Tyrosine phosphorylation of HDAC3 by Src kinase mediates proliferation of HER2-positive breast cancer cells

2018 ◽  
Vol 234 (5) ◽  
pp. 6428-6436 ◽  
Author(s):  
Jaesung Seo ◽  
Garam Guk ◽  
Seung-Ho Park ◽  
Mi-Hyeon Jeong ◽  
Ji-Hoon Jeong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Tyrosine Phosphorylation ◽  
Breast Cancer Cells ◽  
Src Kinase ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

scholarly journals Tumor Extrinsic Factors Mediate Primary T-DM1 Resistance in HER2-Positive Breast Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2331
Author(s):  
Yukinori Endo ◽  
Wen-Jin Wu
Keyword(s):  
Breast Cancer ◽  
Cell Surface ◽  
Cancer Cells ◽  
Tyrosine Phosphorylation ◽  
Breast Cancer Cells ◽  
Synergistic Activity ◽  
Her2 Positive ◽  
Primary Resistance ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

To explore if the tumor microenvironment contributes to the primary resistance of HER2-positive breast cancer cells to T-DM1, we examined whether Matrigel, a basement membrane matrix that provides a three-dimensional (3D) cell culture condition, caused the primary resistance of HER2-positive, T-DM1-sensitive breast cancer cells (JIMT1 and SKBR-3 cells) to T-DM1. This is different from the conventional approach such that the cells are exposed with escalated doses of drug to establish a drug-resistant cell line. We found that these cells were able to grow and form spheroids on the Matrigel in the presence of T-DM1. We further explored the molecular mechanisms that enables these cells to be primarily resistant to T-DM1 and found that EGFR was activated in the spheroids, leading to an increased HER2 tyrosine phosphorylation. This in turn enhances cell growth signaling downstream of EGFR/HER2 in the spheroids. HER2 tyrosine phosphorylation promotes receptor internalization and degradation in the spheroids, which limits T-DM1 access to HER2 on the cell surface of spheroids. Blocking EGFR activity by erlotinib reduces HER2 tyrosine phosphorylation and enhances HER2 cell surface expression. This enables T-DM1 to gain access to HER2 on the cell surface, resumes cell sensitivity to T-DM1, and exhibits synergistic activity with T-DM1 to inhibit the formation of spheroids on Matrigel. The discovery described in this manuscript reveals a novel approach to investigate the primary resistance of HER2-positive breast cancer cells and provides an opportunity to develop a therapeutic strategy to overcome primary resistance to T-DM1 by combing T-DM1 therapy with kinase inhibitors of EGFR.

scholarly journals UCP-2 inhibitor enhanced the efficacy of trastuzumab against HER2 positive breast cancer cells

2021 ◽  
Author(s):  
Jun Hua ◽  
Zhe Zhang ◽  
Lili Zhang ◽  
Yan Sun ◽  
Yuan Yuan
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Neoadjuvant Therapy ◽  
Needle Biopsy ◽  
Breast Cancer Cells ◽  
Her2 Positive ◽  
Trastuzumab Treatment ◽  
Her2 Positive Breast Cancer ◽  
Trastuzumab Therapy ◽  
Positive Breast Cancer

Abstract Purpose This study aimed to investigate the possibility of UCP-2 inhibitor in reducing acquired resistance of trastuzumab to improve the outcome of patients receiving trastuzumab therapy by exploring the relationship between UCP-2 expression and HER2 signaling pathway and examining whether UCP-2 expression was modulated by trastuzumab treatment. Methods 32 women diagnosed with primary HER2-positive breast cancer were recruited in this study. Needle biopsy was obtained from patients before they received at least four cycles neoadjuvant therapy containing trastuzumab in combination with chemotherapy. Surgical tumor biopsy was obtained during surgical procedure after the neoadjuvant therapy. Levels of HER2 phosphorylation and UCP-2 expression were detected by immunohistochemistry (IHC) and compared between tumor needle biopsy tissue and surgical tumor samples of these patients, as well as in BT474 breast cancer cells before and after trastuzumab treatment. HER2-selective phosphorylation/kinase activity inhibitor ONT-380 was used to identify the correlation between HER2 phosphorylation level and UCP-2 expression. UCP-2 inhibitor Genipin was then used to evaluate the apoptosis index in BT474 cells treated with trastuzumab. Results UCP-2 expression was significantly elevated in surgical tumor samples from breast cancer patients receiving trastuzumab in a neoadjuvant setting. We further confirmed our findings in HER2-positive BT474 cell line and found that trastuzumab treatment induced phosphorylation of HER2 and the overexpression of UCP-2, and the latter can be reversed by HER2 selective kinase inhibitor ONT-380. Moreover, UCP-2 inhibitor Genipin significantly enhanced the proliferation suppression effects of trastuzumab and markedly promoted apoptosis. Conclusion Taken together, our study identified UCP-2 as a novel therapeutic target for HER2 positive breast cancer and UCP-2 inhibitor may have great potential to enhance the response rate and efficacy of trastuzumab therapy.

scholarly journals Dual inhibition of IGF1R and ER enhances response to trastuzumab in HER2 positive breast cancer cells

2017 ◽  
Vol 50 (6) ◽  
pp. 2221-2228 ◽  
Author(s):  
Martina S.J. Mcdermott ◽  
Alexandra Canonici ◽  
Laura Ivers ◽  
Brigid C. Browne ◽  
Stephen F. Madden ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Dual Inhibition ◽  
Positive Breast Cancer

scholarly journals Linc01638 Promotes Tumorigenesis in HER2+ Breast Cancer

2018 ◽  
Vol 19 (1) ◽  
pp. 74-80 ◽  
Author(s):  
Peng Liu ◽  
Hailin Tang ◽  
Jiali Wu ◽  
Xingsheng Qiu ◽  
Yanan Kong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Apoptosis ◽  
Breast Cancer Cells ◽  
Her2 Positive ◽  
Mouse Xenograft ◽  
Her2 Positive Breast Cancer ◽  
Mouse Xenograft Model ◽  
Positive Breast Cancer

Background: Long non-coding RNAs play crucial roles in various biological activities and diseases. The role of long intergenic non-coding RNA01638 (linc01638) in breast cancer, especially in HER2-positive breast cancer, remains largely unknown. Objective: To investigate the effect of linc01638 on tumorigenesis in HER2-positive breast cancer. </P><P> Methods: We first used qRT-PCR to detect linc01638 expression in HER2-positive breast cancer cells and tissues. Then we analyzed the effects of linc01638 expression in HER2-positive breast cancer cells through cell apoptosis assay, cell proliferation assay, colony formation assay, and cell invasion assay. We conducted mouse xenograft model to further confirm the role of linc01638 in HER2-positive breast cancer. Moreover, we used Western blot and IHC analysis to access the effect of linc01638 on DNMTs, BRCA1 and PTEN expressions in transplanted tumors. Results: Linc01638 was found to be remarkably overexpressed in HER2-positive breast cancer cells and tissues. Suppression of linc01638 enhanced cell apoptosis, as well as inhibited the growth and invasiveness of HER2-positive breast cancer cells in vitro and tumor progression and metastasis in vivo. Furthermore, inhibition of linc01638 by shRNA attenuated expression of DNMT1, DNMT3a, and DNMT3b, and promoted expression of BRCA1 and PTEN in HER2-positive breast cancer cells and mouse xenograft models. Linc01638 might be a promising biomarker and therapeutic target for treatment of HER2-positive breast cancer.

scholarly journals Oleanolic Acid’s Semisynthetic Derivatives HIMOXOL and Br-HIMOLID Show Proautophagic Potential and Inhibit Migration of HER2-Positive Breast Cancer Cells In Vitro

2021 ◽  
Vol 22 (20) ◽  
pp. 11273
Author(s):  
Natalia Magdalena Lisiak ◽  
Izabela Lewicka ◽  
Mariusz Kaczmarek ◽  
Jacek Kujawski ◽  
Barbara Bednarczyk-Cwynar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Biological Activity ◽  
Cancer Cells ◽  
Oleanolic Acid ◽  
Breast Cancer Cells ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

Approximately 20–30% of the diagnosed breast cancers overexpress the human epidermal growth factor receptor 2 (HER2). This type of cancer is associated with a more aggressive phenotype; thus, there is a need for the discovery of new compounds that would improve the survival in HER2-positive breast cancer patients. It seems that one of the most promising therapeutic cancer strategies could be based on the biological activity of pentacyclic triterpenes’ derivatives and the best-known representative of this group, oleanolic acid (OA). The biological activity of oleanolic acid and its two semisynthetic derivatives, methyl 3-hydroxyimino-11-oxoolean-12-en-28-oate (HIMOXOL) and 12α-bromo-3-hydroxyimonoolean-28→13-olide (Br-HIMOLID), was assessed in SK-BR-3 breast cancer cells (HER2-positive). Viability tests, cell cycle assessment, evaluation of apoptosis, autophagy, and adhesion/migration processes were performed using MTT, clonogenic, cytofluorometry, Western blot, and qPCR. Both derivatives revealed higher cytotoxicity in studied breast cancer cells than the maternal compound, OA. They also decreased cell viability, induced autophagy, and (when applied in sub-cytotoxic concentrations) decreased the migration of SK-BR-3 cells.This study is the first to report the cytostatic, proautophagic (mTOR/LC3/SQSTM/BECN1 pathway), and anti-migratory (integrin β1/FAK/paxillin pathway) activities of HIMOXOL and Br-HIMOLID in HER2-positive breast cancer cells.

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

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.

Pyrotinib sensitizes 5‑fluorouracil‑resistant HER2-positive breast cancer cells to 5‑fluorouracil

2020 ◽  
Author(s):  
Jianing Yi ◽  
Pingyong Yi ◽  
Shuai Chen ◽  
Qian Li ◽  
Runzhang Wu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Combination Treatment ◽  
Breast Cancer Cells ◽  
Continuous Exposure ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Her2 Breast Cancer ◽  
Positive Breast Cancer

Abstract BACKGROUND: Clinical trials have shown that pyrotinib+ capecitabine significantly improved efficacy of patients with human epidermal growth factor receptor 2(HER2) +breast cancer. However, whether pyrotinib sensitizes 5‑Fluorouracil(5‑FU)‑resistant breast cancer cells to 5‑FU is unknown. This study aimed to investigate the effects of pyrotinib on HER2+breast cancer cells with resistance to 5‑FU and provide new clues for the pyrotinib treatment in 5-FU-resistant breast cancer.METHODS: the 5‑FU‑resistant breast cancer cell lines SK-BR-3/FU and MAD-MB-453/FU were established by continuous exposure of the parental cells to 5‑FU.The effects of pyrotinib on these cell lines were examined by growth inhibitory activity assay, reverse transcription‑quantitative polymerase chain reaction, Western blot analysis, high-performance liquid chromatography and animal experiments.RESULTS: Pyrotinib inhibited the proliferation of 5-FU-resistant and parental HER2-positive breast cancer cells and re-sensitized resistant cells to 5-FU by decreasing the expression of thymidylate synthase(TS) and ABC transporter subfamily G member 2(ABCG2). In a xenograft model, combination treatment with 5-FU and pyrotinib showed greater antitumor activity than either agent alone. CONCLUSIONS: Our results offer a preclinical rationale for clinical investigations of combination treatment with pyrotinib and 5-FU for 5-FU-resistant HER2-positive breast cancer.

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