Inactivation of LATS1/2 drives luminal-basal plasticity to initiate basal-like mammary carcinomas
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ABSTRACT:
PROVIDER: PRJNA805501 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17982781.fastq.gz | Fastqsanger.gz | |||
| SRR17982782.fastq.gz | Fastqsanger.gz | |||
| SRR17982783.fastq.gz | Fastqsanger.gz | |||
| SRR17982784.fastq.gz | Fastqsanger.gz | |||
| SRR17982785.fastq.gz | Fastqsanger.gz |
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Project description:Basal breast cancers, an aggressive breast cancer subtype that has poor treatment options, are thought to arise from luminal mammary epithelial cells that undergo basal-like plasticity through poorly understood mechanisms. Using genetic mouse models and ex vivo primary organoid cultures, we show that conditional co-deletion of the LATS1 and LATS2 kinases, key effectors of Hippo pathway signaling, in mature mammary luminal epithelial cells promotes the development of basal-like carcinomas that metastasize over time. Genetic co-deletion experiments revealed that phenotypes resulting from the loss of LATS1/2 activity are dependent on the transcriptional regulators YAP/TAZ. Notably, transcriptional analyses of LATS1/2-deleted mammary epithelial cells revealed a gene expression program that associates with human basal breast cancers. Our study demonstrates in vivo roles for the LATS1/2 kinases in mammary epithelial homeostasis and luminal-basal fate control and implicates signaling networks induced upon the loss of LATS1/2 activity in the development of basal breast cancers.
2022-09-26 | GSE196555 | GEO
Project description:The tumor suppressor LATS1, whose expression is often downregulated in human breast cancer, helps maintain luminal breast cancer cell identity by keeping basal-specific genes in a closed chromatin state, preventing their spurious activation. This is achieved via interaction of LATS1 with the NCOR1 nuclear corepressor and recruitment of HDAC1,driving histone H3K27 deacetylation near NCOR1-repressed “basal” genes. Consequently, decreased expression of LATS1 elevates the expression of such “basal” genes and promotes luminal-to-basal slippage.
2022-10-19 | GSE195715 | GEO
Project description:The tumor suppressor LATS1, whose expression is often downregulated in human breast cancer, helps maintain luminal breast cancer cell identity by keeping basal-specific genes in a closed chromatin state, preventing their spurious activation. This is achieved via interaction of LATS1 with the NCOR1 nuclear corepressor and recruitment of HDAC1,driving histone H3K27 deacetylation near NCOR1-repressed “basal” genes. Consequently, decreased expression of LATS1 elevates the expression of such “basal” genes and promotes luminal-to-basal slippage.
2022-10-19 | GSE195714 | GEO
Project description:Recent studies demonstrate both basal and luminal cells of the prostate gland can initiate tumorigenesis upon oncogenic transformation. However, it remains unclear how molecular mechanisms operating within each cell lineage contribute to the initiation and progression of the prostate cancer. Here we investigate functions of individual miRNAs using genetically engineered mouse models. By both quantitative miR-Seq and in situ hybridization, we identify microRNA-205 (miR-205) as the most highly expressed miRNA and specific to the basal cells in the prostate. MicroRNA-205 expression is further elevated in the basal cells in the well-established Pten null tumorigenic mouse model. To investigate the role of miR-205 in Pten-deletion mediated tumorigenesis, we generated a Pten/miR-205 double knockout mouse model. Concurrent deletion of both miR-205 and Pten significantly compromised tumor progression in both basal and luminal compartments. We observed significantly reduced tumor size and compromised proliferation in both basal and luminal cells. We have previously demonstrated a critical requirement of miR-205 for maintaining the PI(3)K signaling and pAkt levels in skin stem cells. Consistent with this role, we observed strong reduction of pAkt and significantly increased cellular senescence in the basal cells of the dKO, compared to the Pten KO alone. These results suggest that miR-205 is cell-autonomously required for the tumorigenesis of the basal cells. Taken together, we have identified miR-205 as an important regulator in prostate cancer. Our study also reveals an essential and unexpected role of the basal cells for promoting prostate tumorigenesis.
2019-09-16 | GSE75321 | GEO
Project description:Deregulated activity of the LATS tumor suppressors has broad implications on cellular and tissue homeostasis. We examined the consequences of downregulation of either LATS1 or LATS2 in breast cancer. Consistent with their proposed tumor suppressive roles, expression of both paralogs is significantly downregulated in human breast cancer, and loss of either paralog accelerated mammary tumorigenesis in mice. However, each paralog had a distinct impact on breast cancer. Thus, LATS2 depletion in luminal B tumors resulted in metabolic rewiring, with increased glycolysis and reduced PPARg signaling. Furthermore, pharmacological activation of PPARg elicited LATS2-dependent death in luminal B-derived cells. In contrast, LATS1 depletion augmented cancer cell plasticity, skewing luminal B tumors towards increased expression of basal-like features, in association with increased resistance to hormone therapy. Hence, these two closely related paralogs play distinct roles in protection against breast cancer; tumors with reduced expression of either LATS1 or LATS2 may rewire signaling networks differently and thus respond differently to anti-cancer treatments.
2018-10-28 | GSE116817 | GEO
Project description:Deregulated activity of the LATS tumor suppressors has broad implications on cellular and tissue homeostasis. We examined the consequences of downregulation of either LATS1 or LATS2 in breast cancer. Consistent with their proposed tumor suppressive roles, expression of both paralogs is significantly downregulated in human breast cancer, and loss of either paralog accelerated mammary tumorigenesis in mice. However, each paralog had a distinct impact on breast cancer. Thus, LATS2 depletion in luminal B tumors resulted in metabolic rewiring, with increased glycolysis and reduced PPARg signaling. Furthermore, pharmacological activation of PPARg elicited LATS2-dependent death in luminal B-derived cells. In contrast, LATS1 depletion augmented cancer cell plasticity, skewing luminal B tumors towards increased expression of basal-like features, in association with increased resistance to hormone therapy. Hence, these two closely related paralogs play distinct roles in protection against breast cancer; tumors with reduced expression of either LATS1 or LATS2 may rewire signaling networks differently and thus respond differently to anti-cancer treatments.
2018-10-28 | GSE116816 | GEO
Project description:Breast cancers can be classified using whole genome expression into distinct subtypes that show differences in patient prognosis. One of these groups, the basal-like carcinomas, are poorly differentiated, highly metastatic, and genomically unstable. These tumors also contain specific genetic alterations with one example being frequent p53 mutations. The loss of the tumor suppressor gene encoded by the retinoblastoma (RB1) locus is a well-characterized occurrence in many tumor types, however, its role in breast cancer is less clear with many reports demonstrating a Loss of Heterozygosity (LOH) that does not correlate with loss of RB1 protein expression. Here we report that LOH of the RB1 locus was observed at a high frequency in basal-like and luminal B tumors. These tumors also concurrently have low expression of RB1 mRNA as assessed by DNA microarray. As in previous reports, we also did not see a significant correlation between RB1 LOH and protein expression as measured by immunohistochemistry (IHC). p16INK4a, however, was highly expressed both by microarray and IHC, in basal-like tumors only presumably due to a previously reported feedback loop caused by RB1 loss. These results suggest that the functional loss of RB1 is a common event in the progression of basal-like and luminal B breast tumors, which may play a key role in dictating therapeutic responses Keywords: reference x sample Comparison of reference samples against treatment
2010-06-25 | E-GEOD-10884 | biostudies-arrayexpress
Project description:We have used RNA-seq to examine RNA differential expression among three populations, normal basal cells, luminal-derived basal cells (LdBCs) and normal luminal cells.
2019-12-31 | GSE109543 | GEO
Project description:Breast tumors expressing lower levels of Estrogen Receptor (ER) represent a distinct subset of breast cancer characterized by the emergence of basal-like characteristics within tumors that are traditionally considered luminal-like. Lineage tracing of these low-ER tumors in the MMTV-PyMT mouse mammary tumor model revealed that the basal-like tumor cells within these tumors arose from normal luminal epithelial cells, suggesting that luminal-to-basal plasticity is responsible for the evolution and emergence of basal-like characteristics within these tumors. This study aims to identify the potential drivers of this plasticity by using single-cell RNA sequencing to identify populations of lineage-restricted luminal cells and luminal-derived basal cells within the tumor, and comparing their gene expression profiles.
2023-03-01 | GSE214815 | GEO
Project description:Basal-like breast cancers have several well-characterized distinguishing molecular features, but most of these are features of the cancer cells themselves. The unique stromal-epithelial interactions, and more generally, microenvironmental features of basal-like breast cancers, have not been well characterized. To identify characteristic microenvironment features of basal-like breast cancer, we performed cocultures of several basal-like breast cancer cell lines with fibroblasts (reduction mammoplasty-derived fibroblast line; RMF) and compared these to cocultures of luminal breast cancer cell lines with fibroblasts. Interactions between basal-like cancer cells and fibroblasts induced expression of numerous interleukins and chemokines, including IL-6, IL-8, CXCL1, CXCL3, and TGFbeta. Under the influence of fibroblasts, basal-like breast cancer cell lines also showed increased migration in vitro. Migration was less pronounced for luminal lines, but these lines were more likely to have altered proliferation. These differences were relevant to tumor biology in vivo, as the gene set that distinguished luminal and basal-like stromal interactions in coculture also distinguishes basal-like from luminal tumors with 98% accuracy in 10-fold CV and 100% accuracy in an independent test set. However, comparisons between cocultures where cells were in direct contact and cocultures where interaction was solely through soluble factors suggest that there is an important impact of direct cell-to-cell contact. The phenotypes and gene expression changes invoked by cancer cell interactions with fibroblasts support the microenvironment and cell-cell interactions as intrinsic features of breast cancer subtypes. 99 samples were hybridized with Stratagene common reference and profiled on Agilent microarrays.
2011-05-26 | E-GEOD-26411 | biostudies-arrayexpress