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ABSTRACT:
PROVIDER: PRJNA328027 | ENA |
REPOSITORIES: ENA
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Project description:Estrogen receptor-positive (ER⁺) breast cancers frequently recur years after initial treatment with anti-estrogen therapies such as aromatase inhibitors (AIs), often due to emergence from a dormant state. The molecular mechanisms underlying dormancy and recurrence, especially following endocrine therapy, remain poorly understood. In this study, we identify the transcription factor CREB1 as a critical regulator of tumor dormancy and recurrence in ER⁺ breast cancer. By analyzing longitudinal tumor samples from patients treated with AIs, we identified more than 1,000 “dormancy-downregulated genes” (DDGs) that are downregulated and over 1,000 “dormancy-upregulated genes” (DUGs) that are upregulated during therapy-induced dormancy; notably, DDGs are re-expressed and DUGs are downregulated upon tumor recurrence. Transcriptional profiling and pathway enrichment analyses implicated CREB1, along with ER and E2F1, as central regulators of these genes. These findings were validated in estrogen-deprived ER⁺ cell lines and patient-derived xenograft (PDX) models, where dormancy correlated with reduced CREB1 activity and tumor recurrence coincided with CREB1 reactivation. CREB1 inhibition—via small molecule or siRNA knockdown—effectively reversed CREB1, ER, and E2F1 transcriptional programs by downregulating the DDGs while upregulating the DUGs, and reduced cell proliferation and survival in endocrine- and CDK4/6 inhibitor-resistant ER⁺ breast cancer cells. These findings establish CREB1 as a master regulator of transcriptional reprograming in relapsed ER⁺ breast cancers and highlight it as a promising therapeutic target for overcoming resistance to current endocrine and CDK4/6-based therapies.
2026-03-27 | GSE318191 | GEO
Project description:Cell dormancy is a major factor leading to drug resistance as well as the high rate of late recurrence and mortality in estrogen receptor-positive (ER+) breast cancer. Although some studies have highlighted the significant impact of the microenvironment on dormant cells, they have largely overlooked the mechanical forces stemming from the stiffness of the surrounding extracellular matrix. Previously, we demonstrated that soft matrix promotes tumor cell proliferation and migration, while stiff matrix induces tumor cell dormancy and drug resistance. In this study, we present a comprehensive analysis of the proteome and phosphoproteome in response to gradient changes in matrix stiffness, elucidating the mechanisms behind cell dormancy induced drug resistance. Overall, we found that membrane transport and anti-apoptotic processes may be mainly involved in mechanical force induced dormancy resistance of ER+ breast cancer cells.
2024-09-11 | PXD046799 |
Project description:Although the estrogen receptor (ER) positive variant of breast cancer is touted as the most indolent and favorable, the majority of breast cancer deaths are in fact from this subtype. There are several features of this category of breast cancers that likely account for this outcome. The first is that metastatic relapse can occur many years after initial diagnosis of primary disease. The second is that once the cancer cells awaken into full-blown metastatic disease, they are largely resistant to ER-directed therapies (i.e. hormonal therapy, HT). The third is that when metastases do occur, they are invariably in many locations. This observation suggests that these dormant/sleeping metastatic cells are “globally” awakened as if by a “systemic” infection. We suggest that these three processes be not only linked, but underlie the lethal features of metastatic disease. We hypothesized that mtDNA is necessary for the escape from therapy induced tumor dormancy of luminal breast cancer cells
2017-07-01 | GSE84104 | GEO
Project description:Limited knowledge of the changes in estrogen receptor (ER) signaling during the transformation of the normal mammary gland to breast cancer hinders the development of effective prevention and treatment strategies. Differences in estrogen signaling between normal human primary breast epithelial cells and primary breast tumors obtained immediately following surgical excision were explored. Transcriptional profiling of normal ER+ mature luminal mammary epithelial cells and ER+ breast tumors revealed significant difference in the response to estrogen stimulation. Consistent with these differences in gene expression, the normal and tumor ER cistromes were distinct and sufficient to segregate normal breast tissues from breast tumors. The selective enrichment of the DNA binding motif GRHL2 in the breast cancer-specific ER cistrome suggests that it may play a role in the differential function of ER in breast cancer. Depletion of GRHL2 resulted in altered ER binding and differential transcriptional responses to estrogen stimulation. Furthermore, GRHL2 was demonstrated to be essential for estrogen-stimulated proliferation of ER+ breast cancer cells. DLC1 was also identified as an estrogen-induced tumor suppressor in the normal mammary gland with decreased expression in breast cancer. In clinical cohorts, loss of DLC1 and gain of GRHL2 expression are associated with breast cancer and are independently predictive for worse survival. This study suggests that normal ER signaling is lost and tumor-specific ER signaling is gained during breast tumorigenesis. Unraveling these changes in ER signaling during breast cancer progression should aid the development of more effective prevention strategies and targeted therapeutics. SIGNIFICANCE STATEMENT: Abnormal estrogen receptor (ER) signaling drives the majority of breast cancers and is targeted by endocrine therapies. However, in normal breast tissue, ER signaling has been demonstrated to promote benign functions such as development and differentiation. Using genomic techniques to characterize ER function in normal breast and breast tumors, this study reveals differential patterns of ER signaling, suggesting that normal ER signaling is lost and tumorigenic ER signaling gained during breast tumor formation. Better understanding of this process can aid the development of improved breast cancer prevention strategies and therapies.
2019-05-27 | GSE99680 | GEO
Project description:The mainstay of treatment for hormone responsive breast tumors is chemotherapy, followed by targeted endocrine therapy. The vast majority (80%) of estrogen receptor positive tumors also express wild type p53 protein that is the main determinant of the DNA damage response. Tumors that are ER+ and p53WT respond poorly to chemotherapy, although the underlying mechanisms are not completely understood. We describe a novel link between store independent Ca2+ entry (SICE) and resistance to DNA damaging drugs, mediated by the secretory pathway Ca2+-ATPase, SPCA2. In luminal ER+/PR+ breast cancer subtypes, SPCA2 levels are high and correlate with poor survival prognosis. Independent of ion pump activity, SPCA2 elevates baseline Ca2+ levels through SICE and drives cell proliferation. Attenuation of SPCA2 led to increased mitochondrial ROS production, DNA damage and activation of the ATM/ATR-p53 axis leading to G0/G1 phase cell cycle arrest and apoptosis. Resistance to DNA damaging agents including doxorubicin, carboplatin, and ionizing radiation could be reversed by downregulation of SPCA2 expression using curcumin. In conclusion, elevated SPCA2 drives pro-survival and chemotherapy resistance in ER+ p53WT breast tumors by suppressing the DNA damage response. Attenuation of SPCA2 expression by curcumin may have therapeutic potential in treating receptor positive breast cancer. The goal of this study is to investigate store Independent Ca2+ entry regulation of the DNA Damage Response pathway in breast cancer cells
2022-01-26 | GSE148537 | GEO
Project description:Immune surveillance plays a pivotal role in controlling tumor emergence, dormancy and progression, including in breast cancer. Despite its potential clinical relevance, the mechanisms governing dormancy initiation, maintenance and escape, as well as the molecular mediators involved, remain poorly understood. Here, we identify the interferon-inducible chemokine CXCL10 and its receptor CXCR3 as key regulators of immunological dormancy in triple-negative breast cancer (TNBC). By transcriptomic profiling, we observed high expression of Cxcl10 in dormant cells in two different orthotopic, syngeneic models of breast cancer dormancy (D2.0R and 4T1-MR20). Genetic silencing of Cxcl10 in dormant cells or pharmacological blockade of CXCR3 in vivo led to early tumor onset and rapid growth in immunocompetent mice. In contrast, dormant cells effectively formed tumors in immune-deficient mice independently of Cxcl10 status, demonstrating that the CXCL10/CXCR3 axis-mediated dormancy requires a functional immune system. Further analysis confirmed that Cxcl10 silencing altered the local immune microenvironment, reducing CD4+ and CD8+ T cell infiltration while increasing the presence of granulocytic Myeloid Derived Suppressor Cells and Natural Killer cells. Moreover, Cxcl10 silencing significantly increased the burden of tumor cells disseminated to the lung. Leveraging these findings, we identified a CXCL10-mediated dormancy signature that predicts improved overall survival in TNBC patients. Our findings have identified a new mechanism modulating breast cancer dormancy with two important clinical implications: the CXCL10/CXCR3 axis as a potential therapeutic target for improving survival of patients with TNBC, and the CXCL10-dependent dormancy signature as a tool for identifying these patients.
2026-02-02 | GSE304626 | GEO
Project description:In lobular breast cancer, metachronous distant metastasis may become evident many years after primary tumor diagnosis and often affect the ovary. Little is known about tumor dormancy and intratumoral heterogeneity of DNA methylation in metastasis from lobular breast cancer. In this exploratory analysis, DNA methylation patterns were studied in six spacially separated regions of an ovarian metastasis from lobular breast cancer.
2021-12-01 | GSE144359 | GEO
Project description:Breast cancer patients with estrogen receptor positive tumors face a constant risk of disease recurrence for the remainder of their lives. Dormant tumor cells residing in tissues such as the bone marrow may generate clinically significant metastases many years after initial diagnosis. Previous studies suggest that dormant cells display “stem like” properties (CSCs), which may be regulated by the immune system. Although many studies have examined tumor cell intrinsic characteristics of dormancy, the role of the immune system in controlling dormancy and its escape is not well understood. This scientific gap is due, in part, to a lack of immunocompetent mouse models of breast cancer dormancy with many studies involving human xenografts in immunodeficient mice. To overcome this limitation, we studied dormancy in immunocompetent, syngeneic mouse breast cancer models. We find that PyMT, Met-1 and D2.0R cell lines contain CSCs that display both short- and long-term metastatic dormancy in vivo, which is dependent on the host immune system. Natural killer cells were key for the metastatic dormancy phenotype observed for D2.0R and the role of NK cells in regulating CSCs was further investigated. Quiescent D2.0R CSC are resistant to NK cytotoxicity, while proliferative D2.0R CSC were sensitive to NK cytotoxicity both in vitro and in vivo. This resistance was mediated, in part, by the expression of Bach1 and Sox2 transcription factors. NK killing was enhanced by the STING agonist MSA-2. Collectively, our findings demonstrate the important role of immune regulation of breast tumor dormancy and highlight the importance of utilizing immunocompetent models to study this phenomenon.
2024-05-15 | GSE267583 | GEO
Project description:Therapy-induced self-renewal of CD133hi cells regulates escape from tumor dormancy and endocrine-resistant metastatic luminal breast cancer
| PRJNA285078 | ENA
Project description:Interleukin 6 (IL6) signaling has been associated with an aggressive and metastatic phenotype in multiple solid tumors including breast cancer, but its mechanism of action in mediating tumor progression and treatment response is not clear. By exploiting a clinically relevant intraductal xenograft model of estrogen receptor positive (ER+) breast cancer, we demonstrate that IL6 increases both primary tumor growth and distant metastases. By integrating pre-clinical models and clinical specimens, we show that signal transducer and activator of transcription 3 (STAT3) mediates IL6-induced activation of a metastatic gene program from enhancer-elements shared with ER and its pioneer factor FOXA1. Although IL6 activated STAT3 and ER/FOXA1 share cis-regulatory regions, STAT3 drives transcription independent of ER and FOXA1 function, and the IL6/STAT3 gene program is not influenced by ER-targeted therapies, decoupling these two important pathways. This demonstrates that ER/FOXA1 and IL6/STAT3 are two parallel, but independent actionable pathways controlling breast cancer progression.
2021-09-08 | PXD012980 | Pride