5 results on '"Fernandez, SA"'
Search Results
2. Stromal PTEN inhibits the expansion of mammary epithelial stem cells through Jagged-1.
- Author
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Sizemore GM, Balakrishnan S, Hammer AM, Thies KA, Trimboli AJ, Wallace JA, Sizemore ST, Kladney RD, Woelke SA, Yu L, Fernandez SA, Chakravarti A, Leone G, and Ostrowski MC
- Subjects
- 3T3 Cells, Animals, Cancer-Associated Fibroblasts metabolism, Cell Proliferation, Epithelial Cells pathology, Female, Humans, Jagged-1 Protein deficiency, Jagged-1 Protein genetics, Mammary Glands, Animal pathology, Mammary Neoplasms, Animal genetics, Mammary Neoplasms, Animal pathology, Mice, Mice, Transgenic, PTEN Phosphohydrolase deficiency, PTEN Phosphohydrolase metabolism, Receptor, Notch3 metabolism, Signal Transduction, Stromal Cells cytology, Tumor Microenvironment, Epithelial Cells cytology, Jagged-1 Protein metabolism, Mammary Glands, Animal cytology, Mammary Neoplasms, Animal metabolism, PTEN Phosphohydrolase physiology, Stem Cells cytology
- Abstract
Fibroblasts within the mammary tumor microenvironment are active participants in carcinogenesis mediating both tumor initiation and progression. Our group has previously demonstrated that genetic loss of phosphatase and tensin homolog (PTEN) in mammary fibroblasts induces an oncogenic secretome that remodels the extracellular milieu accelerating ErbB2-driven mammary tumor progression. While these prior studies highlighted a tumor suppressive role for stromal PTEN, how the adjacent normal epithelium transforms in response to PTEN loss was not previously addressed. To identify these early events, we have evaluated both phenotypic and genetic changes within the pre-neoplastic mammary epithelium of mice with and without stromal PTEN expression. We report that fibroblast-specific PTEN deletion greatly restricts mammary ductal elongation and induces aberrant alveolar side-branching. These mice concomitantly exhibit an expansion of the mammary epithelial stem cell (MaSC) enriched basal/myoepithelial population and an increase in in vitro stem cell activity. Further analysis revealed that NOTCH signaling, specifically through NOTCH3, is diminished in these cells. Mechanistically, JAGGED-1, a transmembrane ligand for the NOTCH receptor, is downregulated in the PTEN-null fibroblasts leading to a loss in the paracrine activation of NOTCH signaling from the surrounding stroma. Reintroduction of JAGGED-1 expression within the PTEN-null fibroblasts was sufficient to abrogate the observed increase in colony forming activity implying a direct role for stromal JAGGED-1 in regulation of MaSC properties. Importantly, breast cancer patients whose tumors express both low stromal JAG1 and low stromal PTEN exhibit a shorter time to recurrence than those whose tumors express low levels of either alone suggesting similar stromal signaling in advanced disease. Combined, these results unveil a novel stromal PTEN-to-JAGGED-1 axis in maintaining the MaSC niche, and subsequently inhibiting breast cancer initiation and disease progression.
- Published
- 2017
- Full Text
- View/download PDF
3. E2f3 in tumor macrophages promotes lung metastasis.
- Author
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Trikha P, Sharma N, Pena C, Reyes A, Pécot T, Khurshid S, Rawahneh M, Moffitt J, Stephens JA, Fernandez SA, Ostrowski MC, and Leone G
- Subjects
- Animals, Cell Adhesion genetics, Cell Line, Tumor, Cell Movement genetics, Cell Proliferation genetics, Cell Survival genetics, E2F3 Transcription Factor genetics, Female, Gene Expression Regulation, Neoplastic, Humans, Kaplan-Meier Estimate, Lung metabolism, Lung pathology, Lung Neoplasms genetics, Lung Neoplasms secondary, Mammary Neoplasms, Experimental genetics, Mammary Neoplasms, Experimental pathology, Mice, Knockout, Tumor Microenvironment genetics, E2F3 Transcription Factor metabolism, Lung Neoplasms metabolism, Macrophages metabolism, Mammary Neoplasms, Experimental metabolism
- Abstract
The Rb-E2F axis is an important pathway involved in cell-cycle control that is deregulated in a number of cancers. E2f transcription factors have distinct roles in the control of cell proliferation, cell survival and differentiation in a variety of tissues. We have previously shown that E2fs are important downstream targets of a CSF-1 signaling cascade involved in myeloid development. In cancer, tumor-associated macrophages (TAMs) are recruited to the tumor stroma in response to cytokines secreted by tumor cells, and are believed to facilitate tumor cell invasion and metastasis. Using the MMTV-Polyoma Middle T antigen (PyMT) mouse model of human ductal carcinoma, we show that the specific ablation of E2f3 in TAMs, but not in tumor epithelial cells, attenuates lung metastasis without affecting primary tumor growth. Histological analysis and gene expression profiling suggest that E2f3 does not impact the proliferation or survival of TAMs, but rather controls a novel gene expression signature associated with cytoskeleton rearrangements, cell migration and adhesion. This E2f3 TAM gene expression signature was sufficient to predict cancer recurrence and overall survival of estrogen receptor (ER)-positive breast cancer patients. Interestingly, we find that E2f3b but not E2f3a levels are elevated in TAMs from PyMT mammary glands relative to controls, suggesting a differential role for these isoforms in metastasis. In summary, these findings identify E2f3 as a key transcription factor in TAMs, which influences the tumor microenvironment and tumor cell metastasis.
- Published
- 2016
- Full Text
- View/download PDF
4. CSF1-ETS2-induced microRNA in myeloid cells promote metastatic tumor growth.
- Author
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Mathsyaraja H, Thies K, Taffany DA, Deighan C, Liu T, Yu L, Fernandez SA, Shapiro C, Otero J, Timmers C, Lustberg MB, Chalmers J, Leone G, and Ostrowski MC
- Subjects
- Animals, Breast Neoplasms blood supply, Breast Neoplasms metabolism, Cell Line, Tumor, Cell Proliferation, Female, Humans, Macrophage Colony-Stimulating Factor metabolism, Melanoma, Experimental metabolism, Melanoma, Experimental pathology, Melanoma, Experimental secondary, Mice, Mice, Inbred C57BL, Neovascularization, Pathologic genetics, Proto-Oncogene Protein c-ets-2 metabolism, Signal Transduction, Breast Neoplasms genetics, Breast Neoplasms pathology, Macrophages metabolism, Melanoma, Experimental genetics, MicroRNAs genetics
- Abstract
Metastasis of solid tumors is associated with poor prognosis and bleak survival rates. Tumor-infiltrating myeloid cells (TIMs) are known to promote metastasis, but the mechanisms underlying their collaboration with tumor cells remain unknown. Here, we report an oncogenic role for microRNA (miR) in driving M2 reprogramming in TIMs, characterized by the acquisition of pro-tumor and pro-angiogenic properties. The expression of miR-21, miR-29a, miR-142-3p and miR-223 increased in myeloid cells during tumor progression in mouse models of breast cancer and melanoma metastasis. Further, we show that these miRs are regulated by the CSF1-ETS2 pathway in macrophages. A loss-of-function approach utilizing selective depletion of the miR-processing enzyme Dicer in mature myeloid cells blocks angiogenesis and metastatic tumor growth. Ectopic expression of miR-21 and miR-29a promotes angiogenesis and tumor cell proliferation through the downregulation of anti-angiogenic genes such as Col4a2, Spry1 and Timp3, whereas knockdown of the miRs impedes these processes. miR-21 and miR-29a are expressed in Csf1r+ myeloid cells associated with human metastatic breast cancer, and levels of these miRs in CD115+ non-classical monocytes correlates with metastatic tumor burden in patients. Taken together, our results suggest that miR-21 and miR-29a are essential for the pro-tumor functions of myeloid cells and the CSF1-ETS2 pathway upstream of the miRs serves as an attractive therapeutic target for the inhibition of M2 remodeling of macrophages during malignancy. In addition, miR-21 and miR-29a in circulating myeloid cells may potentially serve as biomarkers to measure therapeutic efficacy of targeted therapies for CSF1 signaling.
- Published
- 2015
- Full Text
- View/download PDF
5. Selective roles of E2Fs for ErbB2- and Myc-mediated mammary tumorigenesis.
- Author
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Wu L, de Bruin A, Wang H, Simmons T, Cleghorn W, Goldenberg LE, Sites E, Sandy A, Trimboli A, Fernandez SA, Eng C, Shapiro C, and Leone G
- Subjects
- Alleles, Animals, Breast Neoplasms metabolism, Carcinogenesis, Cell Proliferation, Female, Gene Deletion, Humans, Mammary Neoplasms, Experimental metabolism, Mice, Phosphorylation, Signal Transduction, E2F1 Transcription Factor metabolism, E2F2 Transcription Factor metabolism, E2F3 Transcription Factor metabolism, Mammary Neoplasms, Animal metabolism, Proto-Oncogene Proteins c-myc metabolism, Receptor, ErbB-2 metabolism
- Abstract
Previous studies have demonstrated that cyclin D1, an upstream regulator of the Rb/E2F pathway, is an essential component of the ErbB2/Ras (but not the Wnt/Myc) oncogenic pathway in the mammary epithelium. However, the role of specific E2fs for ErbB2/Ras-mediated mammary tumorigenesis remains unknown. Here, we show that in the majority of mouse and human primary mammary carcinomas with ErbB2/HER2 overexpression, E2f3a is up-regulated, raising the possibility that E2F3a is a critical effector of the ErbB2 oncogenic signaling pathway in the mammary gland. We examined the consequence of ablating individual E2fs in mice on ErbB2-triggered mammary tumorigenesis in comparison to a comparable Myc-driven mammary tumor model. We found that loss of E2f1 or E2f3 led to a significant delay in tumor onset in both oncogenic models, whereas loss of E2f2 accelerated mammary tumorigenesis driven by Myc-overexpression. Furthermore, southern blot analysis of final tumors derived from conditionally deleted E2f3(-/loxP) mammary glands revealed that there is a selection against E2f3(-/-) cells from developing mammary carcinomas, and that such selection pressure is higher in the presence of ErbB2 activation than in the presence of Myc activation. Taken together, our data suggest oncogenic activities of E2F1 and E2F3 in ErbB2- or Myc-triggered mammary tumorigenesis, and a tumor suppressor role of E2F2 in Myc-mediated mammary tumorigenesis.
- Published
- 2015
- Full Text
- View/download PDF
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