HER2-amplified breast cancer: mechanisms of trastuzumab resistance and novel targeted therapies

Gajria, Devika; Chandarlapaty, Sarat

doi:10.1586/era.10.226

Cited by 422 publications

(309 citation statements)

References 102 publications

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“…Evidence from previous studies strongly suggests that the molecular subtype influences the systemic therapy and clinical outcome of BC (11). Her2-amplified BC accounts for ~20-25% of all invasive BC cases, and presents a poor overall survival (OS) rate (12). However, following the development of drugs such as trastuzumab, which selectively targets Her2, an improved prognosis may be achieved for this subtype of BC (12).…”

Section: Introductionmentioning

confidence: 99%

“…Her2-amplified BC accounts for ~20-25% of all invasive BC cases, and presents a poor overall survival (OS) rate (12). However, following the development of drugs such as trastuzumab, which selectively targets Her2, an improved prognosis may be achieved for this subtype of BC (12). Basal-like BC accounts for ~10% of all BC cases, and presents the worst prognosis, as there is currently no available endocrine or targeted therapy for this subtype of BC (13).…”

Section: Introductionmentioning

confidence: 99%

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S100A8/A9 is associated with estrogen receptor loss in breast cancer

Bao

Wang

2016

Oncology Letters

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Abstract. S100A8 and S100A9 are calcium-binding proteins that are secreted primarily by granulocytes and monocytes, and are upregulated during the inflammatory response. S100A8 and S100A9 have been identified to be expressed by epithelial cells involved in malignancy. In the present study, the transcriptional levels of S100A8 and S100A9 were investigated in various subtypes of breast cancer (BC), and the correlation with estrogen receptor 1 (ESR1) and GATA binding protein 3 (GATA3) gene expression was evaluated using microarray datasets. The expression of S100A8 and S100A9 in BC cells was assessed by reverse transcription-polymerase chain reaction (RT-PCR). The regulation of ESR1 and GATA3 by administration of recombinant S100A8/A9 was examined in the BC MCF-7 cell line using quantitative (q)PCR. The association between S100A8 and S100A9 and overall survival (OS) was investigated in GeneChip ® data of BC. The expression levels of S100A8 and S100A9 were higher in human epidermal growth factor receptor 2 (Her2)-amplified and basal-like BC. The messenger (m)RNA levels of S100A8 and S100A9 were inversely correlated with ESR1 and GATA3 expression. S100A8/A9 induced a 10-fold decrease in the mRNA levels of ESR1 in MCF-7 cells. Poor OS was associated with high expression levels of S100A9, but not with high expression levels of S100A8 in BC. In conclusion, strong expression and secretion of S100A8/A9 may be associated with the loss of estrogen receptor in BC, and may be involved in the poor prognosis of Her2 + /basal-like subtypes of BC.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

S100A8/A9 is associated with estrogen receptor loss in breast cancer

Bao

Wang

2016

Oncology Letters

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“…3 de novo and acquired resistance to the anti-HER2 monoclonal antibody trastuzumab have also been identified. 4 Besides, no targeted therapy is available for aggressive triplenegative breast cancer which is characterized by the absence of expression of estrogen, progesterone, and HER2 receptors. 5 These limitations in breast cancer therapy are strong arguments for the search for optimized therapeutic strategies and the development of new therapeutic agents.…”

Section: Introductionmentioning

confidence: 99%

Δ2-Troglitazone promotes cytostatic rather than pro-apoptotic effects in breast cancer cells cultured in high serum conditions

et al. 2016

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We have previously shown that D2-Troglitazone (D2-TGZ) displayed anticancer effects on breast cancer cell lines grown in low serum conditions (1% fetal calf serum (FCS)). The present study was performed in order to characterize the effects of D2-TGZ in high serum containing medium and to determine if starvation could influence the response of breast cancer cells to this compound, keeping in mind the potential interest for breast cancer therapy. We observed that in high serum conditions (10% FCS), a 48 h treatment with D2-TGZ induced a decrease in cell numbers in MDA-MB-231 and MCF-7 breast cancer cell lines. The IC 50 values were higher than in low serum conditions. Furthermore, in contrast to our previous results obtained in 1% FCS conditions, we observed that in 10% FCS-containing medium, MCF-7 cells were more sensitive to D2-TGZ than MDA-MB-231 cells. D2-TGZ also induced endoplasmic reticulum (ER) stress mainly in MDA-MB-231 cells. Besides, in high serum conditions, D2-TGZ induced a G 0 /G 1 cell cycle arrest, an inhibition of BrdU incorporation and a reduced level of cyclin D1. We observed a limited cleavage of PARP and a limited proportion of cells in sub-G 1 phase. Thus, in high serum conditions, D2-TGZ displayed cytostatic effects rather than apoptosis as previously reported in 1% FCS-containing medium. Our results are in accordance with studies suggesting that serum starvation could potentiate the action of diverse anti-cancer agents.

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“…For patients undergoing targeted therapy, HER-2 expression is used as a biomarker for identifying subgroups that are likely to achieve a survival benefit from trastuzumab therapy (6). Unfortunately, trastuzumab resistance is universally observed in both breast cancer and GC.…”

Section: Introductionmentioning

confidence: 99%

Significance and prognostic role of human epidermal growth factor receptor 2 and RAB1A expression in gastric cancer

Huang

Yang

et al. 2018

Oncol Lett

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Abstract. Human epidermal growth factor receptor 2 (HER-2) has an important clinical role in various cancers. However, the prognostic impact of HER-2 in gastric cancer (GC) is controversial. RAB1A is an important small molecule in the mechanistic target of rapamycin signalling pathway, which is one of the downstream signalling pathways of the epidermal growth factor receptor family. In recent years, the aberrant expression of RAB1A has been reported in a number of tumours, but its regulation in GC has not been extensively examined. Therefore, the present study investigated the expression pattern and prognostic significance of HER-2 and RAB1A in gastric adenocarcinoma (CAG). A comprehensive analysis was performed to examine the expression level of HER-2 and RAB1A in 280 cases of paired paraffin-embedded GAC tissues and an additional 120 archived GAC tissue samples. HER-2 and RAB1A protein expression was assessed by immunohistochemistry and cases with a 2+ score for HER-2 expression levels were subjected to fluorescence in situ hybridization to determine the HER-2 amplification status. Furthermore, HER-2 and RAB1A mRNA expression was quantified by reverse transcription-quantitative polymerase chain reaction. The comparison of continuous data between two groups was performed using a paired-samples t-test. Clinical correlations were determined using Pearson's Chi-square and Fisher's exact tests. Kaplan-Meier survival curves were used to estimate overall survival (OS). Cox proportional hazards models were used to determine associations between HER-2 and RAB1A expression and outcomes. Regression analyses were performed to detect the correlation between the mRNA levels of HER-2 and RAB1A in GAC tissues. It was observed that RAB1A was significantly overexpressed in GAC tissues compared with normal tissues (P<0.001). Approximately 12.86% of the 280 GAC patients had HER-2 amplification. Additionally, RAB1A expression was significantly associated with a short OS (P<0.001) but there were no significant differences in survival between the HER-2 high-expression group and the HER-2 low-expression group. Additionally, the co-expression of HER-2 and RAB1A indicated poorer OS than the overexpression of each protein (P=0.001), and the two factors were significantly positively correlated in GAC (P= 0.012). These findings may be used to further explore the molecular mechanisms and regulatory associations among signalling pathways in GC.

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HER2-amplified breast cancer: mechanisms of trastuzumab resistance and novel targeted therapies

Cited by 422 publications

References 102 publications

S100A8/A9 is associated with estrogen receptor loss in breast cancer

S100A8/A9 is associated with estrogen receptor loss in breast cancer

Δ2-Troglitazone promotes cytostatic rather than pro-apoptotic effects in breast cancer cells cultured in high serum conditions

Significance and prognostic role of human epidermal growth factor receptor 2 and RAB1A expression in gastric cancer

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