Evolutionary resistance of metastatic breast cancer
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ABSTRACT:
PROVIDER: PRJNA814379 | ENA |
REPOSITORIES: ENA
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Project description:Evolutionary resistance of metastatic breast cancer
| PRJNA814378 | ENA
Project description:Estrogen receptor positive (ER+) breast cancers that develop resistance to therapies that target the ER are the most common cause of breast cancer death. Beyond mutations in ER, which occur in 25-30% of patients treated with aromatase inhibitors (AIs), our understanding of clinical mechanisms of resistance to ER-directed therapies remains incomplete. We identified activating HER2 mutations in metastatic biopsies from eight patients with ER+ metastatic breast cancer who had developed resistance to ER-directed agents, including AIs, tamoxifen, and fulvestrant. Examination of treatment-naïve primary tumors in five patients revealed no evidence of pre-existing mutations in four of five patients, suggesting that these mutations were acquired under the selective pressure of ER-directed therapy. These mutations were mutually exclusive with ER mutations, suggesting a distinct mechanism of acquired resistance to ER-directed therapies. In vitro analysis confirmed that these mutations conferred estrogen independence. In addition, and in contrast to ER mutations, these mutations resulted in resistance to tamoxifen, fulvestrant, and the CDK4/6 inhibitor palbociclib. Resistance was overcome by combining ER-directed therapy with the irreversible HER2 kinase inhibitor neratinib, highlighting an effective treatment strategy in these patients.
2018-10-19 | GSE121411 | GEO
Project description:PBMCs from metastatic breast cancer patients
| PRJNA730015 | ENA
Project description:Response and Resistance to ER-directed Therapy in ER+ Metastatic Breast Cancer
| PRJNA369715 | ENA
Project description:Identify therapeutic vulnerabilities of palbociclib resistance in metastatic breast cancer patient-derived xenograft models and identify key biomarkers that correlate with development of resistance to inform new treatment directions
2023-07-10 | GSE229235 | GEO
Project description:Aurora US Metastatic Breast Cancer Retrospective Project
| PRJNA767028 | ENA
Project description:Aurora US Metastatic Breast Cancer Retrospective Project
| PRJNA767029 | ENA
Project description:Despite important advances in the treatment of breast cancer, the 5-year survival rate for patients with distant metastasis remains less than 30%. Metastasis is a complex, multi-step process beginning with local invasion and ending with the outgrowth of systemically disseminated cells into actively proliferating metastases that ultimately cause the destruction of vital organs. It is this last step that limits patient survival and, at the same time, remains the least understood mechanistically. Here, we focus on understanding determinants of metastatic outgrowth using metastatic effusion biopsies from stage IV breast cancer patients. By modelling metastatic outgrowth through xenograft transplantation, we show that tumour initiation potential of patient-derived metastatic breast cancer cells across breast cancer subtypes is strongly linked to high levels of EPCAM expression. Breast cancer cells with high EPCAM levels are highly plastic and, upon induction of epithelial-mesenchymal transition (EMT), readily adopt mesenchymal traits while maintaining epithelial identity. In contrast, low EPCAM levels are caused by the irreversible reprogramming to a mesenchymal state with concomitant suppression of metastatic outgrowth. The ability of breast cancer cells to retain epithelial traits is tied to a global epigenetic program that limits the actions of EMT-transcription factor ZEB1, a suppressor of epithelial genes. Our results provide direct evidence that maintenance of epithelial identity is required for metastatic outgrowth while concomitant expression of mesenchymal markers enables plasticity. In contrast, loss of epithelial traits is characteristic of an irreversible mesenchymal reprogramming associated to a deficiency for metastatic outgrowth. Collectively, our data provide a framework for the intricate intercalation of mesenchymal and epithelial traits in metastatic growth.
2023-04-30 | GSE138329 | GEO
Project description:Background: Drug resistance and metastasis are complex processes that remain poorly understood on the molecular level with single-cell resolution. We profiled the transcriptomic changes at the single-cell level associated with cancer cell progression, chemotherapy resistance, and metastasis in samples from a single de novo Stage IV breast cancer patient. Method: Pretreatment biopsy samples and posttreatment surgical specimens from the primary tumor and distant metastases were collected for single-cell RNA sequencing and subsequent cell clustering, copy number variation (CNV) estimation, transcription factor activity estimation, and pseudotime analyses. Results: CNV estimation analysis identified a small pretreatment cancer cell population that resisted chemotherapy and subsequently expanded. In the posttreatment primary tumors, new clones emerged, which we refer to as potential Metastatic Precursor Cells (MPCs), exhibiting the CNV profiles similar to metastatic cells. MPCs appeared to originate from hypoxic regions in the necrotic core of the tumor and exhibited expression profiles indicative of epithelial–mesenchymal transition. Comparison of MPCs to metastatic cancer cells also revealed dynamic changes in transcription factor activities and calcitonin pathway gene expressions. Conclusion: These findings demonstrate the utility of single-patient clinical sample analysis for clonal adaptations underlying tumor drug resistance, regrowth, and metastasis.
2024-10-09 | GSE264205 | GEO
Project description:Beyond acquired mutations in the estrogen receptor (ER), mechanisms of resistance to ER-directed therapies in ER+ breast cancer have not been clearly defined. We conducted a genome-scale functional screen spanning 10,135 genes to investigate genes whose overexpression confer resistance to selective estrogen receptor degraders. Pathway analysis of candidate resistance genes demonstrated that the FGFR, ERBB, insulin receptor, and MAPK pathways represented key modalities of resistance. In parallel, we performed whole exome sequencing in paired pre-treatment and post-resistance biopsies from 60 patients with ER+ metastatic breast cancer who had developed resistance to ER-targeted therapy. The FGFR pathway was altered via FGFR1, FGFR2, or FGF3/FGF4 amplifications or FGFR2 mutations in 24 (40%) of the post-resistance biopsies. In 12 of the 24 post-resistance tumors exhibiting FGFR/FGF alterations, these alterations were not detected in the corresponding pre-treatment tumors, suggesting that they were acquired or enriched under the selective pressure of ER-directed therapy. In vitro experiments in ER+ breast cancer cells confirmed that FGFR/FGF alterations led to fulvestrant resistance as well as cross-resistance to the CDK4/6 inhibitor palbociclib, through activation of the MAPK pathway. The resistance phenotypes were reversed by FGFR inhibitors and, to a lesser extent, MEK inhibitors, suggesting potential treatment strategies.
2020-06-30 | GSE153509 | GEO