Dataset Information

Regulation of TROP2 expression in breast cancer

ABSTRACT: Expression of genes highly correlated with TACSTD2 expression in breast tumors and corresponding patient-derived xenografts (PDXs) and found that 29 genes were overlapping between in 18 breast cancer samples and matching PDXs. Among these genes, TACSTD2 expression strongly correlated with expression of epithelial marker CDH1 (E-Cadherin) (r2=0.823; p<0.001). Expression of TACSTD2 was then compared to expression of CDH1 in breast cancer cell lines from The Cancer Cell Line Encyclopedia (CCLE) (N = 51) and The Library of Integrated Network-Based Cellular Signatures (LINCS) (N = 35). There was also a significant correlation between TACSTD2 and CDH1 in both CCLE (r2=0.564, p < 0.001) and LINCS (r2= 0.755; p < 0.001).

ORGANISM(S): Homo sapiens

PROVIDER: GSE235812 | GEO | 2023/08/21

REPOSITORIES: GEO

ACCESS DATA

Similar Datasets

Project description:Brain metastases are an increasing burden among breast cancer patients, particularly for those with HER2+ and triple negative (TN) subtypes. Mechanistic insight into the pathophysiology of brain metastases and preclinical validation of therapies has relied almost exclusively on intracardiac injection of brain-homing cells derived from highly aggressive TN MDA-MB-231 and HER2+ BT474 breast cancer cell lines. Yet, these well characterized models are far from representing the tumor heterogeneity observed clinically and, due to their fast progression in vivo, their suitability to validate therapies for established brain metastasis remains limited. The goal of this study was to develop and characterize novel human brain metastasis breast cancer patient-derived xenografts (BM-PDXs) to study the biology of brain metastasis and to serve as tools for testing novel therapeutic approaches. We obtained freshly resected brain metastases from consenting donors with breast cancer. Tissue was immediately implanted in the mammary fat pad of female immunocompromised mice and expanded as BM-PDXs. Brain metastases from 3/4 (75%) TN, 1/1 (100%) estrogen receptor positive (ER+), and 5/9 (55.5%) HER2+ clinical subtypes were established as transplantable BM-PDXs. To facilitate tracking of metastatic dissemination using BM-PDXs, we labeled PDX-dissociated cells with EGFP-luciferase followed by re-implantation in mice, and generated a BM-derived cell line (F2-7). Immunohistologic analyses demonstrated that parental and labeled BM-PDXs retained expression of critical clinical markers such as ER, progesterone receptor (PR), epidermal growth factor receptor (EGFR), HER2 and the basal cell marker cytokeratin 5 (CK5). Similarly, RNA sequencing analysis showed clustering of parental, labeled BM-PDXs and their corresponding cell line derivative. Intracardiac injection of dissociated cells from BM-E22-1, resulted in MRI-detectable macrometastases in 4/8 (50%) and micrometastases (8/8) (100%) mice, suggesting that BM-PDXs remain capable of colonizing the brain at high frequencies. Brain metastases developed 8 to 12 weeks after ic injection, located to the brain parenchyma, grew around blood vessels and elicited astroglia activation characteristic of breast cancer brain metastasis. These novel BM-PDXs represent heterogeneous and clinically relevant models to study mechanisms of brain metastatic colonization, with the added benefit of a slower progression rate that makes them suitable for preclinical testing of drugs in therapeutic settings.

Project description:Breast cancer is a heterogeneous collection of disease arising from the breast with distinct molecular and phenotypic features. Certain subsets of patients have tumors that are particularly difficult-to-treat, which include triple-negative breast cancer (TNBC), metastatic/recurrent disease and rare histological variants. To delineate the underlying biology and identify therapeutic candidates for these patients, a series of 37 breast cancer patient-derived xenografts (PDX) from both chemo-naïve and pre-treated specimens was generated from 81 transplant attempts. Whole-genome and transcriptome sequencing revealed marked fidelity of the molecular landscape for the majority of PDXs in comparison to parental tumors. Reverse-phase protein array analysis of PDXs further identified potential therapeutic targets. Metastatic potential varied between PDXs, where low-penetrance lung micrometastases was the most common pattern of dissemination and observed in 34.5% of models. Three PDXs recapitulated the metastatic localization seen in the corresponding patients, including two lines with high-frequency metastases to multiple vital organ systems, while another PDX displayed tropism to the skull-base. Chemosensitivity profiling was performed in vivo with standard-of-care agents (doxorubicin, cisplatin, gemcitabine or paclitaxel), where multi-drug chemoresistance was found in 60.0% of PDXs and 64.7% of responses were concordant with pre-engraftment responses observed in the patient. Consolidating chemogenomic data identified potentially actionable features in 97.2% of PDXs, and marked regressions were seen in vivo when a subset of these underwent proof-of-concept functional studies. This included FGFR inhibitor sensitivity in a FGFR1-amplified lobular carcinoma, mTOR inhibitor sensitivity in a recurrent neuroendocrine breast cancer with proteomic evidence of mTOR/PI3K activation, and platinum sensitivity in a TNBC with BRCA1 germline mutation predicted as benign. Together, this clinically-annotated PDX library with comprehensive molecular and phenotypic profiling serves as a resource for both discovery and validation preclinical studies on difficult-to-treat breast tumors.

Project description:G0/G1 switch gene 2 (G0S2) is known to inhibit lipolysis through inhibition of adipose triglyceride lipase (ATGL). Although G0S2 has also been proposed to be involved in cancer progression, this role appears complex, and mechanisms are unclear. We recently reported a role for G0S2 in ER+ breast cancer suppression as low G0S2 expression correlated with increased recurrence after antiestrogen therapy and increased G0S2 expression sensitized ER+ breast cancer cells to tamoxifen and PI3K/mTOR inhibitors. In this report we dissect the role of G0S2 in ER+ versus ER- breast cancer. Overexpression of G0S2 in ER- breast cancer cells increased cell proliferation while G0S2 overexpression in ER+ breast cancer cells decreased cell proliferation. Transcriptome analysis revealed that G0S2 mediated distinct but overlapping transcriptional responses in ER- and ER+ cells. G0S2 reduced genes associated with an epithelial phenotype, especially in ER- cells, including CDH1, ELF3, STEAP4 and TACSTD2 suggesting promotion of the epithelial-mesenchymal transition (EMT). G0S2 also repressed estrogen signaling and estrogen receptor target gene signatures, especially in ER+ cells, including TFF1 and TFF3. In addition, G0S2 overexpression increased cell migration in ER- cells and increased estrogen deprivation sensitivity in ER+ cells. Interestingly, two genes downstream of ATGL in fat utilization, HMGCS1 and HMGCS2, that are also rate-limiting in steroid hormone biosynthesis, were downregulated in G0S2 overexpressing ER+ cells. In addition, HSD17B11, a gene that converts estradiol to its less estrogenic derivative, estrone, was highly upregulated in G0S2 overexpressing ER+ cells, suggesting G0S2 overexpression has a negative effect of estradiol production and maintenance. High levels of estrone were confirmed to be present in G0S2 overexpressing cells. High expression of G0S2 and HSD17B11 was associated with improved relapse free survival in breast cancer patients while high expression of HMGSC1 was associated with poor survival. In addition, the expression of G0S2 positively and negatively correlated respectively, with expression of HSD17B11 and HMGSC1 in patient samples. Finally, we deleted G0S2 in breast cancer prone MMTV-PyMT mice that have been hypothesized to be partially estrogen sensitive during early stages of tumorigenesis but develop ER- tumors. In this context, G0S2 functioned as a tumor promoter, with G0S2 null mice demonstrating a slight increase in tumor latency and decrease in tumor weight and a larger inhibitory effect on tumor metastasis. Our data indicates a complex role for G0S2 in breast cancer, dependent on ER status, that may be mediated in part by suppression of the estrogen signaling pathway.

Dataset Information

Regulation of TROP2 expression in breast cancer

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure