scholarly journals Proliferative Classification of Intracranially Injected HER2-positive Breast Cancer Cell Lines

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1811
Author(s):  
Yuka Kuroiwa ◽  
Jun Nakayama ◽  
Chihiro Adachi ◽  
Takafumi Inoue ◽  
Shinya Watanabe ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastasis ◽  
Cell Lines ◽  
Breast Cancer Cell Lines ◽  
Breast Cancers ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer Cell ◽  
The Brain ◽  
Positive Breast Cancer

HER2 is overexpressed in 25–30% of breast cancers, and approximately 30% of HER2-positive breast cancers metastasize to the brain. Although the incidence of brain metastasis in HER2-positive breast cancer is high, previous studies have been mainly based on cell lines of the triple-negative subtype, and the molecular mechanisms of brain metastasis in HER2-positive breast cancer are unclear. In the present study, we performed intracranial injection using nine HER2-positive breast cancer cell lines to evaluate their proliferative activity in brain tissue. Our results show that UACC-893 and MDA-MB-453 cells rapidly proliferated in the brain parenchyma, while the other seven cell lines moderately or slowly proliferated. Among these nine cell lines, the proliferative activity in brain tissue was not correlated with either the HER2 level or the HER2 phosphorylation status. To extract signature genes associated with brain colonization, we conducted microarray analysis and found that these two cell lines shared 138 gene expression patterns. Moreover, some of these genes were correlated with poor prognosis in HER2-positive breast cancer patients. Our findings might be helpful for further studying brain metastasis in HER2-positive breast cancer.

scholarly journals RANK signaling increases after anti-HER2 therapy contributing to the emergence of resistance in HER2-positive breast cancer

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Adrián Sanz-Moreno ◽  
Sonia Palomeras ◽  
Kim Pedersen ◽  
Beatriz Morancho ◽  
Tomas Pascual ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cell Lines ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer Cell ◽  
Rank Signaling ◽  
Positive Breast Cancer

Abstract Background Around 15–20% of primary breast cancers are characterized by HER2 protein overexpression and/or HER2 gene amplification. Despite the successful development of anti-HER2 drugs, intrinsic and acquired resistance represents a major hurdle. This study was performed to analyze the RANK pathway contribution in HER2-positive breast cancer and anti-HER2 therapy resistance. Methods RANK and RANKL protein expression was assessed in samples from HER2-positive breast cancer patients resistant to anti-HER2 therapy and treatment-naive patients. RANK and RANKL gene expression was analyzed in paired samples from patients treated with neoadjuvant dual HER2-blockade (lapatinib and trastuzumab) from the SOLTI-1114 PAMELA trial. Additionally, HER2-positive breast cancer cell lines were used to modulate RANK expression and analyze in vitro the contribution of RANK signaling to anti-HER2 resistance and downstream signaling. Results RANK and RANKL proteins are more frequently detected in HER2-positive tumors that have acquired resistance to anti-HER2 therapies than in treatment-naive ones. RANK (but not RANKL) gene expression increased after dual anti-HER2 neoadjuvant therapy in the cohort from the SOLTI-1114 PAMELA trial. Results in HER2-positive breast cancer cell lines recapitulate the clinical observations, with increased RANK expression observed after short-term treatment with the HER2 inhibitor lapatinib or dual anti-HER2 therapy and in lapatinib-resistant cells. After RANKL stimulation, lapatinib-resistant cells show increased NF-κB activation compared to their sensitive counterparts, confirming the enhanced functionality of the RANK pathway in anti-HER2-resistant breast cancer. Overactivation of the RANK signaling pathway enhances ERK and NF-κB signaling and increases lapatinib resistance in different HER2-positive breast cancer cell lines, whereas RANK loss sensitizes lapatinib-resistant cells to the drug. Our results indicate that ErbB signaling is required for RANK/RANKL-driven activation of ERK in several HER2-positive cell lines. In contrast, lapatinib is not able to counteract the NF-κB activation elicited after RANKL treatment in RANK-overexpressing cells. Finally, we show that RANK binds to HER2 in breast cancer cells and that enhanced RANK pathway activation alters HER2 phosphorylation status. Conclusions Our data support a physical and functional link between RANK and HER2 signaling in breast cancer and demonstrate that increased RANK signaling may contribute to the development of lapatinib resistance through NF-κB activation. Whether HER2-positive breast cancer patients with tumoral RANK expression might benefit from dual HER2 and RANK inhibition therapy remains to be elucidated.

HSP90 inhibition in HER2-positive breast cancer cells

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14573-e14573
Author(s):  
Z. Qadir ◽  
J. Crown ◽  
M. R. Jensen ◽  
M. Clynes ◽  
D. Slamon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Breast Cancer Cells ◽  
Hsp90 Inhibitor ◽  
Breast Cancer Cell Lines ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer Cell ◽  
Positive Breast Cancer

e14573 Background: HSP90 is required for the stability and activity of HER2 and downstream proteins, such as Akt, which play a key role in survival. We aimed to assess the anti-tumor effect of the HSP90 inhibitor NVP-AUY922 in HER-2 positive breast cancer cell lines. Methods: HER2 positive breast cancer cell lines with varied sensitivity to trastuzumab (Sensitive: BT474, SKBR3; acquired resistance: BT474Res, SKBR3Res; innate resistance: HCC1419, HCC1954, MDA-MB-453) were treated with the HSP90 inhibitor NVP-AUY922 (Novartis) and trastuzumab. IC50s were determined using the acid phosphatase assay. HER2, Akt and HSP90 levels were determined by immunoblotting after treatment with NVP-AUY922. Combinations of NVP-AUY922 with docetaxel, cisplatin and 5'-deoxy-5-fluorouridine (5-DFUR) were tested in BT474 and SKBR3 cells. Results: All of the HER2 positive cells were sensitive to NVP-AUY922, with IC50s ranging from 5.5 to 16.4 nM. Combined treatment with NVP-AUY922 (10 nM) and trastuzumab (10 nM) showed significantly greater inhibition of growth than either trastuzumab or NVP-AUY922 alone in BT474 and BT474Res cell lines (p<0.005). In SKBR3 and SKBR3Res cells, dual treatment with NVP-AUY922 and trastuzumab did not significantly increase response compared to NVP-AUY922 alone ( Table 1 ). Treatment with NVP-AUY922 resulted in a dose-dependent decrease in HER2 and Akt levels in trastuzumab-sensitive and -resistant cells. Combinations of docetaxel, cisplatin or 5-DFUR with NVP- AUY922 were antagonistic in both BT474 and SKBR3 cells (CI values >1). Conclusions: This study demonstrates that NVP-AUY922 has anti-tumor activity in trastuzumab-sensitive, and in both innate and acquired trastuzumab-resistant HER2 positive breast cancer cells. The antagonistic interactions observed for combinations of NVP-AUY922 with chemotherapy do not favour clinical evaluation of such combinations. However, combinations with other targeted therapies, such as trastuzumab, warrant further investigation. [Table: see text] [Table: see text]

ADAM17 as a novel therapeutic target for HER2-positive breast cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 622-622
Author(s):  
Sumainizah Sukor ◽  
Patricia M. McGowan ◽  
Maeve Mullooly ◽  
Aisling Pierce ◽  
John Crown ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Growth ◽  
Cell Lines ◽  
Breast Cancer Cell ◽  
Breast Cancer Cell Lines ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Growth Inhibitory ◽  
Positive Breast Cancer Cell ◽  
Positive Breast Cancer

622 Background: Although the HER2 gene is amplifiend/overexpressed in 15-20% of breast cancers, only a proportion of these patients benefit from anti-HER2 therapy. Clearly additional biomarkers and/or therapeutic targets are necessary to enhance efficacy and improve outcome in these patients. Here, we tested the hypothesis that inhibition of ADAM17-mediated release of HER ligands may enhance response to trastuzumab and lapatinib. Methods: The ADAM17-selective inhibitor, PF-5480090 (Pfizer) both alone and in combination with lapatinib, trastuzumab or 5FU was tested for potential growth inhibitory effects on a panel of 4 HER2-positive breast cancer cell lines (BT474, MDA-MB-453, SKBR3 and JIMT-1). Results: Using the MTT viability assay, treatment with 1 µM TMI-2 resulted in a significant reduction in cell proliferation compared to vehicle control in BT474 (p=0.01), MDA-MB-453 (p < 0.005), JIMT-1 (p=0.002) and SKBR3 cells (p < 0.005). Addition of PF-5480090 to lapatinib resulted in a significant reduction in cell growth compared to lapatinib alone (JIMT-1: p < 0.005; SKBR3: p < 0.005; MDA-MB-453: p < 0.005), while addition of PF-5480090 to trastuzumab resulted in significant reduction in cell growth compared to trastuzumab alone (JIMT-1: p < 0.005; SKBR3: p < 0.005; MDA-MB-453: p=0.001). Addition of PF-5480090 to 5FU resulted in significant reduction in growth compared to 5FU alone (JIMT-1: p < 0.005; SKBR3: p < 0.005; MDA-MB-453: p=0.001). Consistent with its ability to block proliferation, addition of PF-5480090 significantly reduced release of TGFalpha (BT474: p=0.003; JIMT1: p=0.023; SKBR3: p=0.036 and MDA-MB-453: p=0.014). Conclusions: Inhibitionof ADAM17 resulted in growth inhibitory responses in HER2-positive breast cancer cell lines. Furthermore, addition of PF-5480090 to lapatinib, trastuzumab or 5FU resulted in significant growth inhibition compared to these agents alone. We propose that inhibition of ADAM17 may be used in combination with existing treatments for HER2-positive breast cancer. Acknowledgement. The authors thank SFI (SRC award, 08/SRC/B1410 to MTCI) for funding this work.

Effect of afatinib alone and in combination with trastuzumab in HER2-positive breast cancer cell lines.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 632-632 ◽  
Author(s):  
Alexandra Canonici ◽  
Kasper Pedersen ◽  
Brigid Browne ◽  
Martina McDermott ◽  
Naomi Walsh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer Cell ◽  
Positive Breast Cancer

632 Background: Trastuzumab and lapatinib have been shown to significantly improve the prognosis for HER2 positive breast cancer patients. However, resistance is a significant clinical problem. The aim of this study is to assess the activity of afatinib, an irreversible pan-HER tyrosine kinase inhibitor, in HER2 overexpressing breast cancer cell lines, including trastuzumab and/or lapatinib resistant cells. Methods: Using proliferation assays, the effect of afatinib was assessed alone and in combination with trastuzumab in HER2 positive cell lines. The effect of afatinib on HER2, Erk and Akt was determined by immunoblotting. Results: The eight HER2 positive breast cancer cell lines tested, including trastuzumab and/or lapatinib resistant cells, responded to afatinib with IC50values ranging from 5 to 80 nM. The combination of afatinib and trastuzumab was additive in four trastuzumab sensitive cell lines and one model of acquired trastuzumab resistant HER2 positive breast cancer. In the remaining three trastuzumab and/or lapatinib resistant cell lines, combined treatment with trastuzumab and afatinib showed no enhancement compared to afatinib alone. Finally, afatinib decreased the phosphorylation of HER2 and Erk in all cell lines tested. Conclusions: Our results suggest that afatinib has activity in HER2 positive breast cancer, including trastuzumab and/or lapatinib resistant breast cancer. We also demonstrate that afatinib in combination with trastuzumab may be more effective than either agent alone in trastuzumab sensitive breast cancer. [Table: see text]

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