Tumor Suppressor PLK2 May Serve as a Biomarker in Triple-Negative Breast Cancer for Improved Response to PLK1 Therapeutics

Polo-like kinase (PLK) family members play important roles in cell-cycle regulation. The founding member PLK1 is oncogenic and preclinically validated as a cancer therapeutic target. Paradoxically, frequent loss of chromosome 5q11–35, which includes PLK2, is observed in basal-like breast cancer. In this study, we found that PLK2 was tumor suppressive in breast cancer, preferentially in basal-like and triple-negative breast cancer (TNBC) subtypes. Knockdown of PLK1 rescued phenotypes induced by PLK2 loss both in vitro and in vivo. We also demonstrated that PLK2 directly interacted with PLK1 at prometaphase through the kinase but not the polo-box domains of PLK2, suggesting PLK2 functioned at least partially through the interaction with PLK1. Furthermore, an improved treatment response was seen in both Plk2-deleted/low mouse preclinical and patient-derived xenograft (PDX) TNBC models using the PLK1 inhibitor volasertib alone or in combination with carboplatin. Reexpression of PLK2 in an inducible PLK2-null mouse model reduced the therapeutic efficacy of volasertib. In summary, this study delineates the effects of chromosome 5q loss in TNBC that includes PLK2, the relationship between PLK2 and PLK1, and how this may render PLK2-deleted/low tumors more sensitive to PLK1 inhibition in combination with chemotherapy. Significance: The tumor-suppressive role of PLK2, and its relationship with oncogene PLK1, provide a mechanistic rationalization to use PLK1 inhibitors in combination with chemotherapy to treat PLK2-low/deleted tumors. TNBC, and other cancers with low PLK2 expression, are such candidates to leverage precision medicine to identify patients who might benefit from treatment with these inhibitors.

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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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Lamin B2 promotes the progression of triple negative breast cancer via mediating cell proliferation and apoptosis

Bioscience Reports ◽

10.1042/bsr20203874 ◽

2021 ◽

Vol 41 (1) ◽

Author(s):

Cui-Cui Zhao ◽

Jing Chen ◽

Li-Ying Zhang ◽

Hong Liu ◽

Chuan-Gui Zhang ◽

...

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Cancer Progression ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

The Cancer Genome Atlas ◽

Proliferation And Apoptosis

Abstract Triple negative breast cancer (TNBC) is a more common type of breast cancer with high distant metastasis and poor prognosis. The potential role of lamins in cancer progression has been widely revealed. However, the function of lamin B2 (LMNB2) in TNBC progression is still unclear. The present study aimed to investigate the role of LMNB2 in TNBC. The cancer genome atlas (TCGA) database analysis and immunohistochemistry (IHC) were performed to examine LMNB2 expression levels. LMNB2 short hairpin RNA plasmid or lentivirus was used to deplete the expression of LMNB2 in human TNBC cell lines including MDA-MB-468 and MDA-MB-231. Alterations in cell proliferation and apoptosis in vitro and the nude mouse tumorigenicity assay in vivo were subsequently analyzed. The human TNBC tissues shown high expression of LMNB2 according to the bioinformation analysis and IHC assays. LMNB2 expression was correlated with the clinical pathological features of TNBC patients, including pTNM stage and lymph node metastasis. Through in vitro and in vivo assays, we confirmed LMNB2 depletion suppressed the proliferation and induced the apoptosis of TNBC cells, and inhibited tumor growth of TNBC cells in mice, with the decrease in Ki67 expression or the increase in caspase-3 expression. In conclusion, LMNB2 may promote TNBC progression and could serve as a potential therapeutic target for TNBC treatment.

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CircPLK1 sponges miR-296-5p to facilitate triple-negative breast cancer progression

Epigenomics ◽

10.2217/epi-2019-0093 ◽

2019 ◽

Vol 11 (10) ◽

pp. 1163-1176 ◽

Cited By ~ 16

Author(s):

Yanan Kong ◽

Lu Yang ◽

Weidong Wei ◽

Ning Lyu ◽

Yutian Zou ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Expression Profiles ◽

Proliferation And Metastasis ◽

Underlying Mechanisms

Aim: To investigate the role of circRNAs in triple-negative breast cancer (TNBC) and the underlying mechanisms. Materials & methods: We performed circRNA microarrays to explore the expression profiles of TNBC cell lines. Experiments in vitro and in vivo were conducted to explore the effects of circPLK1 on tumor proliferation and metastasis as well as the interaction between circPLK1, miR-296-5p and PLK1 in TNBC. Results & conclusion: CircPLK1 was significantly upregulated in TNBC and associated with poor survivals. CircPLK1 knockdown inhibited cell growth and invasion in vitro as well as tumor occurrence and metastasis in vivo. CircPLK1-miR-296-5p- PLK1 axis regulates tumor progression by ceRNA mechanism in TNBC, indicating that circPLK1 may serve as a prognostic factor and novel therapeutic target for TNBC.

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Aspirin attenuates YAP and β-catenin expression by promoting β-TrCP to overcome docetaxel and vinorelbine resistance in triple-negative breast cancer

Cell Death and Disease ◽

10.1038/s41419-020-2719-2 ◽

2020 ◽

Vol 11 (7) ◽

Cited By ~ 1

Author(s):

Ji Ma ◽

Zhenhai Fan ◽

Qiulin Tang ◽

Hongwei Xia ◽

Tao Zhang ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Predictive Biomarker ◽

Drug Resistant ◽

Therapeutic Approaches ◽

Combined Use

Abstract The use of aspirin has been associated with reduced breast cancer risk, but it is litter known if aspirin overcomes chemoresistance in triple-negative breast cancer (TNBC). Herein, we demonstrated that changes in the expression of Yes-associated protein (YAP) and β-catenin might be a promising predictive biomarker for neoadjuvant chemotherapy sensitivity in TNBC patients. Inhibition of YAP or β-catenin enhanced the cytotoxicity of the anti-microtubule agents docetaxel and vinorelbine against drug-resistant TNBC cells as well as the sensitivity of these cells to the agents in vitro and in vivo. Interestingly, aspirin not only significantly inhibited the growth of TNBC cells, but also attenuated YAP and β-catenin expression by upregulating the E3 ubiquitin ligase β-TrCP to abolished docetaxel and vinorelbine resistance. The combination of aspirin and docetaxel or vinorelbine remarkably inhibited the growth of drug-resistant TNBC cells in vitro and in vivo. Moreover, TNBC patients with high YAP and/or β-catenin expression had a higher risk of relapse or mortality than patients with low YAP and/or β-catenin expression. Collectively, our study discovered a novel role of aspirin based on its anticancer effect, and put forward some possible mechanisms of chemoresistance in TNBC. The combined use of aspirin and anti-microtubule drugs presented several promising therapeutic approaches for TNBC treatment.

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BC200 overexpression contributes to luminal and triple negative breast cancer pathogenesis

BMC Cancer ◽

10.1186/s12885-019-6179-y ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 2

Author(s):

Maria Barton ◽

Julia Santucci-Pereira ◽

Olivia G. Vaccaro ◽

Theresa Nguyen ◽

Yanrong Su ◽

...

Keyword(s):

Breast Cancer ◽

Cell Lines ◽

Breast Cancer Cell ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Breast Cancer Cell Lines ◽

Nulliparous Women

Abstract Background Long non coding RNAs (lncRNAs) are RNA molecules longer than 200 nucleotides that are not translated into proteins, but regulate the transcription of genes involved in different cellular processes, including cancer. Epidemiological analyses have demonstrated that parous women have a decreased risk of developing breast cancer in postmenopausal years if they went through a full term pregnancy in their early twenties. We here provide evidence of the role of BC200 in breast cancer and, potentially, in pregnancy’s preventive effect in reducing the lifetime risk of developing breast cancer. Methods Transcriptome analysis of normal breast of parous and nulliparous postmenopausal women revealed that several lncRNAs are differentially expressed in the parous breast. RNA sequencing of healthy postmenopausal breast tissue biopsies from eight parous and eight nulliparous women showed that there are 42 novel lncRNAs differentially expressed between these two groups. Screening of several of these 42 lncRNAs by RT-qPCR in different breast cancer cell lines, provided evidence that one in particular, lncEPCAM (more commonly known as BC200), was a strong candidate involved in cancer progression. Proliferation, migration, invasion and xerograph studies confirmed this hypothesis. Results The poorly studied oncogenic BC200 was selected to be tested in vitro and in vivo to determine its relevance in breast cancer and also to provide us with an understanding of its role in the increased susceptibility of the nulliparous women to cancer. Our results show that BC200 is upregulated in nulliparous women, and breast cancer cells and tissue. The role of BC200 is not completely understood in any of the breast cancer subtypes. We here provide evidence that BC200 has a role in luminal breast cancer as well as in the triple negative breast cancer subtype. Conclusion When overexpressed in luminal and triple negative breast cancer cell lines, BC200 shows increased proliferation, migration, and invasion in vitro. In vivo, overexpression of BC200 increased tumor size. Although treatment for cancer using lncRNAs as targets is in its infancy, the advancement in knowledge and technology to study their relevance in disease could lead to the development of novel treatment and preventive strategies for breast cancer.

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Knockdown of PC4 Increases Chemosensitivity of Oxaliplatin in Triple Negative Breast Cancer by Supressing mTOR Pathway

10.21203/rs.3.rs-101235/v1 ◽

2020 ◽

Author(s):

Qing Wang ◽

Le Ma ◽

Long Chen ◽

Hongdan Chen ◽

Min Luo ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Potential Role ◽

Triple Negative ◽

Mtor Pathway ◽

Promising Therapeutic Target ◽

Response To Chemotherapy

Abstract Background: The response to chemotherapy is an important factor in the prognosis of patients with triple negative breast cancer (TNBC). Human positive coactivator 4 (PC4) is a multifunctional nuclear protein, that is highly expressed in various tumors including breast cancer and shows a potential role in cancer development and progression. However, the role of PC4 in chemotherapeutic responses of TNBC remains unclear. Our work aim to identify the role of PC4 in the response to oxaliplatin (Oxa) of TNBC patients.Results: We found that PC4 is significantly upregulated in TNBC cells compared with non-TNBC cells, implying its potential role in TNBC. Then, in vivo and in vitro studies revealed that knockdown of PC4 increased chemosensitivity of Oxa in TNBC by supressing mTOR pathway.Conclusions: Our findings demonstrated the signatures of PC4 in the chemotherapeutic response of TNBC, and indicated that PC4 might be a promising therapeutic target for TNBC.

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Tumor suppressor PLK2 may serve as a biomarker in triple-negative breast cancer for improved response to PLK1 therapeutics

10.1101/2021.06.16.448722 ◽

2021 ◽

Author(s):

Yang Gao ◽

Elena B Kabotyanski ◽

Elizabeth Villegas ◽

Jonathan H. Shepherd ◽

Deanna Acosta ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Kinase Domain ◽

Null Mouse ◽

Mouse Tumor ◽

Breast Cancers ◽

Cancer Subtypes

Polo-like kinase (PLK) family members play important roles in cell cycle regulation. The founding member PLK1 is oncogenic and preclinically validated as a cancer therapeutic target. Paradoxically, PLK2 (chromosome 5q11.2) is frequently deleted in human breast cancers, preferentially in basal-like and triple-negative breast cancer subtypes. Here, we found that PLK2 was tumor suppressive in breast cancer and knockdown of PLK1 rescued phenotypes induced by PLK2-loss both in vitro and in vivo. We also demonstrated that PLK2 directly interacted with PLK1 at prometaphase and that mutations in the kinase domain of PLK2, but not polo-box binding domains, changed their interaction pattern. Furthermore, treatment of syngeneic transplantation mouse tumor models and patient-derived xenografts using the PLK1 inhibitor volasertib alone, or in combination with carboplatin, indicated that PLK2-low breast tumors had a significantly better response to these drugs. Re-expression of PLK2 in an inducible PLK2-null mouse model reduced the therapeutic efficacy of volasertib. Taken together, our data suggest PLK2 loss may serve as a biomarker to predict response to PLK1 therapeutics, alone and in combination with chemotherapy.

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Cyclin B2 (CCNB2) Stimulates the Proliferation of Triple-Negative Breast Cancer (TNBC) Cells In Vitro and In Vivo

Disease Markers ◽

10.1155/2021/5511041 ◽

2021 ◽

Vol 2021 ◽

pp. 1-9

Author(s):

Shuai Wu ◽

Rui Su ◽

Hongyan Jia

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Triple Negative Breast Cancer ◽

Potential Role ◽

Triple Negative ◽

Targeting Therapy ◽

A Cell

Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer. Currently, targeting therapy makes great advances for the treatment of TNBC, whereas more effective therapeutic targets are urgently needed. Cyclin B2 (CCNB2), which belongs to B-type cyclins, is known as a cell cycle regulator. CCNB2 is synthesized at G1 phase in cancer cells and downregulated at anaphase. The defects of CCNB2 led to the abnormal cell cycle and tumorigenesis. Though there are wide effects of CCNB2 on multiple types of tumors, the potential role of CCNB2 in TNBC progression is still unclear. Herein, we found that CCNB2 was highly expressed in human TNBC tissues and correlated with the prognosis and clinical pathological features including tumor size ( p = 0.022 ∗ ) and pTNM stage ( p = 0.021 ∗ ) of patients with TNBC. CCNB2 could promote the proliferation of TNBC cells in vitro and in mice. Our findings therefore confirmed the involvement of CCNB2 in TNBC progression and provided the evidence that CCNB2 could serve as a promising molecular target of TNBC.

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Lysyl oxidase engineered lipid nanovesicles for the treatment of triple negative breast cancer

Scientific Reports ◽

10.1038/s41598-021-84492-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Alessandro De Vita ◽

Chiara Liverani ◽

Roberto Molinaro ◽

Jonathan O. Martinez ◽

Kelly A. Hartman ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Lysyl Oxidase ◽

Tumor Biology ◽

Oncology Research ◽

Related Enzyme

AbstractIn the field of oncology research, a deeper understanding of tumor biology has shed light on the role of environmental conditions surrounding cancer cells. In this regard, targeting the tumor microenvironment has recently emerged as a new way to access this disease. In this work, a novel extracellular matrix (ECM)-targeting nanotherapeutic was engineered using a lipid-based nanoparticle chemically linked to an inhibitor of the ECM-related enzyme, lysyl oxidase 1 (LOX), that inhibits the crosslinking of elastin and collagen fibers. We demonstrated that, when the conjugated vesicles were loaded with the chemotherapeutic epirubicin, superior inhibition of triple negative breast cancer (TNBC) cell growth was observed both in vitro and in vivo. Moreover, in vivo results displayed prolonged survival, minimal cytotoxicity, and enhanced biocompatibility compared to free epirubicin and epirubicin-loaded nanoparticles. This all-in-one nano-based ECM-targeting chemotherapeutic may provide a key-enabling technology for the treatment of TNBC.

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GCH1 induces immunosuppression through metabolic reprogramming and IDO1 upregulation in triple-negative breast cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-002383 ◽

2021 ◽

Vol 9 (7) ◽

pp. e002383

Author(s):

Jin-Li Wei ◽

Si-Yu Wu ◽

Yun-Song Yang ◽

Yi Xiao ◽

Xi Jin ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Molecular Taxonomy ◽

Underlying Mechanism ◽

Metabolic Reprogramming ◽

Sequencing Data ◽

Aryl Hydrocarbon

PurposeRegulatory T cells (Tregs) heavily infiltrate triple-negative breast cancer (TNBC), and their accumulation is affected by the metabolic reprogramming in cancer cells. In the present study, we sought to identify cancer cell-intrinsic metabolic modulators correlating with Tregs infiltration in TNBC.Experimental designUsing the RNA-sequencing data from our institute (n=360) and the Molecular Taxonomy of Breast Cancer International Consortium TNBC cohort (n=320), we calculated the abundance of Tregs in each sample and evaluated the correlation between gene expression levels and Tregs infiltration. Then, in vivo and in vitro experiments were performed to verify the correlation and explore the underlying mechanism.ResultsWe revealed that GTP cyclohydrolase 1 (GCH1) expression was positively correlated with Tregs infiltration and high GCH1 expression was associated with reduced overall survival in TNBC. In vivo and in vitro experiments showed that GCH1 increased Tregs infiltration, decreased apoptosis, and elevated the programmed cell death-1 (PD-1)-positive fraction. Metabolomics analysis indicated that GCH1 overexpression reprogrammed tryptophan metabolism, resulting in L-5-hydroxytryptophan (5-HTP) accumulation in the cytoplasm accompanied by kynurenine accumulation and tryptophan reduction in the supernatant. Subsequently, aryl hydrocarbon receptor, activated by 5-HTP, bound to the promoter of indoleamine 2,3-dioxygenase 1 (IDO1) and thus enhanced the transcription of IDO1. Furthermore, the inhibition of GCH1 by 2,4-diamino-6-hydroxypyrimidine (DAHP) decreased IDO1 expression, attenuated tumor growth, and enhanced the tumor response to PD-1 blockade immunotherapy.ConclusionsTumor-cell-intrinsic GCH1 induced immunosuppression through metabolic reprogramming and IDO1 upregulation in TNBC. Inhibition of GCH1 by DAHP serves as a potential immunometabolic strategy in TNBC.

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