Trastuzumab-decorated nanoparticles for in vitro and in vivo tumor-targeting hyperthermia of HER2+ breast cancer

2017 ◽  
Vol 5 (35) ◽  
pp. 7369-7383 ◽  
Author(s):  
Javad Hamzehalipour Almaki ◽  
Rozita Nasiri ◽  
Ani Idris ◽  
Mahtab Nasiri ◽  
Fadzilah Adibah Abdul Majid ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Targeting ◽  
Magnetic Core ◽  
Core Shell ◽  
Hyperthermia Treatment ◽  
Her2 Breast Cancer

In this study, a magnetic core–shell modified tumor-targeting nanocarrier (MNPs-PEG–TRA) was engineered and demonstrated for the efficientin vitroandin vivohyperthermia treatment of breast cancer.

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

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

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

2019 ◽  
Vol 39 (2) ◽  
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.

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

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Lili Jiang ◽  
Liangliang Ren ◽  
Han Chen ◽  
Jinyuan Pan ◽  
Zhuojun Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Recurrence ◽  
Early Recurrence ◽  
Trastuzumab Resistance ◽  
Her2 Positive ◽  
Her2 Breast Cancer ◽  
Structural Maintenance Of Chromosome ◽  
Underlying Mechanisms

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.

scholarly journals EZH2-mediated PP2A inactivation confers resistance to HER2-targeted breast cancer therapy

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Yi Bao ◽  
Gokce Oguz ◽  
Wee Chyan Lee ◽  
Puay Leng Lee ◽  
Kakaly Ghosh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clonal Selection ◽  
Acquired Resistance ◽  
Epigenetic Mechanism ◽  
Regulatory Subunit ◽  
Breast Cancers ◽  
Her2 Breast Cancer ◽  
Phosphatase 2A

AbstractHER2-targeted therapy has yielded a significant clinical benefit in patients with HER2+ breast cancer, yet disease relapse due to intrinsic or acquired resistance remains a significant challenge in the clinic. Here, we show that the protein phosphatase 2A (PP2A) regulatory subunit PPP2R2B is a crucial determinant of anti-HER2 response. PPP2R2B is downregulated in a substantial subset of HER2+ breast cancers, which correlates with poor clinical outcome and resistance to HER2-targeted therapies. EZH2-mediated histone modification accounts for the PPP2R2B downregulation, resulting in sustained phosphorylation of PP2A targets p70S6K and 4EBP1 which leads to resistance to inhibition by anti-HER2 treatments. Genetic depletion or inhibition of EZH2 by a clinically-available EZH2 inhibitor restores PPP2R2B expression, abolishes the residual phosphorylation of p70S6K and 4EBP1, and resensitizes HER2+ breast cancer cells to anti-HER2 treatments both in vitro and in vivo. Furthermore, the same epigenetic mechanism also contributes to the development of acquired resistance through clonal selection. These findings identify EZH2-dependent PPP2R2B suppression as an epigenetic control of anti-HER2 resistance, potentially providing an opportunity to mitigate anti-HER2 resistance with EZH2 inhibitors.

Antihormone induced compensatory signalling in breast cancer: an adverse event in the development of endocrine resistance

2011 ◽  
Vol 5 (2) ◽  
Author(s):  
Julia M.W. Gee ◽  
Robert I. Nicholson ◽  
Denise Barrow ◽  
Carol M. Dutkowski ◽  
Lindy Goddard ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinases ◽  
Acquired Resistance ◽  
Endocrine Resistance ◽  
Clinical Relapse ◽  
Her2 Breast Cancer ◽  
Targeted Inhibitors ◽  
Resistant Cells

AbstractUsing MCF7 breast cancer cells, it has been shown that antihormones promote expression/activity of oestrogen-repressed tyrosine kinases, notably EGFR, HER2 and Src. These inductive events confer responsiveness to targeted inhibitors (e.g., gefitinib, trastuzumab, saracatinib). We observed that these antihormone-induced phenomena are common to ER+HER2– and ER+HER2+ breast cancer models in vitro, where targeting of EGFR, HER2 or Src alongside antihormone improves antitumour response and delays/prevents endocrine resistance. Such targeted inhibitors also subvert acquired endocrine resistant cells which retain increased EGFR, HER2 and Src (e.g., TAMR and FASR models derived after 6–12 months of tamoxifen or Faslodex treatment). Thus, antihormone-induced tyrosine kinases comprise “compensatory signalling” crucial in limiting maximal initial antihormone response and subsequently driving acquired resistance in vitro. However, despite such convincing preclinical findings from our group and others, clinical trials examining equivalent antigrowth factor strategies have proved relatively disappointing. Our new studies deciphering underlying causes reveal that further antihormone-promoted events could be pivotal in vivo. Firstly, Faslodex induces HER3 and HER4 which sensitise ER+ cells to heregulin, a paracrine growth factor that overcomes endocrine response and diminishes antitumour effect of agents targeting EGFR, HER2 or Src alongside antihormone. Secondly, extended antihormone exposure (experienced by ER+ cells prior to adjuvant clinical relapse) can “reprogramme” the compensatory kinase profile in vitro, hindering candidate antigrowth factor targeting of endocrine resistance. Faslodex resistant cells maintained with this antihormone for 3 years in vitro lose EGFR/HER2 dependency, gaining alternative mitogenic/invasion kinases. Deciphering these previously unrecognised antihormone-induced events could provide superior treatments to control endocrine relapse in the clinic.

Abstract LB132: CDK8/19 inhibition overcomes in vitro and in vivo resistance to lapatinib in HER2+ breast cancer via STAT1 and STAT3

2021 ◽  
Author(s):  
Xiaokai Ding ◽  
Amanda C. Sharko ◽  
Martina S-J McDermott ◽  
Hao Ji ◽  
Alexander Chumanevich ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Her2 Breast Cancer

Functionalized nanoscale β-1,3-glucan to improve Her2+ breast cancer therapy: In vitro and in vivo study

2015 ◽  
Vol 202 ◽  
pp. 49-56 ◽  
Author(s):  
Zahra Nasrollahi ◽  
Shahla Roudbar Mohammadi ◽  
Esmail Mollarazi ◽  
Mohammad Hossein Yadegari ◽  
Zuhair Mohammad Hassan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Therapy ◽  
In Vivo Study ◽  
Breast Cancer Therapy ◽  
Her2 Breast Cancer

scholarly journals Fatty Acid Synthase Is a Key Enabler for Endocrine Resistance in Heregulin-Overexpressing Luminal B-Like Breast Cancer

2020 ◽  
Vol 21 (20) ◽  
pp. 7661
Author(s):  
Javier A. Menendez ◽  
Inderjit Mehmi ◽  
Adriana Papadimitropoulou ◽  
Travis Vander Steen ◽  
Elisabet Cuyàs ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
Therapeutic Potential ◽  
Endocrine Resistance ◽  
Luminal B ◽  
Her2 Breast Cancer ◽  
Mcf 7

HER2 transactivation by the HER3 ligand heregulin (HRG) promotes an endocrine-resistant phenotype in the estrogen receptor-positive (ER+) luminal-B subtype of breast cancer. The underlying biological mechanisms that link them are, however, incompletely understood. Here, we evaluated the putative role of the lipogenic enzyme fatty acid synthase (FASN) as a major cause of HRG-driven endocrine resistance in ER+/HER2-negative breast cancer cells. MCF-7 cells engineered to stably overexpress HRG (MCF-7/HRG), an in vitro model of tamoxifen/fulvestrant-resistant luminal B-like breast cancer, showed a pronounced up-regulation of FASN gene/FASN protein expression. Autocrine HRG up-regulated FASN expression via HER2 transactivation and downstream activation of PI-3K/AKT and MAPK-ERK1/2 signaling pathways. The HRG-driven FASN-overexpressing phenotype was fully prevented in MCF-7 cells expressing a structural deletion mutant of HRG that is sequestered in a cellular compartment and lacks the ability to promote endocrine-resistance in an autocrine manner. Pharmacological inhibition of FASN activity blocked the estradiol-independent and tamoxifen/fulvestrant-refractory ability of MCF-7/HRG cells to anchorage-independently grow in soft-agar. In vivo treatment with a FASN inhibitor restored the anti-tumor activity of tamoxifen and fulvestrant against fast-growing, hormone-resistant MCF-7/HRG xenograft tumors in mice. Overall, these findings implicate FASN as a key enabler for endocrine resistance in HRG+/HER2- breast cancer and highlight the therapeutic potential of FASN inhibitors for the treatment of endocrine therapy-resistant luminal-B breast cancer.

scholarly journals Au@Pt Core-Shell Nanoparticle Bioconjugates for the Therapy of HER2+ Breast Cancer and Hepatocellular Carcinoma. Model Studies on the Applicability of 193mPt and 195mPt Radionuclides in Auger Electron Therapy

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 2051
Author(s):  
Kamil Wawrowicz ◽  
Agnieszka Majkowska-Pilip ◽  
Damian Gaweł ◽  
Ewelina Chajduk ◽  
Tadeusz Pieńkowski ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hepatocellular Carcinoma ◽  
Auger Electron ◽  
High Efficiency ◽  
Specific Binding ◽  
Core Shell ◽  
Cell Nuclei ◽  
Her2 Breast Cancer ◽  
Electron Therapy

193mPt and 195mPt radionuclides are therapeutically attractive Auger electron emitters with notably high Auger electron yield per decay. The present paper summarizes the first step of research on the applications of core-shell (Au@Pt) nanoparticles for electron Auger therapy of HER2+ (human epidermal growth factor receptor 2) breast cancer and hepatocellular carcinoma. Gold nanoparticles (30 nm) were synthesized covered with a platinum shell at high efficiency (>80%) and were further evaluated for in vitro studies such as binding affinity, internalization and cytotoxicity. To find the mechanism(s) responsible for platinum cytotoxicity in HepG2 cells, the platinum concentration in isolated cell nuclei and cytoplasm was determined using ICP-MS (inductively coupled plasma mass spectrometry). Lack of platinum in cell nuclei suggests that the cytotoxic effect is associated with the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Studies carried out on the SKOV-3 cell line with the use of a synthesized targeting bioconjugate (Au@Pt-PEG-trastuzumab) revealed a high affinity of this preparation to HER2+ cells, its internalization, its placement in the perinuclear area and partial intranuclear location. The specific binding for HER2 negative cells, MDA-MB-231, was negligible and Au@Pt-PEG-trastuzumab did not enter these cells. The results obtained are promising and warrant future investigation of Auger electron therapy using 193mPt and 195mPt based radiopharmaceuticals.

Sign in / Sign up

Export Citation Format

Share Document