Effects of iron modulation on mesenchymal stem cell-induced drug resistance in estrogen receptor-positive breast cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE196312 | GEO | 2022/07/21
REPOSITORIES: GEO
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Project description:Estrogen receptor-positive (ER+) breast cancer commonly disseminates to bone marrow, where interactions with mesenchymal stromal cells (MSCs) shape disease trajectory. Using a co-culture model, we performed an integrated transcriptomic and proteomic analysis of processes induced in ER+ breast cancer cells by close contact with MSCs, but not merely by conditioned media. Computational approaches identified a 52-protein/mRNA ‘signature’ which stratified patients at high risk for relapse, and implicated long-distance intercellular transport via tunneling nanotubes (TNTs) as a means for their ‘acquisition’ by the tumor cell from MSCs. Bioinformatic analyses helped prioritize one gene/protein, CCDC88A/GIV, a multi-functional adapter protein known to drive metastasis. MSCs upregulated GIV in ER+ breast cancer cells through connexin 43-mediated intercellular transport. Stable expression of GIV conferred resistance to clinical anti-estrogen drugs, enhanced tumor dissemination, and recapitulated the 52-gene signature. These data establish a new multi-omic resource for the regulation of breast cancer by MSCs via intercellular transport and validate as proof-of-concept how one transported protein, GIV, orchestrates aggressive disease states.
2024-07-02 | PXD039860 | Pride
Project description:Estrogen receptor-positive (ER+) breast cancer commonly disseminates to bone marrow, where interactions with mesenchymal stromal cells (MSCs) shape disease trajectory. We modeled these interactions using tumor-MSC co-cultures and using an integrated transcriptome-proteome-network-analyses workflow identified a comprehensive catalog of contact-induced changes. Induced genes/proteins—some borrowed and others tumor-intrinsic response—were not recapitulated merely by conditioned media. Protein-protein interaction networks reveal the rich connectome between the ‘borrowed’ and ‘intrinsic’ components. Bioinformatic analyses helped prioritize one of the ‘borrowed’ components, CCDC88A/GIV, a bona-fide multi-modular metastasis-related protein. MSCs upregulated GIV in ER+ breast cancer cells through connexin (Cx)43-facilitated intercellular long-distance transport. Stable expression of GIV recapitulated ~20% of both the ‘borrowed’ and the ‘intrinsic’ gene induction patters observed during contact cocultures, conferred resistance to clinical anti-estrogen drugs, and enhanced tumor dissemination. These data provide a multiomic insight into the role of MSC→tumor cell intercellular transport and validate as proof-of-concept how transport of one such candidate, GIV, from the haves (MSCs) to have-nots (ER+ breast cancer) orchestrates aggressive disease states.
2024-06-21 | GSE224321 | GEO
Project description:Estrogen receptor-positive (ER+) breast cancer commonly disseminates to bone marrow, where interactions with mesenchymal stromal cells (MSCs) shape disease trajectory. We modeled these interactions using tumor-MSC co-cultures and using an integrated transcriptome-proteome-network-analyses workflow identified a comprehensive catalog of contact-induced changes. Induced genes/proteins—some borrowed and others tumor-intrinsic response—were not recapitulated merely by conditioned media. Protein-protein interaction networks reveal the rich connectome between the ‘borrowed’ and ‘intrinsic’ components. Bioinformatic analyses helped prioritize one of the ‘borrowed’ components, CCDC88A/GIV, a bona-fide multi-modular metastasis-related protein. MSCs upregulated GIV in ER+ breast cancer cells through connexin (Cx)43-facilitated intercellular long-distance transport. Stable expression of GIV recapitulated ~20% of both the ‘borrowed’ and the ‘intrinsic’ gene induction patters observed during contact cocultures, conferred resistance to clinical anti-estrogen drugs, and enhanced tumor dissemination. These data provide a multiomic insight into the role of MSC→tumor cell intercellular transport and validate as proof-of-concept how transport of one such candidate, GIV, from the haves (MSCs) to have-nots (ER+ breast cancer) orchestrates aggressive disease states.
2024-06-21 | GSE224320 | GEO
Project description:Estrogen receptor-positive (ER+) breast cancer commonly disseminates to bone marrow, where interactions with mesenchymal stromal cells (MSCs) shape disease trajectory. We modeled these interactions using tumor-MSC co-cultures and using an integrated transcriptome-proteome-network-analyses workflow identified a comprehensive catalog of contact-induced changes. Induced genes/proteins—some borrowed and others tumor-intrinsic response—were not recapitulated merely by conditioned media. Protein-protein interaction networks reveal the rich connectome between the ‘borrowed’ and ‘intrinsic’ components. Bioinformatic analyses helped prioritize one of the ‘borrowed’ components, CCDC88A/GIV, a bona-fide multi-modular metastasis-related protein. MSCs upregulated GIV in ER+ breast cancer cells through connexin (Cx)43-facilitated intercellular long-distance transport. Stable expression of GIV recapitulated ~20% of both the ‘borrowed’ and the ‘intrinsic’ gene induction patters observed during contact cocultures, conferred resistance to clinical anti-estrogen drugs, and enhanced tumor dissemination. These data provide a multiomic insight into the role of MSC→tumor cell intercellular transport and validate as proof-of-concept how transport of one such candidate, GIV, from the haves (MSCs) to have-nots (ER+ breast cancer) orchestrates aggressive disease states.
2024-06-21 | GSE224319 | GEO
Project description:The origin and the contribution of breast tumor heterogeneity to its progression are not clear. We investigated the effect of a growing orthotopic tumor formed by an aggressive estrogen receptor (ER)-negative breast cancer cell line on the metastatic potential of a less aggressive ER-positive breast cancer cell line for the elucidation of how the presence of heterogeneous cancer cells might affect each other’s metastatic behavior. ER positive ZR-75-1/GFP/puro cells, resistant to puromycin and non-tumorigenic/non-metastatic without exogenous estrogen supplementation, were injected intracardiacally into mice bearing growing orthotopic tumors, formed by ER negative MDA-MB-231/GFP/Neo cells resistant to G418. A variant cell line B6, containing both estrogen-dependent and -independent cells, were isolated from GFP expressing cells in the bone marrow and re-inoculated in nude mice to generate an estrogen-independent cell line B6TC.
2011-05-25 | E-GEOD-27515 | biostudies-arrayexpress
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:Molecular drivers underlying bone metastases in human cancer are not well understood, in part due to constraints in bone tissue sampling. Here, we undertook RNA sequencing of circulating tumor cells (CTCs) obtained from blood samples of women with metastatic estrogen receptor (ER)+ breast cancer, comparing cases with progression in bone versus visceral organs. Among the activated cellular pathways in CTCs from bone-predominant breast cancer is Androgen Receptor (AR) signaling. AR gene expression is evident, as is its constitutively active splicing variant AR-v7. AR expression within CTCs is correlated with the duration of treatment with aromatase inhibitors, suggesting that it may contribute to acquired resistance to anti-estrogen therapy. In an established breast cancer xenograft model, a bone-tropic derivative displays increased AR expression, whose genetic or pharmacologic suppression reduces metastases to bone but not to lungs. Together, these observations identify AR signaling in CTCs from women with bone-predominant ER+ breast cancer, and provide a rationale for testing androgen inhibitors in this subset of patients.
2018-02-19 | GSE86978 | GEO
Project description:Hormone therapy targeting estrogen receptor (ER) is the principal treatment for ER-positive breast cancers but many cancers develop resistance to anti-estrogens. Cyclin-dependent kinase 8 (CDK8) is a transcriptional regulator of several oncogenic pathways. Expression levels of CDK8 and ERα are inversely correlated in breast cancers suggesting a functional association between CDK8 and ER. CDK8 inhibition by selective small-molecule inhibitors, by shRNA knockdown or by CRISPR-Cas9 knockout suppressed estrogen-induced transcription, with no significant effects on ERα protein expression or phosphorylation. CDK8 inhibition also abrogated the mitogenic effect of estrogen on ER-positive breast cancer cells and potentiated growth inhibition by the ER antagonist fulvestrant. In vivo, administration of a CDK8 inhibitor suppressed ER-positive breast cancer xenograft growth and augmented the effects of fulvestrant with no apparent toxicity. CDK8 inhibitors also suppressed the development of estrogen independence in ER-positive breast cancer cells. These results identify CDK8 as a novel drug target for breast cancer therapy.
2017-02-14 | GSE93193 | GEO
Project description:Metastases of breast cancer is a prevalent problem with over 25% of patients suffering with metastatic disease. Of the patients that present with metastatic disease, the majority are estrogen receptor positive (ER+) and have skeletal metastases. These skeletal metastases can cause several issues including pathological fractures, chronic pain, and hypercalcemia. Currently, there are not any cures for metastatic breast cancer in bone and only therapies to mediate the osteolysis caused by breast cancer. The bone microenvironment presents various physical forces that can act on the tumor cell that has been studied in ER- cells, however, the physical forces on ER+ tumor cells have not been widely evaluated. In this study, we explored the transcriptional changes that occur at different matrix rigidities associated with the bone microenvironment (bone marrow: 0.5 kPa to 32 kPa; cortical and trabecular bone – 2 x 107 kPa). We observed that lower stiffnesses contributed to increased gene signatures associated with interleukin signaling. Additionally, we observed that downstream estrogen signaling outputs were modified. These interesting findings give us insights on what may be changing when ER+ tumor cells encounter rigidities associated with the bone microenvironment.
2024-09-09 | GSE274519 | GEO
Project description:Estrogen and estrogen receptor (ER) signaling play critical roles in the development of ER-positive breast cancer, and endocrine therapy is the frontline treatment for ER-positive breast cancer patients. However, the primary and acquired resistance to endocrine therapy including tamoxifen and fulvestrant remains as the major challenge in the clinic. Here, we identified an estrogen-induced lncRNA, LINC02568, through transcriptomic analysis, which is highly expressed in ER-positive breast cancer. LINC02568 is functional important in ER-positive breast cancer cell growth in vitro and tumorigenesis in vivo as well as endocrine therapy resistance. Mechanically, we demonstrated that LINC02568 regulates, in trans, estrogen/ERα-induced gene transcriptional activation by sponging miR-1233-5p to stabilize ESR1 mRNA in the cytoplasm. Meanwhile, LINC02568 contributes to tumor-specific pH homeostasis in breast cancer cells by regulating CA12 in cis in the nucleus. The dual functions of LINC02568 together contribute to breast cancer cell growth and tumorigenesis as well as endocrine therapy resistance. Antisense oligonucleotides (ASO) targeting LINC02568 significantly inhibits ER-positive breast cancer cell growth in vitro and tumorigenesis in vivo as well as resensitize tamoxifen-resistant cells to tamoxifen. Furthermore, combination treatment with ASO targeting LINC02568 and tamoxifen exhibits synergistic effect on tumor growth. Taken together, our findings revealed dual mechanisms of LINC02568 in regulating ERα signaling and pH homeostasis in ER-positive breast cancer, and indicated that targeting LINC02568 might represent a potential therapeutic avenue in clinic.
2023-09-13 | GSE217190 | GEO