Trastuzumab-Resistant Luminal B Breast Cancer Cells Show Basal-Like Cell Growth Features Through NF-κB-Activation

Kanzaki, Hirotaka; Mukhopadhya, Nishit K.; Cui, Xiaojiang; Ramanujan, V. Krishnan; Murali, Ramachandran

doi:10.1089/mab.2015.0056

Cited by 10 publications

(12 citation statements)

References 57 publications

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“…Even in the case that the same cell line, BT-474, is used, different mechanisms have been reported. For example, we had found that nuclear factor-kappa B (NF-kappaB) was constitutively activated in the BT-474-R cells [ 23 ]. In the process of acquiring the resistance, several different molecular alterations may emerge depending on the culture condition in vitro and microenviromental conditions in vivo .…”

Section: Discussionmentioning

confidence: 99%

“…HER2-positive human breast cancer cell line BT-474 (catalog number: HTB-20) was purchased from American Type Culture Collection (Manassas, VA, USA). BT-474-R was previously established by treating BT-474 with increasing doses of trastuzumab (from 0.1 μg/mL to 40 μg/mL) for 10 months [ 23 ]. To obtain trastuzumab/lapatinib-dual resistant BT-474 (named as BT-474-RL2), BT-474-R was additionally treated with increasing doses of lapatinib (from 0.1 μM to 5 μM) for 6 months.…”

Section: Methodsmentioning

confidence: 99%

“…To understand the molecular basis for resistance to HER2-targeted therapies, we previously established a trastuzumab-resistant breast cancer cell line (named as BT-474-R) from a trastuzumab-sensitive cell line with HER2 amplification (BT-474) by treating BT-474 cells with increasing doses of trastuzumab [ 23 ]. Analysis showed that nuclear factor-kappa B (NF-kappaB) was constitutively activated in the BT-474-R cells mimicking the phenotype of basal-like breast cancers.…”

Section: Introductionmentioning

confidence: 99%

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Yes1 signaling mediates the resistance to Trastuzumab/Lap atinib in breast cancer

et al. 2017

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BackgroundOverexpression of human epidermal growth factor receptor 2 (HER2) is observed in approximately 15–23% of breast cancers and these cancers are classified as HER2-positive breast cancer. Trastuzumab is the first-line targeted therapeutic drug for HER2-positive breast cancer and has improved patient overall survival. However, acquired resistance to trastuzumab is still a critical issue in breast cancer treatment. We previously established a trastuzumab-resistant breast cancer cell line (named as BT-474-R) from a trastuzumab-sensitive HER2-amplified cell line BT-474. Lapatinib is also a molecular-targeted drug for HER2-positive breast cancer, which acquired the resistance to trastuzumab. Acquired resistance to lapatinib is also an issue to be conquered.MethodsWe established trastuzumab/lapatinib-dual resistant cell line (named as BT-474-RL2) by additionally treating BT-474-R with lapatinib. We analyzed the mechanisms of resistance to trastuzumab and lapatinib. Besides, we analyzed the effect of the detected resistance mechanism in HER2-positive breast cancer patients.ResultsProto-oncogene tyrosine-protein kinase Yes1, which is one of the Src family members, was amplified, overexpressed and activated in BT-474-R and BT-474-RL2. Silencing of Yes1 by siRNA induced both BT-474-R and BT-474-RL2 to restore the sensitivity to trastuzumab and lapatinib. Pharmaceutical inhibition of Yes1 by the Src inhibitor dasatinib was also effective to restore the sensitivity to trastuzumab and lapatinib in the two resistant cell lines. Combination treatment with dasatinib and trastuzumab induced down-regulation of signaling molecules such as HER2 and Akt. Moreover, the combination treatments induced G1-phase cell-cycle arrest and apoptosis. Consistent with cell line data, high expression of Yes1 mRNA was correlated with worse prognosis in patients with HER2-positive breast cancer.ConclusionYes1 plays an important role in acquired resistance to trastuzumab and lapatinib in HER2-positive breast cancer. Our data suggest that pharmacological inhibition of Yes1 may be an effective strategy to overcome resistance to trastuzumab and lapatinib.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Yes1 signaling mediates the resistance to Trastuzumab/Lap atinib in breast cancer

et al. 2017

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“…Bortezomib treatment demonstrated to induce apoptosis and to act synergistically with trastuzumab in this breast cancer subtype (258,259). In the case of HER2-positive ER-positive breast cancer cell lines resistant to trastuzumab, the NF-κB pathway showed to be constitutively activated and its blockade improved the tumor response to trastuzumab (260).…”

Section: Trastuzumabmentioning

confidence: 99%

Tumor Necrosis Factor α Blockade: An Opportunity to Tackle Breast Cancer

et al. 2020

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Breast cancer is the most frequently diagnosed cancer and the principal cause of mortality by malignancy in women and represents a main problem for public health worldwide. Tumor necrosis factor α (TNFα) is a pro-inflammatory cytokine whose expression is increased in a variety of cancers. In particular, in breast cancer it correlates with augmented tumor cell proliferation, higher malignancy grade, increased occurrence of metastasis and general poor prognosis for the patient. These characteristics highlight TNFα as an attractive therapeutic target, and consequently, the study of soluble and transmembrane TNFα effects and its receptors in breast cancer is an area of active research. In this review we summarize the recent findings on TNFα participation in luminal, HER2-positive and triple negative breast cancer progression and metastasis. Also, we describe TNFα role in immune response against tumors and in chemotherapy, hormone therapy, HER2-targeted therapy and anti-immune checkpoint therapy resistance in breast cancer. Furthermore, we discuss the use of TNFα blocking strategies as potential therapies and their clinical relevance for breast cancer. These TNFα blocking agents have long been used in the clinical setting to treat inflammatory and autoimmune diseases. TNFα blockade can be achieved by monoclonal antibodies (such as infliximab, adalimumab, etc.), fusion proteins (etanercept) and dominant negative proteins (INB03). Here we address the different effects of each compound and also analyze the use of potential biomarkers in the selection of patients who would benefit from a combination of TNFα blocking agents with HER2-targeted treatments to prevent or overcome therapy resistance in breast cancer.

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“…In recent years, other potential mechanisms of acquired resistance to TRA in Her2-like BC have been discovered and studied, such as the increased phosphorylation of the nuclear factor kappa B (NF-kB) p65 subunit (20, 21). Understanding the molecular mechanisms that contribute to the acquired resistance will ultimately allow for the identification of biomarkers that can be used to predict response to TRA therapy, as well as the identification of molecular targets for new therapeutics development.…”

Section: Introductionmentioning

confidence: 99%

ANKRD44 Gene Silencing: A Putative Role in Trastuzumab Resistance in Her2-Like Breast Cancer

et al. 2019

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Trastuzumab is an effective therapeutic treatment for Her2-like breast cancer; despite this most of these tumors develop resistance to therapy due to specific gene mutations or alterations in gene expression. Understanding the mechanisms of resistance to Trastuzumab could be a useful tool in order to identify combinations of drugs that elude resistance and allow a better response for the treated patients. Twelve primary biopsies of Her2+/hormone receptor negative (ER-/PgR-) breast cancer patients were selected based on the specific response to neoadjuvant therapy with Trastuzumab and their whole exome was sequenced leading to the identification of 18 informative gene mutations that discriminate patients selectively based on response to treatment. Among these genes, we focused on the study of the ANKRD44 gene to understand its role in the mechanism of resistance to Trastuzumab. The ANKRD44 gene was silenced in Her2-like breast cancer cell line (BT474), obtaining a partially Trastuzumab-resistant breast cancer cell line that constitutively activates the NF-kb protein via the TAK1/AKT pathway. Following this activation an increase in the level of glycolysis in resistant cells is promoted, also confirmed by the up-regulation of the LDHB protein and by an increased TROP2 protein expression, found generally associated with aggressive tumors. These results allow us to consider the ANKRD44 gene as a potential gene involved in Trastuzumab resistance.

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Trastuzumab-Resistant Luminal B Breast Cancer Cells Show Basal-Like Cell Growth Features Through NF-κB-Activation

Cited by 10 publications

References 57 publications

Yes1 signaling mediates the resistance to Trastuzumab/Lap atinib in breast cancer

Yes1 signaling mediates the resistance to Trastuzumab/Lap atinib in breast cancer

Tumor Necrosis Factor α Blockade: An Opportunity to Tackle Breast Cancer

ANKRD44 Gene Silencing: A Putative Role in Trastuzumab Resistance in Her2-Like Breast Cancer

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