Molecular mechanisms of PD-1 immune checkpoint inhibitors in mouse mammary tumours
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE268752 | GEO | 2024/08/01
REPOSITORIES: GEO
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Project description:The organisation of the mammary epithelial cell hierarchy and how these cells relate to the presentation of human breast tumours is poorly understood. Our results demonstrate that the luminal cell compartment of the mouse mammary gland can be resolved into terminally differentiated oestrogen receptor (ER)+ luminal cells, ER+ luminal progenitors and ER- luminal progenitors. The ER+ luminal progenitors are unique in regards to cell survival, as they are relatively insensitive to loss of oestrogen and progesterone when compared to the other types of mammary epithelial cells. Analysis of normal human breast tissue reveals a similar hierarchical organisation that is composed of terminally differentiated luminal cells and relatively differentiated (EpCAM+CD49f+ALDH-) and undifferentiated (EpCAM+CD49f+ALDH+) luminal progenitors. In addition, approximately one third of human breast samples examined contained an additional population that had a luminal progenitor phenotype, but is characterised by low expression of ERBB3 and low proliferative potential. Parent-progeny relationship experiments demonstrated that all luminal progenitor populations in both species are highly plastic and, at low frequencies, can generate progeny representing all mammary cell types. Gene expression profiling demonstrates that the ER- luminal progenitors in the mouse and the undifferentiated ALDH+ luminal progenitors in the human have gene signatures that resemble those obtained from basal-like breast tumours. Overall, our work reveals a more defined mammary cell hierarchy, which may in turn provide greater insight into the aetiology of breast cancer.
2012-10-11 | GSE35399 | GEO
Project description:The organisation of the mammary epithelial cell hierarchy and how these cells relate to the presentation of human breast tumours is poorly understood. Our results demonstrate that the luminal cell compartment of the mouse mammary gland can be resolved into terminally differentiated oestrogen receptor (ER)+ luminal cells, ER+ luminal progenitors and ER- luminal progenitors. The ER+ luminal progenitors are unique in regards to cell survival, as they are relatively insensitive to loss of oestrogen and progesterone when compared to the other types of mammary epithelial cells. Analysis of normal human breast tissue reveals a similar hierarchical organisation that is composed of terminally differentiated luminal cells and relatively differentiated (EpCAM+CD49f+ALDH-) and undifferentiated (EpCAM+CD49f+ALDH+) luminal progenitors. In addition, approximately one third of human breast samples examined contained an additional population that had a luminal progenitor phenotype, but is characterised by low expression of ERBB3 and low proliferative potential. Parent-progeny relationship experiments demonstrated that all luminal progenitor populations in both species are highly plastic and, at low frequencies, can generate progeny representing all mammary cell types. Gene expression profiling demonstrates that the ER- luminal progenitors in the mouse and the undifferentiated ALDH+ luminal progenitors in the human have gene signatures that resemble those obtained from basal-like breast tumours. Overall, our work reveals a more defined mammary cell hierarchy, which may in turn provide greater insight into the aetiology of breast cancer. Normal human breast tissues from reduction mammoplasties were dissociated into single cells and the epithelial cell populations were flow sorted. Total RNA was extracted for each group in 11 independent patient samples.
2012-10-11 | E-GEOD-35399 | biostudies-arrayexpress
Project description:Immunophenotyping of tumor microenvironment (TME) is crucial for immunotherapy efficacy in patients with solid tumours. However, strategies to characterize TME are largely limited with huge heterogeneity. We show that endoplasmic reticular oxidoreductase-1α (ERO1A) induces an immune-suppressive TME and resistance to PD-1 blockade by promoting endoplasmic reticulum (ER) stress response. Single-cell RNA sequencing analyses confirm that ERO1A is correlated with immunosuppression and dysfunction of CD8+ T cell along anti-PD-1 treatment. Ablation of Ero1a in tumours promotes the infiltration of lymphocytes as well as cytotoxicity of CD8+ T cells and enhances response to anti-PD-1 treatment in mouse models.
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Project description:breast cancer. Combined IGF and estrogen-targeted therapy may improve the benefit of hormonal therapy alone. We employed a postmenopausal model of estrogen-dependent breast cancer in vitro and in vivo using the aromatase-expressing MCF-7/AC-1cells. Using this model, we investigated the anti-tumor effects of the dual IGF-1R/InsR tyrosine kinase inhibitor, BMS-754807 alone and in combination with letrozole or tamoxifen in vivo. We used microarrays to compare gene expression changes of MCF7 breast xenograft treated with either BMS754807, or Tamoxifen or Letrozole alone; or Tamoxifen or Letrozole in combination with BMS754807 for 28 days Breast xenograft MCF7 bearing mice treated with either BMS754807, or Tamoxifen or Letrozole alone; or Tamoxifen or Letrozole in combination with BMS754807 for 28 days. RNA were extracted from tumors and hybridizedon Affymetrix microarrays to compare gene expression changes
2011-11-02 | E-GEOD-33366 | biostudies-arrayexpress
Project description:breast cancer. Combined IGF and estrogen-targeted therapy may improve the benefit of hormonal therapy alone. We employed a postmenopausal model of estrogen-dependent breast cancer in vitro and in vivo using the aromatase-expressing MCF-7/AC-1cells. Using this model, we investigated the anti-tumor effects of the dual IGF-1R/InsR tyrosine kinase inhibitor, BMS-754807 alone and in combination with letrozole or tamoxifen in vivo. We used microarrays to compare gene expression changes of MCF7 breast xenograft treated with either BMS754807, or Tamoxifen or Letrozole alone; or Tamoxifen or Letrozole in combination with BMS754807 for 28 days
2011-11-02 | GSE33366 | GEO
Project description:SV7tert AML cells were obtained from ATCC and cultured in Dulbecco's modified essential medium (DMEM), glutamine (4mmol) and 10% foetal bovine serum (FBS). Two million SV7tertAML cells were subcutaneously injected into nude mice either with or without subcutaneous oestrogen pellets (n=4 per group); oestrogen was added using 0.36mg 60 day release oestrogen pellets implanted sub-cutaneously. Mice were housed in pathoflex isolators at 26°C, on 12 hour light / dark cycles. Irradiated RB2 diet and autoclaved water provided ad libertum. All oestrogen treated mice inoculated with SV7tertAML cells developed subcutaneous tumours which required termination of the animals at six weeks due to tumour load. These primary tumours were removed and fragments placed subcutaneously in further nude mice which went on to develop tumours both in the presence and absence of oestrogen. Mice were weighed weekly and their clinical condition closely monitored by a trained observer. Mice were terminated individually when the tumour cross-sectional area reached 250mm2 or sooner, which has previously been seen to be below the limit of 10% of initial body weight set by the UKCCCR guidelines. Tumours were removed and a portion flash frozen in liquid nitrogen. RNA was extracted from five tumours from oestrogen treated and control animals. Equal quantities of RNA was pooled and quality checked by Agilent Bioanylyser. Experimenter name = Simon Johnson Experimenter institute = Queens Medical Centre Keywords: estrogen treatment, angiomyolipoma xenograft tumors
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Project description:Analysis of 104 breast cancer biopsies (removed prior to any treatment with tamoxifen or chemotherapeutic agents) from patients aged between 31 years and 89 years at the time of diagnosis (mean age = 58 years). Twenty were less than 50 years and seventy-seven women were 50 years, or older, at diagnosis. The size of the tumours ranged between 0.6 cm and 8.0 cm (mean = 2.79 cm). Eighteen tumours were T1 (<2 cm) in maximal dimension; 83 were T2 (2M-bM-^@M-^S5 cm) and 3 tumours were T3 (>5 cm). Eighty-two were invasive ductal carcinoma, 17 were invasive lobular and five were tumours of special type (two tubular and three mucinous). Eleven tumours were grade 1; 40 were grade 2; and 53 were grade 3. Sixty-seven tumours were oestrogen receptor (ER) positive and 34 were ER negative (ER status was determined by Enzyme Immuno-Assay (EIA); a positive result was defined as more than 200 fmol/g protein). ER status was not available for 3 patients. Forty-five tumours had no axillary metastases and 59 tumours had metastasised to axillary lymph nodes. Sixty-nine women were treated with post-operative tamoxifen; 26 did not receive tamoxifen. Fifty patients were treated with adjuvant systemic chemotherapy (CMF +/M-bM-^HM-^R adriamycin); 45 patients did not receive chemotherapy. Details regarding tamoxifen and systemic chemotherapy were not available for 9 patients. Maximal follow-up was 3,026 days with a mean follow-up of 1,887 days. 17 normal breast tissues were also assayed. Gene expression profiling of 104 breast cancer and 17 normal breast biopsies.
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