Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA151839 | ENA |
REPOSITORIES: ENA
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Project description:Estrogen and progesterone receptor dynamics in patient-derived luminal breast cancer xenografts
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Project description:scRNA-seq analysis of patient-derived luminal breast cancer xenografts
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Project description:ChIPseq analysis of patient-derived luminal breast cancer xenografts with progestins
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Project description:RNAseq analysis of patient-derived luminal breast cancer xenografts treated with progestins
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Project description:One of the greatest advances in therapy of estrogen receptor positive breast cancer has been the development of endocrine therapy. More than two thirds of primary breast tumors express estrogen receptor alpha (ERα) and their growth is mainly dependent on estrogen receptor activity. Several therapeutic approaches have thus been designed to inhibit ER activity in breast tissue. Tamoxifen, a selective ER modulator, is one of the main treatment options for premenopausal women with advanced ER positive breast cancer, and has also become well established as adjuvant therapy in the early breast cancer setting (Davies et al., 2011; Group, 1998; Jaiyesimi et al., 1995). In contrast to tamoxifen, which in other tissues such as bone and endometrium, can exert partial agonistic activity (Braithwaite et al., 2003; Fisher et al., 1994; Pietras, 2006), the selective ER downregulator, fulvestrant, is a potent ER antagonist. Binding of fulvestrant to ER inhibits receptor dimerization and nuclear uptake, prevents estrogen-response element binding and accelerates ER degradation (Dauvois et al., 1993; Dowsett et al., 2005; Fawell et al., 1990; Wakeling et al., 1991). Fulvestrant is approved for treatment of postmenopausal women with advanced breast cancer who have relapsed or progressed on first-line endocrine therapy (Howell et al., 2002; Osborne et al., 2002; Robertson et al., 2003). Estrogen deprivation by treatment with aromatase inhibitors (such as letrozole, anastrozole or exemestane) which block synthesis of estrogens is another effective therapy option in postmenopausal women (Bonneterre et al., 2000; Cuzick et al., 2010; Dowsett et al., 2010; Mouridsen et al., 2001; Nabholtz et al., 2000). The large majority of patients with ER+ breast cancer experience an initial response to endocrine therapy, however, in many of these patients, the disease subsequently progresses and eventually anti-estrogen therapy ceases to have effect. Biomarkers predicting response to estrogen deprivation and new alternative treatments targeting the pathways supporting estrogen independent growth are therefore urgently needed (Patani and Martin, 2014; Patani et al., 2013). In order to understand how tumors respond to withdrawal of their main growth signal, a comparison of molecular features of tumor before and during endocrine therapy is necessary, and the fate of individual cancer cell sub-clones should be monitored. Since studies of cellular dynamics are very difficult to perform with clinical material, we made use of a patient derived, estrogen dependent, orthotopically growing luminal-like primary breast cancer xenograft model (PDX) (Bergamaschi et al., 2009; Huuse et al., 2012). This PDX model is a representative model for luminal breast cancers as the molecular characteristics, cellular heterogeneity and estrogen dependency of the primary tumor are retained over many passages. Functionally different subpopulations of cancer cells were previously defined by expression of the markers CD24 and SSEA-4 in this model (Skrbo et al., 2014), and it is therefore a suitable model for comparison of cellular and molecular effects of estrogen deprivation and ER-signaling inhibition. In this study, a quantitative MS-based proteomic analysis using SILAC and a label-free approach were performed, aiming to map changes in protein expression induced by endocrine therapy. Inhibition of ER-signaling seemed to induce CD24 and SSEA-4 expression on residual tumor cells. Proteomic analysis revealed overexpression of enzymes involved in TCA cycle, oxidative phosphorylation and fatty acid beta-oxidation following endocrine treatment when compared to untreated tumors. These results indicated possible reprogramming of cell metabolism and utilization of aerobic respiration, i.e. oxidative phosphorylation, in response to endocrine therapy.
2022-02-28 | PXD002352 | Pride
Project description:RNAseq analysis of cell lines established from patient-derived luminal breast cancer xenografts
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Project description:Acquired resistance to endocrine therapy occurs with high frequency in patients with luminal breast cancer (LBC). We report here the establishment of four patient-derived xenograft models of LBC with acquired resistance in vivo to tamoxifen and estrogen deprivation.
2014-07-09 | GSE55561 | GEO
Project description:Albeit responding well to therapy, estrogen receptor positive breast cancers frequently become subsequently resistant. This leads to distant metastasis and release of circulating tumor cells (CTCs) into the blood stream and ends with the death of the patient. Here we analyzed the proteome of CTC-ITB-01 by mass spectrometry and quantified 7954 different proteins using MCF-7 as a reference proteome. The data were deposited in a database for public access. CTC-ITB-01 is a CTC cell line derived from a patient with metastatic and estrogen receptor alpha (ER-alpha) positive breast cancer. We found remarkable high levels of the protein sushi domain-containing protein 2 (SUSD2) in CTC-ITB-01. Presence of SUSD2 in CTC of patients with breast cancer was confirmed by CellSearch (9/23 CTC positive cases). Ectonucleotide pyrophosphatase /phosphodiesterase family member 1 (ENPP1) was detected in CTC-ITB-01 and confirmed in CTC of breast cancer patients (n=3). ENPP1 can mediate immune evasion of tumor cells. Overexpression of SUSD2 in MCF-7 revealed upregulation of ER-alpha, 78 kDa glucose-regulated protein (GRP78) downregulation of programmed cell death protein 4 (PDCD4). GRP78 mediates resistance to chemotherapy, whereas loss of PDCD4 is involved in drug resistance and malignant transformation. Database search revealed significantly reduced overall survival in luminal breast cancer for low PDCD4 levels (n=348; p=0.0323). In conclusion, high levels of SUSD2 may confer improved cytoprotection of metastatic breast cancer cells and their CTC travelers to distant organs in the blood.
2025-02-04 | PXD047444 | Pride