Elisabeth C. Inwald ◽

Christoph Moehle ◽

Olaf Ortmann ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Cancer Cells ◽

Triple Negative Breast Cancer ◽

Breast Cancer Cells ◽

Triple Negative ◽

Estrogen Receptor Β

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PVT1 affects EMT and cell proliferation and migration via regulating p21 in triple-negative breast cancer cells cultured with mature adipogenic medium

Acta Biochimica et Biophysica Sinica ◽

10.1093/abbs/gmy129 ◽

2018 ◽

Vol 50 (12) ◽

pp. 1211-1218 ◽

Cited By ~ 9

Author(s):

Lingli Wang ◽

Ruirui Wang ◽

Zi Ye ◽

Yanyan Wang ◽

Xiao Li ◽

...

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Cancer Cells ◽

Triple Negative Breast Cancer ◽

Breast Cancer Cells ◽

Triple Negative ◽

Cell Proliferation And Migration ◽

And Migration ◽

Cells Cultured ◽

Proliferation And Migration

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CTPS1 promotes malignant progression of triple-negative breast cancer with transcriptional activation by YBX1

Journal of Translational Medicine ◽

10.1186/s12967-021-03206-5 ◽

2022 ◽

Vol 20 (1) ◽

Author(s):

Yuxiang Lin ◽

Jie Zhang ◽

Yan Li ◽

Wenhui Guo ◽

Lili Chen ◽

...

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Triple Negative Breast Cancer ◽

Transcriptional Activation ◽

Triple Negative ◽

Pearson Correlation ◽

Disease Free Survival ◽

Luciferase Reporter

Abstract Background Cytidine nucleotide triphosphate synthase 1 (CTPS1) is a CTP synthase which play critical roles in DNA synthesis. However, its biological regulation and mechanism in triple-negative breast cancer (TNBC) has not been reported yet. Methods The expression of CTPS1 in TNBC tissues was determined by GEO, TCGA databases and immunohistochemistry (IHC). The effect of CTPS1 on TNBC cell proliferation, migration, invasion, apoptosis and tumorigenesis were explored in vivo and in vitro. In addition, the transcription factor Y-box binding protein 1 (YBX1) was identified by bioinformatics methods, dual luciferase reporter and chromatin immunoprecipitation (CHIP) assays. Pearson correlation analysis was utilized to assess the association between YBX1 and CTPS1 expression. Results CTPS1 expression was significantly upregulated in TNBC tissues and cell lines. Higher CTPS1 expression was correlated with a poorer disease-free survival (DFS) and overall survival (OS) in TNBC patients. Silencing of CTPS1 dramatically inhibited the proliferation, migration, invasion ability and induced apoptosis of MDA-MB-231 and HCC1937 cells. Xenograft tumor model also indicated that CTPS1 knockdown remarkably reduced tumor growth in mice. Mechanically, YBX1 could bind to the promoter of CTPS1 to promote its transcription. Furthermore, the expression of YBX1 was positively correlated with CTPS1 in TNBC tissues. Rescue experiments confirmed that the enhanced cell proliferation and invasion ability induced by YBX1 overexpression could be reversed by CTPS1 knockdown. Conclusion Our data demonstrate that YBX1/CTPS1 axis plays an important role in the progression of TNBC. CTPS1 might be a promising prognosis biomarker and potential therapeutic target for patients with triple-negative breast cancer.

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