Project description:Breast cancer is a multifaceted disease, exhibiting significant molecular, histological, and pathological diversity. Factors that impact this heterogeneity are poorly understood; however, transformation of distinct normal cell populations of the breast may generate different tumor phenotypes. Our previous study demonstrates that the polyomavirus middle T antigen (PyMT) oncogene can establish diverse tumor subtypes when broadly expressed within mouse mammary epithelial cells. Herein, we assess the molecular, histological, and metastatic outcomes from distinct mammary cell populations transformed with PyMT. By combining several methodologies, including lentiviral infection, cell sorting, and transplantation, we have characterized tumors arising from enriched populations of mammary epithelial cells. We have found that expression of PyMT within different cell populations influences tumor histology, molecular subtype, and metastatic potential.
Project description:Breast cancer is a multifaceted disease, exhibiting significant molecular, histological, and pathological diversity. Factors that impact this heterogeneity are poorly understood; however, transformation of distinct normal cell populations of the breast may generate different tumor phenotypes. Our previous study demonstrates that the polyomavirus middle T antigen (PyMT) oncogene can establish diverse tumor subtypes when broadly expressed within mouse mammary epithelial cells. Herein, we assess the molecular, histological, and metastatic outcomes from distinct mammary cell populations transformed with PyMT. By combining several methodologies, including lentiviral infection, cell sorting, and transplantation, we have characterized tumors arising from enriched populations of mammary epithelial cells. We have found that expression of PyMT within different cell populations influences tumor histology, molecular subtype, and metastatic potential. 32 samples, 1 from each of 32 mouse mammary tumors arising from transplanted mouse mamary epithelial cells (MMECs) transduced with PyMT-expressing lentivirus. MMECs were sorted into four different types prior to transplant: luminal CD133+ (8 samples), luminal CD133- (11 samples), stem (6 samples), and basal (7 samples). The background for the cell donor and transplant recipients mice was FVB/NJ obtained from Jackson Laboratories.
Project description:S100A10 (p11) is a plasminogen receptor that regulatess cellular plasmin generation by cancer cells. In the current study we used the MMTV-PyMT mouse breast cancer model to investigate the role of p11 in oncogenesis. Genetic deletion of p11 resulted in significantly decreased tumor onset, growth rate and spontaneous pulmonary metastatic burden in the PyMT/p11-KO mice. This phenotype was accompanied by substantial reduction in Ki67 positivity, macrophage infiltration and decreased vascular density in the primary tumors, and appearance of invasive carcinoma and pulmonary metastasis. Surprisingly, immunohistochemical analysis of wild-type MMTV-PyMT mice failed to detect p11 expression in the tumors or metastatic tumor cells and loss of p11 did not decrease plasmin generation in the PyMT tumors and cells. Furthermore, tumor cells expressing p11 displayed dramatically reduced lung metastasis when injected into p11-depleted mice, further strengthening the stromal role of p11. Transcriptome analysis of the p11-depleted tumors showed marked reduction in genes involved in breast cancer development, progression, and inflammation such as AREG, MUC1 and S100A8. The PyMT/p11-KO tumors displayed remarkable increase in inflammatory cytokines such as IL-6, IL-10 and IFN-γ. Gene expression profiling and immunohistochemistry primary breast cancer samples showed that p11 mRNA and protein was significantly higher in tumors compared to normal mammary tissue. The mRNA expression was significantly associated with poor patient prognosis and significantly elevated in high grade, triple negative tumors and tumors with high proliferative index. We used microarray to detail the global programme of gene expression underlying reduced growth/establishment of P11-KO PyMT tumours.
Project description:This SuperSeries is composed of the following subset Series: GSE30864: Gene expression of polyoma middle T antigen induced mammary tumors [AKXD x PyMT] GSE30865: Gene expression of polyoma middle T antigen induced mammary tumors [NZB x PyMT] GSE31223: Gene expression of polyoma middle T antigen induced mammary tumors [RNA_Seq : MOLF x PyMT] Refer to individual Series
Project description:Transcriptional profiling of miRNA levels in mammary tumors from 18 [PyMT x AKXD]F1 sublines. The PyMT strain was FVB/N-TgN(MMTV-PyVT)634Mul.
Project description:Transcriptional profiling of miRNA levels in mammary tumors from 18 [PyMT x AKXD]F1 sublines. The PyMT strain was FVB/N-TgN(MMTV-PyVT)634Mul. Mammary tumor total RNA from mice representing one of 18 AKXD RI strains were pooled to represent each strain and expression profiled using a custom miRNA microarray.
Project description:The tumour stroma is believed to contribute to some of the most malignant characteristics of epithelial tumours. However, signalling between stromal and tumour cells is complex and remains poorly understood. Here we show that the genetic inactivation of Pten in stromal fibroblasts of mouse mammary glands accelerated the initiation, progression and malignant transformation of mammary epithelial tumours. This was associated with the massive remodelling of the extracellular matrix (ECM), innate immune cell infiltration and increased angiogenesis. Loss of Pten in stromal fibroblasts led to increased expression, phosphorylation (T72) and recruitment of Ets2 to target promoters known to be involved in these processes. Remarkably, Ets2 inactivation in Pten stroma-deleted tumours ameliorated disruption of the tumour microenvironment and was sufficient to decrease tumour growth and progression. Global gene expression profiling of mammary stromal cells identified a Pten-specific signature that was highly represented in the tumour stroma of patients with breast cancer. These findings identify the Pten-Ets2 axis as a critical stroma-specific signalling pathway that suppresses mammary epithelial tumours.