NCAPG confers trastuzumab resistance via activating SRC/STAT3 signaling pathway in HER2-positive breast cancer

AbstractHER2+ breast cancer (BC) is characterized by rapid growth, early recurrence, early metastasis, and chemoresistance. Trastuzumab is the most effective treatment for HER2+ BC and effectively reduces the risk of recurrence and death of patients. Resistance to trastuzumab results in cancer recurrence and metastasis, leading to poor prognosis of HER2+ BC. In the present study, we found that non-structural maintenance of chromosome condensin 1 complex subunit G (NCAPG) expression was highly upregulated in trastuzumab-resistant HER2+ BC. Ectopic NCAPG was positively correlated with tumor relapse and shorter survival in HER2+ BC patients. Moreover, overexpression of NCAPG promoted, while silencing of NCAPG reduced, the proliferative and anti-apoptotic capacity of HER2+ BC cells both in vitro and in vivo, indicating NCAPG reduces the sensitivity of HER2+ BC cells to trastuzumab and may confer trastuzumab resistance. Furthermore, our results suggest that NCAPG triggers a series of biological cascades by phosphorylating SRC and enhancing nuclear localization and activation of STAT3. To summarize, our study explores a crucial role for NCAPG in trastuzumab resistance and its underlying mechanisms in HER2+ BC, and suggests that NCAPG could be both a potential prognostic marker as well as a therapeutic target to effectively overcome trastuzumab resistance.

Download Full-text

O80: GREMLIN-1 PROMOTES TUMOURIGENESIS AND METASTASIS IN HER2 POSITIVE BREAST CANCER

British Journal of Surgery ◽

10.1093/bjs/znab117.080 ◽

2021 ◽

Vol 108 (Supplement_1) ◽

Author(s):

C Zabkiewicz ◽

L Ye ◽

R Hargest

Keyword(s):

Breast Cancer ◽

Cellular Growth ◽

Breast Cancers ◽

Her2 Positive ◽

Mesenchymal Transition ◽

Her2 Breast Cancer ◽

Bmp Signalling ◽

Gremlin 1

Abstract Introduction HER2 over-expression denotes poor prognosis in breast cancers.Bone morphogenetic protein(BMP) signalling is known to interact with EGF signalling, co-regulating breast cancer progression.BMP antagonist Gremlin-1 may influence breast cancer disease progression, but this remains unexplored in HER2 positive breast cancers. Method GREM1 and HER2 expression, and clinical outcomes were examined in clinical cohorts.GREM1 overexpression or pEF control plasmid were transduced into BT474 HER2+breast cancer cells. In vitro function tests using BT474 pEF and BT474GREM1cells include 2D/3D growth, migration, and expression of epithelial to mesenchymal transition(EMT)markers. Signalling cascades were examined in BT474 treated with RhGremlin-1. In vivo, BALB/c nude mice underwent either mammary injection or intra-cardiac injection of BT474pEF or BT474GREM1 cells and disease burden assessed. Result GREM1 expression correlates with HER2 in breast tumours(p=0.03) and is higher in metastatic HER2 positive cancers (p = 0.04). HER2 positive patients with high GREM1 have poor survival(p = 0.0002). BT474GREM1cells have up-regulated markers of EMT compared to control. BT474 RhGremlin-1 treated cells have active AKT pathway signalling, independent of BMP signalling. In vitro, BT474GREM1cells significantly proliferate and migrate compared to control(p<0.05 and p < 0.001).This is confirmed in vivo, BT474GREM1 mice grew significantly larger mammary tumours(p<0.05) and had more PETCT metastatic hotspots. Conclusion Gremlin-1 is correlated with poor outcomes in HER2 patients and promotes breast cancer cellular growth, migration and metastasis.Gremlin-1 is a novel area of research with potential as a prognostic biomarker and therapeutic target for personalised, effective, breast cancer outcomes. Take-home message BMP antagonists are gaining interest for their potential in breast cancer prognosis and therapeutics.This novel area of research shows BMP antagonist Gremlin-1 is of importance in HER2 positive breast cancers. DRAGONS DEN

Download Full-text

A novel HSP90 inhibitor targeting the C-terminal domain attenuates trastuzumab resistance in HER2-positive breast cancer

Molecular Cancer ◽

10.1186/s12943-020-01283-6 ◽

2020 ◽

Vol 19 (1) ◽

Author(s):

Jung Min Park ◽

Yoon-Jae Kim ◽

Soeun Park ◽

Minsu Park ◽

Lee Farrand ◽

...

Keyword(s):

Breast Cancer ◽

Hsp90 Inhibitor ◽

Trastuzumab Resistance ◽

Her2 Positive ◽

Mammosphere Formation ◽

Her2 Positive Breast Cancer ◽

Induced Apoptosis ◽

Positive Breast Cancer

AbstractTrastuzumab resistance in HER2-positive breast cancer is associated with a poorer prognosis. HSP90 is thought to play a major role in such resistance, but N-terminal inhibitors of this target have had little success. We sought to investigate the utility of NCT-547, a novel, rationally-designed C-terminal HSP90 inhibitor in the context of overcoming trastuzumab resistance. NCT-547 treatment significantly induced apoptosis without triggering the heat shock response (HSR), accompanied by caspase-3/− 7 activation in both trastuzumab-sensitive and -resistant cells. NCT-547 effectively promoted the degradation of full-length HER2 and truncated p95HER2, while also attenuating hetero-dimerization of HER2 family members. The impairment of cancer stem-like traits was observed with reductions in ALDH1 activity, the CD24low/CD44high subpopulation, and mammosphere formation in vitro and in vivo. NCT-547 was an effective inhibitor of tumor growth and angiogenesis, and no toxic outcomes were found in initial hepatic and renal analysis. Our findings suggest that NCT-547 may have applications in addressing trastuzumab resistance in HER2-positive breast cancer.

Download Full-text

miR-200c suppresses stemness and increases cellular sensitivity to trastuzumab in HER2+ breast cancer

10.1101/130682 ◽

2017 ◽

Author(s):

Cailu Song ◽

Jin Wang ◽

Hua Wang ◽

Peng Liu ◽

Longzhong Liu ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Target Genes ◽

Breast Cancer Cell Lines ◽

Breast Cancer Patients ◽

Trastuzumab Resistance ◽

Her2 Positive ◽

Her2 Breast Cancer ◽

Mcf 7

AbstractResistance to trastuzumab remains a major obstacle in HER2-overexpressing breast cancer treatment. miR-200c is important for many functions in cancer stem cells (CSCs), including tumor recurrence, metastasis and resistance. We hypothesized that miR-200c contributes to trastuzumab resistance and stemness maintenance in HER2-overexpressing breast cancer. In this study, we used HER2-positive SKBR3, HER2-negative MCF-7, and their CD44+CD24- phenotype mammospheres SKBR3-S and MCF-7-S to verify. Our results demonstrated that miR-200c was weakly expressed in breast cancer cell lines and cell line stem cells. Overexpression of miR-200c resulted in a significant reduction in the number of tumor spheres formed and the population of CD44+CD24- phenotype mammospheres in SKBR3-S. Combining miR-200c with trastuzumab can significantly reduce proliferation and increase apoptosis of SKBR3 and SKBR3-S. Overexpression of miR-200c also eliminated its downstream target genes. These genes were highly expressed and positively related in breast cancer patients. Overexpression of miR-200c also improved the malignant progression of SKBR3-S and SKBR3 in vivo. miR-200c plays an important role in the maintenance of the CSC-like phenotype and increases drug sensitivity to trastuzumab in HER2+ cells and stem cells.Summary statementmiRNAs are critical in stemness maintenance and drug resistance. These data link maintenance of the stemness-related phenotype and the sensitivity of HER2+ breast cancer to miR-200c in response to trastuzumab.

Download Full-text

circCDYL2 promotes trastuzumab resistance via sustaining HER2 downstream signaling in breast cancer

Molecular Cancer ◽

10.1186/s12943-021-01476-7 ◽

2022 ◽

Vol 21 (1) ◽

Author(s):

Yun Ling ◽

Gehao Liang ◽

Qun Lin ◽

Xiaolin Fang ◽

Qing Luo ◽

...

Keyword(s):

Breast Cancer ◽

Critical Role ◽

Disease Free Survival ◽

Trastuzumab Resistance ◽

Her2 Positive ◽

Downstream Signaling ◽

Cell Vitality ◽

Potential Biomarker

Abstract Background Approximate 25% HER2-positive (HER2+) breast cancer (BC) patients treated with trastuzumab recurred rapidly. However, the mechanisms underlying trastuzumab resistance remained largely unclear. Methods Trastuzumab-resistant associated circRNAs were identified by circRNAs high-throughput screen and qRT-PCR in HER2+ breast cancer tissues with different trastuzumab response. The biological roles of trastuzumab-resistant associated circRNAs were detected by cell vitality assay, colony formation assay, Edu assay, patient-derived xenograft (PDX) models and orthotopic animal models. For mechanisms research, the co-immunoprecipitation, Western blot, immunofluorescence, and pull down assays confirmed the relevant mechanisms of circRNA and binding proteins. Results We identified a circRNA circCDYL2, which was overexpressed in trastuzumab-resistant patients, which conferred trastuzumab resistance in breast cancer cells in vitro and in vivo. Mechanically, circCDYL2 stabilized GRB7 by preventing its ubiquitination degradation and enhanced its interaction with FAK, which thus sustained the activities of downstream AKT and ERK1/2. Trastuzumab-resistance of HER2+ BC cells with high circCDYL2 could be reversed by FAK or GRB7 inhibitor. Clinically, HER2+ BC patients with high levels of circCDYL2 developed rapid recurrence and had shorter disease-free survival (DFS) and overall survival (OS) following anti-HER2 therapy compared to those with low circCDYL2. Conclusions circCDYL2-GRB7-FAK complex plays a critical role in maintaining HER2 signaling, which contributes to trastuzumab resistance and circCDYL2 is a potential biomarker for trastuzumab-resistance in HER2+ BC patients.

Download Full-text

Yanghe Huayan decoction inhibits the capability of trans-endothelium and angiogenesis of HER2+ breast cancer via pAkt signaling

Bioscience Reports ◽

10.1042/bsr20181260 ◽

2019 ◽

Vol 39 (2) ◽

Cited By ~ 1

Author(s):

Xiao-Fei Liu ◽

Jing-Wei Li ◽

Hong-Zhi Chen ◽

Zi-Yuan Sun ◽

Guang-Xi Shi ◽

...

Keyword(s):

Breast Cancer ◽

Chinese Medicine ◽

Precancerous Lesion ◽

Tumor Development ◽

Akt Activation ◽

Her2 Breast Cancer ◽

Prevention And Treatment

Abstract Background: Yanghe Huayan Decoction (YHD), a traditional Chinese medicine, is one of the most common complementary medicine currently used in the treatment of breast cancer (BC). It has been recently linked to suppress precancerous lesion and tumor development. The current study sought to explore the role of YHD on trans-endothelium and angiogenesis of BC. Methods: HER2+ BC cells were treated with YHD, Trastuzumab, or the combination in vitro and in vivo to compare the effects of them on trans-endothelium and angiogenesis features. The present study also investigated the potential molecular mechanism of YHD in inhibiting angiogenesis of BC. Results: YHD significantly suppressed the invasion and angiogenesis of BC cells via elevated pAkt signaling. Administration of YHD in vivo also strikingly repressed angiogenesis in tumor grafts. Conclusion: YHD could partially inhibit and reverse tumorigenesis of BC. It also could inhibit Akt activation and angiogenesis in vitro and in vivo. Its effect was superior to trastuzumab. Thus it was suitable for prevention and treatment of BC.

Download Full-text

A Novel Small Molecular Antibody, HER2-Nanobody, Inhibits Tumor Proliferation in HER2-Positive Breast Cancer Cells In Vitro and In Vivo

Frontiers in Oncology ◽

10.3389/fonc.2021.669393 ◽

2021 ◽

Vol 11 ◽

Author(s):

Yan Yan ◽

Xiao Cheng ◽

Lin Li ◽

Rumeng Zhang ◽

Yong Zhu ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Suppressive Effect ◽

Her2 Positive ◽

Her2 Positive Breast Cancer ◽

Large Molecular Weight ◽

Positive Breast Cancer

Breast cancer is the most common malignant cancer in women worldwide, especially in developing countries. Herceptin is a monoclonal antibody with an antitumor effect in HER2-positive breast cancer. However, the large molecular weight of Herceptin limited its employment. In this study, we constructed and screened HER2-nanobody and verified its tumor-suppressive effect in HER2-positive breast cancer cells. HER2-nanobody was established, filtrated, purified, and was demonstrated to inhibit cell total number, viability, colony formation and mitosis, and promote cell apoptosis in HER2-positive breast cancer cells in vitro. Treated with HER2-nanobody, tumor growth was significantly inhibited by both intratumor injection and tail intravenous injection in vivo. The phosphorylation of ERK and AKT was restrained by HER2-nanobody in HER2-positive breast cancer cells. RAS-RAF-MAPK and PI3K-AKT-mTOR are two important pathways involved in HER2. It was credible for HER2-nanobody to play the tumor suppressive role by inhibiting the phosphorylation of ERK and AKT. Therefore, HER2-nanobody could be employed as a small molecular antibody to suppress HER2-positive breast cancer.

Download Full-text

Dual anti-HER2 blockade in late-line treatment of metastatic HER2-positive breast cancer

Medical Council ◽

10.21518/2079-701x-2021-20-156-159 ◽

2021 ◽

pp. 156-159

Author(s):

M. A. Frolova ◽

M. B. Stenina

Keyword(s):

Breast Cancer ◽

Treatment Options ◽

Migration And Invasion ◽

Line Treatment ◽

Her2 Positive ◽

Her2 Positive Breast Cancer ◽

Wide Range ◽

Positive Breast Cancer

In recent years, there has been a wide range of treatment options for patients with metastatic HER2-positive breast cancer, resulting in the highest life expectancy for these patients among all subtypes. The addition of pertuzumab to trastuzumab and docetaxel has been shown to increase overall survival and is therefore recognized as the standard first-line treatment. The most optimal second-line treatment option is trastuzumab emtansine. In addition, various combinations of cytostatics and anti HER2 targeting agents can be used. The choice of treatment options in heavily pretreated patients is of great interest. If they have not previously received pertuzumab, is it worth to use it and which combination is the best? One possible option is the combination of eribulin with the dual anti-HER2 blockade with trastuzumab and pertuzumab. Eribulin is an anti-microtubule agent that irreversibly blocks mitosis. In addition, it has non-mitotic effects – in vivo and in vitro experiments demonstrated its ability to restore normal tumor vascularization, reduce the area of hypoxia and, as a consequence, decrease tumor cells migration and invasion. This article represents a clinical case of the use of eribulin with double anti-HER2 blockade in the 6th line of treatment in a patient with metastatic HER2-positive breast cancer. Long-term control of the disease (within 2 years) with a satisfactory quality of life has been demonstrated.

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

Preclinical and phase I clinical studies of KW-2450, a dual IGF-1R/IR tyrosine kinase inhibitor, in combination with lapatinib and letrozole

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835918786858 ◽

2018 ◽

Vol 10 ◽

pp. 175883591878685 ◽

Cited By ~ 1

Author(s):

Hiroshi Umehara ◽

Yoshimi Maekawa ◽

Fumito Koizumi ◽

Makiko Shimizu ◽

Toshio Ota ◽

...

Keyword(s):

Breast Cancer ◽

Phase I ◽

Drug Combination ◽

Phase I Trial ◽

Kinase Inhibitor ◽

Her2 Positive ◽

Grade 3 ◽

Mcf 7

Background: KW-2450 is an oral dual insulin-like growth factor-1 receptor/insulin receptor tyrosine kinase inhibitor. We investigated the in vitro and in vivo preclinical activity of KW-2450 plus lapatinib and letrozole and conducted a phase I trial of the triple-drug combination in one male and 10 postmenopausal female patients with advanced/metastatic hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Methods: A series of in vitro and in vivo animal studies was undertaken of KW-2450 in combination with lapatinib and hormonal agents. The phase I trial was conducted to establish the safety, tolerability, and recommended phase II dose (RP2D) of KW-2450 administered in combination with lapatinib and letrozole. Results: Preclinical studies showed KW-2450 and lapatinib act synergistically to induce in vitro apoptosis and inhibit growth of HER2-positive MDA-MB-361 and BT-474 breast cancer cell lines. This combined effect was confirmed in vivo using the MDA-MB-361 xenograft model. KW-2450 showed synergistic in vitro growth inhibition with letrozole and 4-hydroxytamoxifen in ER-positive MCF-7 breast cancer cells and MCF-7-Ac1 aromatase-transfected MCF-7 cells. In the phase I study, dose-limiting toxicity (DLT; grade 3 rash and grade 3 hyperglycemia, respectively) occurred in two of three patients at the dose of KW-2450 25 mg/day plus lapatinib 1500 mg/day and letrozole 2.5 mg/day. The RP2D of the triple-drug combination was established as KW-2450 25 mg/day, lapatinib 1250 mg/day, and letrozole 2.5 mg/day with no DLT at this dose level. Conclusions: The proposed phase II study of the RP2D for the triple-drug combination did not progress because of anticipated difficulty in patient enrollment and further clinical development of KW-2450 was terminated.

Download Full-text

Liquid biopsies to track trastuzumab resistance in metastatic HER2-positive gastric cancer

Gut ◽

10.1136/gutjnl-2018-316522 ◽

2018 ◽

Vol 68 (7) ◽

pp. 1152-1161 ◽

Cited By ~ 23

Author(s):

De-Shen Wang ◽

Ze-Xian Liu ◽

Yun-Xin Lu ◽

Hua Bao ◽

Xue Wu ◽

...

Keyword(s):

Gastric Cancer ◽

In Situ Hybridisation ◽

Targeted Sequencing ◽

In Vivo Studies ◽

Fluorescence In Situ Hybridisation ◽

Trastuzumab Resistance ◽

Liquid Biopsies ◽

Her2 Positive

ObjectiveTo monitor trastuzumab resistance and determine the underlying mechanisms for the limited response rate and rapid emergence of resistance of HER2+ metastatic gastric cancer (mGC).DesignTargeted sequencing of 416 clinically relevant genes was performed in 78 paired plasma and tissue biopsy samples to determine plasma-tissue concordance. Then, we performed longitudinal analyses of 97 serial plasma samples collected from 24 patients who were HER2+ to track the resistance during trastuzumab treatment and validated the identified candidate resistance genes.ResultsThe results from targeted sequencing-based detection of somatic copy number alterations (SCNA) of HER2 gene were highly consistent with fluorescence in situ hybridisation data, and the detected HER2 SCNA was better than plasma carcinoembryonic antigen levels at predicting tumour shrinkage and progression. Furthermore, most patients with innate trastuzumab resistance presented high HER2 SCNA during progression compared with baseline, while HER2 SCNA decreased in patients with acquired resistance. PIK3CA mutations were significantly enriched in patients with innate resistance, and ERBB2/4 genes were the most mutated genes, accounting for trastuzumab resistance in six (35.3%) and five (29.4%) patients in baseline and progression plasma, respectively. Patients with PIK3CA/R1/C3 or ERBB2/4 mutations in the baseline plasma had significantly worse progression-free survival. Additionally, mutations in NF1 contributed to trastuzumab resistance, which was further confirmed through in vitro and in vivo studies, while combined HER2 and MEK/ERK blockade overcame trastuzumab resistance.ConclusionLongitudinal circulating tumour DNA sequencing provides novel insights into gene alterations underlying trastuzumab resistance in HER2+mGC.

Download Full-text