Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA120877 | ENA |
REPOSITORIES: ENA
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Project description:Despite advances in HER2+ breast cancer treatment, resistance to anti-HER2 therapies remains a significant clinical challenge. This study investigated the role of the endocannabinoid system, specifically the HER2-CB2R heterodimer, in trastuzumab resistance mechanisms. Analysis of human breast cancer samples revealed that decreased HER2-CB2R expression following neoadjuvant treatment, primarily due to CB2R reduction, correlated with poor long-term outcomes. Using cell and animal models, we demonstrated that trastuzumab resistance is dependent on CB2R expression, as it occurs upon CB2R downregulation and is reversible through CB2R re-expression. Mechanistically, CB2R loss enables cancer cells to evade antitumor IFN-γ signaling while promoting a shift from HER2-CB2R to HER2-EGFR dimers, reducing dependence on HER2 signaling and increasing reliance on EGFR-mediated pathways. Importantly, EGFR inhibition resensitized resistant cells to trastuzumab's antitumor effects. This work identifies a novel resistance mechanism involving CB2R-mediated receptor heterodimerization and IFN-γ signaling modulation, establishes HER2-CB2R/EGFR heterodimer status and CB2R/EGFR expression as potential predictive biomarkers, and supports dual HER2/EGFR targeting as a promising strategy to overcome trastuzumab resistance in HER2+ breast cancer patients.
2026-05-07 | PXD065700 | Pride
Project description:In a 3D coculture with stroma cells derived from breast cancer patients’ brain metastasis, HER2+ breast cancer cells were protected from HER2-targeted therapies, particularly the EGFR/HER2 small molecule inhibitor neratinib. To get insight into how this protection arises, ATAC-seq on coculture cells with or without neratinib as performed.
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Project description:Activated HER2 and EGFR stimulate the Ras small GTPases, which in turn primarily activate the MAPK, PI3K-Akt and RalGEF-Ral pathways. While activation of the MAPK and PI3K-Akt pathways downstream of HER2 and EGFR promote mammary tumorigenesis, little is known regarding the role of the RalGEF-Ral pathway. RalGEFs convert the small GTPases RalA and RalB to an active GTP-bound state. Of the two proteins, only activated RalA is transforming, while RalB is more important for cell motility, and hence we investigated the role of RalA in HER2-overexpressing and EGFR-positive breast cancer. We now report that shRNA-mediated knockdown of RalA reduced the in vitro transformed growth and in vivo tumorigenic growth of MDA-MB-231 human breast cancer cells, while knockdown of RalB reduced migration and invasion. Lastly, we demonstrate that expression of activated HER2 increases RalA-GTP levels, and that a number of genes associated with activated RalA are elevated in tumor compared to normal mammary tissue. Taken together, these results suggest a possible role for RalA in mammary tumorigenesis. Four independent cultures of HEK-HT cells stably infected with a retrovirus confirmed to expressed RalAQ72L and four independent cultures of HEK-HT cells stably infected with a control retrovirus RalA activation expression analysis
2016-02-13 | E-GEOD-19295 | biostudies-arrayexpress
Project description:In a 3D coculture with stroma cells derived from breast cancer patients’ brain metastasis, HER2+ breast cancer cells were protected from HER2-targeted therapies, particularly the EGFR/HER2 small molecule inhibitor neratinib. To get insight into how this protection arises, a Synthetic Notch (SynNotch) reporter model allowed to study the effect of direct contact between stroma and cancer cells.
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Project description:Recent studies suggested that crosstalk between ERα and EGFR/HER2 pathways plays a critical role in mediating endocrine therapy resistance. Several targeting EGFR/HER2 signaling inhibitors including FDA-approved lapatinib and gefitinib as well as a novel dual tyrosine kinase inhibitor (TKI) sapitnib showed greater inhibitory efficacies. However, how a 3D chromatin landscape of the response to the inhibition to EGFR/HER2 pathway remains to be elucidated. In this study, we conducted in situ Hi-C and RNA-seq in two ERα+ breast cancer cell systems, tamoxifen-sensitive MCF7 and T47D and tamoxifen-resistant MCF7TR and T47DTR before and after the treatment of sapitnib. We identified differential response of topologically associated domains (TADs), looping genes and expressed genes. Interestingly, we found that many differential TADs and looping genes are reversible, indicating that EGFR/HER2 signaling may play a role in reshaping and rewiring the high order genome organization. We further examined and recapitulated the reversible looping genes in 3D spheroids of breast cancer cells. Our data provides a rich resource for further evaluating chromatin structural response to anti-EGFR/HER2 targeted therapies in endocrine-resistant breast cancer.
2020-12-01 | GSE144378 | GEO
Project description:Recent studies suggested that crosstalk between ERα and EGFR/HER2 pathways plays a critical role in mediating endocrine therapy resistance. Several targeting EGFR/HER2 signaling inhibitors including FDA-approved lapatinib and gefitinib as well as a novel dual tyrosine kinase inhibitor (TKI) sapitnib showed greater inhibitory efficacies. However, how a 3D chromatin landscape of the response to the inhibition to EGFR/HER2 pathway remains to be elucidated. In this study, we conducted in situ Hi-C and RNA-seq in two ERα+ breast cancer cell systems, tamoxifen-sensitive MCF7 and T47D and tamoxifen-resistant MCF7TR and T47DTR before and after the treatment of sapitnib. We identified differential response of topologically associated domains (TADs), looping genes and expressed genes. Interestingly, we found that many differential TADs and looping genes are reversible, indicating that EGFR/HER2 signaling may play a role in reshaping and rewiring the high order genome organization. We further examined and recapitulated the reversible looping genes in 3D spheroids of breast cancer cells. Our data provides a rich resource for further evaluating chromatin structural response to anti-EGFR/HER2 targeted therapies in endocrine-resistant breast cancer.
2020-12-01 | GSE144377 | GEO
Project description:Acquired or innate lack of response to standard HER2-targeted therapies remains a clinical issue in patients with HER2-positive breast cancer. Here, we investigated the role of the cannabinoid CB2 receptor (CB2R) in trastuzumab resistance. In human breast cancer samples, a decreased expression of HER2-CB2R heterodimers following neoadjuvant treatment, due to CB2R downregulation, was linked to poor long-term outcomes. Using various preclinical models, we demonstrate that CB2R drives trastuzumab resistance. Mechanistically, CB2R loss enabled cancer cells to evade antitumor IFN-γ signaling while promoting a shift from HER2-CB2R to HER2-EGFR heterodimers, thus reducing dependence on HER2 and increasing reliance on EGFR-mediated pathways. Moreover, EGFR inhibition restored trastuzumab sensitivity. In summary, we reveal an unprecedented role for CB2R as a key regulator of oncogenic and immune signaling in response to anti-HER2 therapy and its potential as a predictive biomarker of therapeutic efficacy. We also propose dual HER2/EGFR targeting and non-CB2R-selective cannabinoid therapies as potential strategies to overcome CB2R-mediated trastuzumab resistance. Together, these findings position the endocannabinoid system as a pivotal and actionable node to elucidate, anticipate, and counteract resistance to HER2-targeted therapies.
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Project description:Activated HER2 and EGFR stimulate the Ras small GTPases, which in turn primarily activate the MAPK, PI3K-Akt and RalGEF-Ral pathways. While activation of the MAPK and PI3K-Akt pathways downstream of HER2 and EGFR promote mammary tumorigenesis, little is known regarding the role of the RalGEF-Ral pathway. RalGEFs convert the small GTPases RalA and RalB to an active GTP-bound state. Of the two proteins, only activated RalA is transforming, while RalB is more important for cell motility, and hence we investigated the role of RalA in HER2-overexpressing and EGFR-positive breast cancer. We now report that shRNA-mediated knockdown of RalA reduced the in vitro transformed growth and in vivo tumorigenic growth of MDA-MB-231 human breast cancer cells, while knockdown of RalB reduced migration and invasion. Lastly, we demonstrate that expression of activated HER2 increases RalA-GTP levels, and that a number of genes associated with activated RalA are elevated in tumor compared to normal mammary tissue. Taken together, these results suggest a possible role for RalA in mammary tumorigenesis.
2016-02-13 | GSE19295 | GEO
Project description:To combine inhibition of EGFR/HER2 and targeting of the cytosolic roles of PCNA using the APIM-peptide, and study the anti-cancer effects of this combinatory therapy in in vitro and in vivo breast cancer models.
2020-01-15 | PXD011044 | Pride