Attenuation of PITPNM1 Signaling Cascade Can Inhibit Breast Cancer Progression

Phosphatidylinositol transfer protein membrane-associated 1 (PITPNM1) contains a highly conserved phosphatidylinositol transfer domain which is involved in phosphoinositide trafficking and signaling transduction under physiological conditions. However, the functional role of PITPNM1 in cancer progression remains unknown. Here, by integrating datasets of The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer (METABRIC), we found that the expression of PITPNM1 is much higher in breast cancer tissues than in normal breast tissues, and a high expression of PITPNM1 predicts a poor prognosis for breast cancer patients. Through gene set variation analysis (GSEA) and gene ontology (GO) analysis, we found PITPNM1 is mainly associated with carcinogenesis and cell-to-cell signaling ontology. Silencing of PITPNM1, in vitro, significantly abrogates proliferation and colony formation of breast cancer cells. Collectively, PITPNM1 is an important prognostic indicator and a potential therapeutic target for breast cancer.

Download Full-text

LINC01977 Promotes Breast Cancer Progression and Chemoresistance to Doxorubicin by Targeting miR-212-3p/GOLM1 Axis

Frontiers in Oncology ◽

10.3389/fonc.2021.657094 ◽

2021 ◽

Vol 11 ◽

Author(s):

Zheng Li ◽

Yaming Li ◽

Xiaolong Wang ◽

Yiran Liang ◽

Dan Luo ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Prognostic Indicator ◽

Breast Cancer Progression ◽

Luciferase Reporter ◽

Breast Cancer Patients ◽

Therapeutic Approaches ◽

Rna Immunoprecipitation ◽

Oncogenic Driver

Long non-coding RNAs(lncRNAs) play an important role in cancer initiation and progression. However, hub lncRNAs involved in breast cancer still remain underexplored. In this study, integrated bioinformatics analysis was used to define LINC01977 as a key oncogenic driver in breast cancer. Subsequently, in vitro assays showed that LINC01977 could significantly promote breast cancer progression and chemoresistance to doxorubicin. To further investigate its biological mechanism, we performed dual-luciferase reporter assay, real-time PCR, RNA immunoprecipitation (RIP), and rescue assay. Our results indicated that LINC01977 may function as ceRNA to prevent GOLM1 gene from miRNA-mediated repression by sponging miR-212-3p. Overall, LINC01977 can serve as a novel prognostic indicator, and help develop more effective therapeutic approaches for breast cancer patients.

Download Full-text

Targeting PKM2 promotes chemosensitivity of breast cancer cells in vitro and in vivo

Cancer Biomarkers ◽

10.3233/cbm-210111 ◽

2021 ◽

pp. 1-10

Author(s):

Yu Wang ◽

Han Zhao ◽

Ping Zhao ◽

Xingang Wang

Keyword(s):

Breast Cancer ◽

Neoadjuvant Chemotherapy ◽

Cancer Cells ◽

Cancer Patients ◽

Poor Prognosis ◽

Breast Cancer Cells ◽

Breast Cancer Patients ◽

Cancer Tissues

BACKGROUND: Pyruvate kinase M2 (PKM2) was overexpressed in many cancers, and high PKM2 expression was related with poor prognosis and chemoresistance. OBJECTIVE: We investigated the expression of PKM2 in breast cancer and analyzed the relation of PKM2 expression with chemotherapy resistance to the neoadjuvant chemotherapy (NAC). We also investigated whether PKM2 could reverse chemoresistance in breast cancer cells in vitro and in vivo. METHODS: Immunohistochemistry (IHC) was performed in 130 surgical resected breast cancer tissues. 78 core needle biopsies were collected from breast cancer patients before neoadjuvant chemotherapy. The relation of PKM2 expression and multi-drug resistance to NAC was compared. The effect of PKM2 silencing or overexpression on Doxorubicin (DOX) sensitivity in the MCF-7 cells in vitro and in vivo was compared. RESULTS: PKM2 was intensively expressed in breast cancer tissues compared to adjacent normal tissues. In addition, high expression of PKM2 was associated with poor prognosis in breast cancer patients. The NAC patients with high PKM2 expression had short survival. PKM2 was an independent prognostic predictor for surgical resected breast cancer and NAC patients. High PKM2 expression was correlated with neoadjuvant treatment resistance. High PKM2 expression significantly distinguished chemoresistant patients from chemosensitive patients. In vitro and in vivo knockdown of PKM2 expression decreases the resistance to DOX in breast cancer cells in vitro and tumors in vivo. CONCLUSION: PKM2 expression was associated with chemoresistance of breast cancers, and could be used to predict the chemosensitivity. Furthermore, targeting PKM2 could reverse chemoresistance, which provides an effective treatment methods for patients with breast cancer.

Download Full-text

HNRNPH1-stabilized LINC00662 promotes ovarian cancer progression by activating the GRP78/p38 pathway

Oncogene ◽

10.1038/s41388-021-01884-5 ◽

2021 ◽

Author(s):

Yong Wu ◽

Qinhao Guo ◽

Xingzhu Ju ◽

Zhixiang Hu ◽

Lingfang Xia ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Progression ◽

Prognostic Indicator ◽

Mapk Signaling ◽

The Cancer Genome Atlas ◽

Cancer Genome Atlas ◽

Proliferation And Metastasis ◽

Nuclear Ribonucleoprotein

AbstractNumerous studies suggest an important role for copy number alterations (CNAs) in cancer progression. However, CNAs of long intergenic noncoding RNAs (lincRNAs) in ovarian cancer (OC) and their potential functions have not been fully investigated. Here, based on analysis of The Cancer Genome Atlas (TCGA) database, we identified in this study an oncogenic lincRNA termed LINC00662 that exhibited a significant correlation between its CNA and its increased expression. LINC00662 overexpression is highly associated with malignant features in OC patients and is a prognostic indicator. LINC00662 significantly promotes OC cell proliferation and metastasis in vitro and in vivo. Mechanistically, LINC00662 is stabilized by heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1). Moreover, LINC00662 exerts oncogenic effects by interacting with glucose-regulated protein 78 (GRP78) and preventing its ubiquitination in OC cells, leading to activation of the oncogenic p38 MAPK signaling pathway. Taken together, our results define an oncogenic role for LINC00662 in OC progression mediated via GRP78/p38 signaling, with potential implications regarding therapeutic targets for OC.

Download Full-text

Twist-mediated PAR1 induction is required for breast cancer progression and metastasis by inhibiting Hippo pathway

Cell Death and Disease ◽

10.1038/s41419-020-2725-4 ◽

2020 ◽

Vol 11 (7) ◽

Author(s):

Yifan Wang ◽

Ruocen Liao ◽

Xingyu Chen ◽

Xuhua Ying ◽

Guanping Chen ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Invasive Breast Cancer ◽

Breast Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Hippo Pathway ◽

Breast Cancer Patients ◽

Mesenchymal Transition

Abstract Breast cancer is considered to be the most prevalent cancer in women worldwide, and metastasis is the primary cause of death. Protease-activated receptor 1 (PAR1) is a GPCR family member involved in the invasive and metastatic processes of cancer cells. However, the functions and underlying mechanisms of PAR1 in breast cancer remain unclear. In this study, we found that PAR1 is highly expressed in high invasive breast cancer cells, and predicts poor prognosis in ER-negative and high-grade breast cancer patients. Mechanistically, Twist transcriptionally induces PAR1 expression, leading to inhibition of Hippo pathway and activation of YAP/TAZ; Inhibition of PAR1 suppresses YAP/TAZ-induced epithelial-mesenchymal transition (EMT), invasion, migration, cancer stem cell (CSC)-like properties, tumor growth and metastasis of breast cancer cells in vitro and in vivo. These findings suggest that PAR1 acts as a direct transcriptionally target of Twist, can promote EMT, tumorigenicity and metastasis by controlling the Hippo pathway; this may lead to a potential therapeutic target for treating invasive breast cancer.

Download Full-text

Enhancers mapping uncovers phenotypic heterogeneity and evolution in patients with luminal breast cancer

10.1101/193771 ◽

2017 ◽

Author(s):

Darren K. Patten ◽

Giacomo Corleone ◽

Balázs Győrffy ◽

Edina Erdős ◽

Alina Saiakhova ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Regulatory Elements ◽

Phenotypic Heterogeneity ◽

Endocrine Treatment ◽

Clinical Samples ◽

Luminal Breast Cancer ◽

Breast Cancer Patients ◽

Expression Of Genes

AbstractThe degree of intrinsic and interpatient phenotypic heterogeneity and its role in tumour evolution is poorly understood. Phenotypic divergence can be achieved via the inheritance of alternative transcriptional programs1,2. Cell-type specific transcription is maintained through the activation of epigenetically-defined regulatory regions including promoters and enhancers1,3,4. In this work, we annotated the epigenome of 47 primary and metastatic oestrogen-receptor (ERα)-positive breast cancer specimens from clinical samples, and developed strategies to deduce phenotypic heterogeneity from the regulatory landscape, identifying key regulatory elements commonly shared across patients. Highly shared regions contain a unique set of regulatory information including the motif for the transcription factor YY1. In vitro work shows that YY1 is essential for ERα transcriptional activity and defines the critical subset of functional ERα binding sites driving tumor growth in most luminal patients. YY1 also control the expression of genes that mediate resistance to endocrine treatment. Finally, we show that H3K27ac levels at active enhancer elements can be used as a surrogate of intra-tumor phenotypic heterogeneity, and to track expansion and contraction of phenotypic subpopulations throughout breast cancer progression. Tracking YY1 and SLC9A3R1 positive clones in primary and metastatic lesions, we show that endocrine therapies drive the expansion of phenotypic clones originally underrepresented at diagnosis. Collectively, our data show that epigenetic mechanisms significantly contribute to phenotypic heterogeneity and evolution in systemically treated breast cancer patients.

Download Full-text

Promoter Methylation Status of the Retinoic Acid Receptor-Beta 2 Gene in Breast Cancer Patients: A Case Control Study and Systematic Review

Breast Care ◽

10.1159/000489874 ◽

2019 ◽

Vol 14 (2) ◽

pp. 117-123 ◽

Cited By ~ 1

Author(s):

Kheirollah Yari ◽

Zohreh Rahimi

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Retinoic Acid Receptor ◽

Methylation Status ◽

Normal Breast ◽

Breast Cancer Patients ◽

Retinoic Acid Receptor Beta ◽

Cancer Tissues ◽

Breast Tissues ◽

Receptor Beta

Background: We aimed to determine the promoter methylation status of the retinoic acid receptor-beta 2 (RARβ2) gene among breast cancer patients and to review relevant studies in this field in various populations. Methods: We analyzed 400 samples which comprised blood specimens from 102 breast cancer patients, 102 first-degree female relatives of patients, 100 cancer-free females, 48 breast cancer tissues, and 48 adjacent normal breast tissues from the same patients. The RARβ2 methylation status was determined using methylation-specific polymerase chain reaction (MSP) and DNA sequencing methods. Results: The presence of combined partially methylated (MU) and fully methylated (MM) forms of the RARβ2 gene (MU+MM) in the blood of patients was associated with susceptibility to breast cancer (odds ratio = 4.7, p = 0.05). A significantly higher frequency of the MM genotype was observed in cancer tissue (10.4%) compared to matched adjacent normal breast tissue (0%) (p = 0.02). Conclusion: We found a higher frequency of RARβ2 gene methylation in the blood and cancer tissues of patients compared to the blood of controls and adjacent normal breast tissues. The survey of studies on various populations demonstrated a higher RARβ2 methylation frequency in breast cancer patients compared to normal individuals, and many reports suggest a significant association between hypermethylation of the gene and susceptibility to breast cancer.

Download Full-text

Expression of MALAT1 Promotes Trastuzumab Resistance in HER2 Overexpressing Breast Cancers

Cancers ◽

10.3390/cancers12071918 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1918

Author(s):

Yanyuan Wu ◽

Marianna Sarkissyan ◽

Ochanya Ogah ◽

Juri Kim ◽

Jaydutt V. Vadgama

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Akt Pathway ◽

Breast Cancers ◽

Trastuzumab Resistance ◽

Mesenchymal Transition ◽

Cancer Tissues

Background: Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is associated with cancer progression. Our study examined the role of MALAT1 in breast cancer and the mechanisms involved in the regulation of MALAT1. Methods: In vitro cell and in vivo animal models were used to examine the role of MALAT1 in breast cancer. The interaction of FOXO1 (Forkhead Box O1) at the promoter region of MALAT1 was investigated by chromatin immunoprecipitation (ChIP) assay. Results: The data shows an elevated expression of MALAT1 in breast cancer tissues and cells compared to non-cancer tissues and cells. The highest level of MALAT1 was observed in metastatic triple-negative breast cancer and trastuzumab-resistant HER2 (human epidermal growth factor receptor 2) overexpressing (HER2+) cells. Knockdown of MALAT1 in trastuzumab-resistant HER2+ cells reversed epithelial to mesenchymal transition-like phenotype and cell invasiveness. It improved the sensitivity of the cell’s response to trastuzumab. Furthermore, activation of Akt by phosphorylation was associated with the upregulation of MALAT1. The transcription factor FOXO1 regulates the expression of MALAT1 via the PI3/Akt pathway. Conclusions: We show that MALAT1 contributes to HER2+ cell resistance to trastuzumab. Targeting the PI3/Akt pathway and stabilizing FOXO1 translocation could inhibit the upregulation of MALAT1.

Download Full-text

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.

Download Full-text

Nuclear ING3 Expression Is Correlated With a Good Prognosis of Breast Cancer

Frontiers in Oncology ◽

10.3389/fonc.2020.589009 ◽

2021 ◽

Vol 10 ◽

Author(s):

Xiaoyan Wu ◽

Chuang Chen ◽

Bin Luo ◽

Dandan Yan ◽

Honglin Yan ◽

...

Keyword(s):

Breast Cancer ◽

Cox Regression ◽

Histological Grade ◽

Normal Breast ◽

Breast Cancer Patients ◽

Her2 Positive ◽

Positive Type ◽

Cox Regression Analysis ◽

Cancer Tissues ◽

Breast Tissues

The inhibitor of growth (ING) family was discovered as the type II tumor suppressors, which regulated the proliferation, apoptosis, differentiation, angiogenesis, metastasis, and invasion of tumor cells through multiple pathways. ING3, a new member of ING family, has been reported to be downregulated in several types of tumors. However, few studies on ING3 in breast cancer have been reported. In this study, we investigated the expression of ING3 and determined its prognostic value in breast cancer. The immunohistochemistry was performed to evaluate the expression of ING3 in tissue microarrays (TMA) including breast cancer tissues (n=211) and normal breast tissues (n=50). In normal breast tissues, ING3 protein was detected in both the cytoplasm and nucleus. In breast cancer tissues, ING3 protein was principally detected in the cytoplasm. Compared with normal breast tissues, the expression of ING3 in nucleus was remarkably reduced in breast cancer tissues. The downregulated ING3 in nucleus was significantly correlated with clinicopathological characteristics including histological grade, lymph node metastasis, and the status of ER and PR. In HER2 positive-type and triple-negative breast cancer (TNBC) patients, it had the lower rate of nuclear ING3 with high expression than that in luminal-type. Moreover, Kaplan-Meier curves demonstrated that the reduced expression of ING3 in nucleus was correlated with a poorer 5-DFS and 5-OS of breast cancer patients. Importantly, multivariate Cox regression analysis suggested that the reduced expression of ING3 in nucleus was an independent prognostic factor in breast cancer. Our study comprehensively described the expression of ING3 in breast cancer for the first time and proved that it was an independent prognostic predictor of breast cancer, as well as a new idea for study of breast cancer.

Download Full-text

Inhibition of UGT8 suppresses basal-like breast cancer progression by attenuating sulfatide–αVβ5 axis

Journal of Experimental Medicine ◽

10.1084/jem.20172048 ◽

2018 ◽

Vol 215 (6) ◽

pp. 1679-1692 ◽

Cited By ~ 14

Author(s):

Qianhua Cao ◽

Xingyu Chen ◽

Xuebiao Wu ◽

Ruocen Liao ◽

Panpan Huang ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Biosynthetic Pathway ◽

Treatment Options ◽

Prognostic Indicator ◽

Inhibitory Effect ◽

Breast Cancer Patients ◽

Elevated Expression ◽

Basal Like Breast Cancer ◽

Pharmacologic Inhibition

Basal-like breast cancer (BLBC) is associated with a poor clinical outcome as a result of the few treatment options and poor therapeutic response. Here, we report that elevated expression of urine diphosphate–galactose ceramide galactosyltransferase (UGT8) specifically occurs in BLBC and predicts poor prognosis in breast cancer patients. UGT8 expression is transcriptionally up-regulated by Sox10, triggering the sulfatide biosynthetic pathway; increased sulfatide activates integrin αVβ5-mediated signaling that contributes to BLBC progression. UGT8 expression promotes, whereas UGT8 knockdown suppresses tumorigenicity and metastasis. Importantly, we identify that zoledronic acid (ZA), a marketed drug for treating osteoporosis and bone metastasis, is a direct inhibitor of UGT8, which blocks the sulfatide biosynthetic pathway. Significantly, a clinically achievable dosage of ZA exhibits apparent inhibitory effect on migration, invasion, and lung metastasis of BLBC cells. Together, our study suggests that UGT8 is a potential prognostic indicator and druggable target of BLBC and that pharmacologic inhibition of UGT8 by ZA offers a promising opportunity for treating this challenging disease.

Download Full-text