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  • 1
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    Abstract 2301: Epigenetic regulation of microRNA-200a and 141 by proto-oncogene PELP1: Role in breast cancer progression and metastasis
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 8_Supplement ( 2012-04-15), p. 2301-2301
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 2301-2301
    Abstract: Endocrine therapy is a key component of adjuvant therapy for estrogen receptor (ER)-positive breast cancer. However, initial or acquired resistance frequently occurs and tumor recurs as advanced metastatic disease. Accumulating evidence suggests that ER-coregulators play an essential role in cancer progression. Metastatic tumors exhibit increased expression of coregulators and their deregulation occurs in both ER+ve and ER-ve tumors. Proline glutamic acid rich protein (PELP1) is an ER coregulator, its expression is upregulated during breast cancer progression to metastasis and PELP1 is an independent prognostic predictor of shorter breast cancer specific survival. The objective of this study is to examine the mechanism and significance of PELP1 regulation of microRNAs and its effect on breast cancer metastasis. We have used both ER+ve (ZR75, MCF7) and ER-ve (MDAMB231) models that either stably overexpress PELP1 or PELP1shRNA. Boyden chamber, wound healing, and invasion assays demonstrated that PELP1 down regulation significantly affect migration of both ER+ve and ER-ve cells. Epithelial to Mesenchymal Transition (EMT) real time qPCR Array (Super array) studies identified PELP1 modulate expression of eight genes involved in the EMT (including Snail, Twist, ZEB1, ZEB2, Vimentin and MMPs). In xenograft assays, overexpression of PELP1 in non-metastatic ZR75, MCF7 cells increased their propensity for metastasis in vivo, while PELP1 knockdown in metastatic MDAMB231 model cells decreased in vivo metastasis. Mechanistic studies using whole genome microRNA array analysis using PELP1 model cells revealed that miR200a and miR141 were significantly upregulated in cells expressing PELP1-shRNA compared to control shRNA expressing cells. Accordingly, over expression of PELP1 in low metastatic model cells decreased expression of miR200a and miR141. Chromatin immunoprecipitation (ChIP) analysis revealed recruitment of PELP1 to the proximal promoter region of miR-200a and miR141. Mechanistic studies showed PELP1 down regulate expression of metastasis suppressive microRNAs (miR200a and miR141) by promoting repressive chromatin modifications via its association with HDAC2. Accordingly, HDAC inhibitors reversed PELP1 driven repressive effects. Further, ectopic expression of miR200a and miR141 mimetics decreased PELP1 mediated metastatic functions. Collectively, these findings demonstrate for the first time a previously unknown role for PELP1 in the epigenetic control of miR-200a and miR141. These results reveal that PELP1 play a role in breast cancer metastasis by promoting cell motility / EMT by modulating miRNA expression. Understanding how proto-oncogene PELP1 plays a role in metastasis will be useful in maximizing treatment opportunities for metastatic breast cancer. This study is funded by T32CA148724 NIH Postdoctoral Fellowship Grant. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2301. doi:1538-7445.AM2012-2301
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2012-2301
    RVK:
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    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 2
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    Significance of PELP1 in ER-Negative Breast Cancer Metastasis
    American Association for Cancer Research (AACR) ; 2012
    In:  Molecular Cancer Research Vol. 10, No. 1 ( 2012-01-01), p. 25-33
    Details
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 10, No. 1 ( 2012-01-01), p. 25-33
    Abstract: Breast cancer metastasis is a major clinical problem. The molecular basis of breast cancer progression to metastasis remains poorly understood. PELP1 is an estrogen receptor (ER) coregulator that has been implicated as a proto-oncogene whose expression is deregulated in metastatic breast tumors and whose expression is retained in ER-negative tumors. We examined the mechanism and significance of PELP1-mediated signaling in ER-negative breast cancer progression using two ER-negative model cells (MDA-MB-231 and 4T1 cells) that stably express PELP1-shRNA. These model cells had reduced PELP1 expression (75% of endogenous levels) and exhibited less propensity to proliferate in growth assays in vitro. PELP1 downregulation substantially affected migration of ER-negative cells in Boyden chamber and invasion assays. Using mechanistic studies, we found that PELP1 modulated expression of several genes involved in the epithelial mesenchymal transition (EMT), including MMPs, SNAIL, TWIST, and ZEB. In addition, PELP1 knockdown reduced the in vivo metastatic potential of ER-negative breast cancer cells and significantly reduced lung metastatic nodules in a xenograft assay. These results implicate PELP1 as having a role in ER-negative breast cancer metastasis, reveal novel mechanism of coregulator regulation of metastasis via promoting cell motility/EMT by modulating expression of genes, and suggest PELP1 may be a potential therapeutic target for metastatic ER-negative breast cancer. Mol Cancer Res; 10(1); 25–33. ©2011 AACR.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    URL: Article
    DOI: 10.1158/1541-7786.MCR-11-0456
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 3
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    Abstract B106: Role of TGF-beta superfamily ligand and estrogen signaling in mediating osteoblastic tumorigenesis of prostate cancer cells.
    American Association for Cancer Research (AACR) ; 2011
    In:  Molecular Cancer Therapeutics Vol. 10, No. 11_Supplement ( 2011-11-12), p. B106-B106
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 10, No. 11_Supplement ( 2011-11-12), p. B106-B106
    Abstract: Prostate cancer metastasizes to bone in 80% of patients suffering from advanced disease. The nature of bone lesions is predominantly osteoblastic resulting in severe bone pain, hypocalcemia and nerve compression syndromes. Transforming growth factor-beta (TGFβ), which is a multifunctional cytokine, is a critical regulator of osteogenesis. Our group has recently shown that TGFβ signaling helps in promoting osteoblastic metastasis by a novel human prostate cancer cell line, PacMetUT1. TGFβ has been suggested to be one of the physiological upregulatory factors of bone aromatase in human osteoblast-like cells. Recent data further implicates an aberrant aromatase expression and estrogen signaling in the development of prostate malignancy. However, the effect of TGFβ superfamily ligands on aromatase expression and estrogen production and the mechanism by which osteoblastic lesions are formed have not been intensively investigated in prostate cancer cells. We hypothesize that TGFβ and other growth factors released from tumor cells can induce aromatase gene expression and activity in bone cells leading to an enhanced estradiol synthesis which would in turn lead to an increase in bone formation as estrogen is a known osteogenic factor. We examined the effect of TGFβ and BMP-4/7 on aromatase expression and osteogenic differentiation of pre-osteoblastic cells in vitro. Treatment with TGFβ 1 and BMP-4/7 resulted in an increase in aromatase expression in both mouse pre-osteoblasts and human bone marrow-derived mesenchymal stem cells. Treatment with letrozole (aromatase inhibitor) as well as an anti-estrogen (ICI 182, 780) resulted in a decrease in osteoblastic differentiation of mesenchymal stem cells as measured by alkaline phosphatase activity assay and expression of osteogenic markers by quantitative real-time PCR analysis. Furthermore, 17-β estradiol treatment of PacMetUT1 cells resulted in an enhanced anchorage-dependent and independent cell growth in vitro. This effect was very significantly inhibited by tamoxifen treatment, which is a selective estrogen receptor modulator. 17-β estradiol also induced a change in cell morphology of PacMetUT1 cells with a reduction in E-cadherin expression. Our results demonstrate an aromatase-mediated induction in osteogenesis by TGFβ superfamily ligands in the pre-osteoblastic cells and a stimulatory effect of estrogen signaling on PacMetUT1 cell tumorigencity in vitro. Future studies will delineate whether the induction of aromatase mediates osteoblastic bone metastasis of prostate cancer cells in vivo and if combination treatment of TGFβ and aromatase inhibitors can be used as a novel therapeutic strategy, to alleviate bone metastasis in prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B106.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-11-B106
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 4
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    Abstract 3968: Mutation and phosphorylation of p53 may switch TGF-beta from a tumor suppressor to a tumor promoter
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 3968-3968
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 3968-3968
    Abstract: Transforming growth factor-β (TGF-β) is a tumor suppressor during early tumor outgrowth, but becomes a tumor promoter at later stages by enhancing tumor cell motility, invasion and metastasis. Therefore, anti-TGF-β cancer therapy should exercise great caution due to the dual nature of the TGF-β signaling. However, it is still unclear when the TGF-β inhibitor should be applied to abrogate the tumor-promoting activity of TGF-β signaling. Thus, studies aiming to unravel key mechanisms by which TGF-β signaling is switched from tumor suppressor to tumor promoter will greatly benefit the design of efficient clinical treatment of cancer with TGF-β inhibitors. Recently, it was reported that the oncogenic activity of TGF-β in the MDA-MB-231 breast cancer cells was due to the presence of the mutant p53. TGF-β-induced cell migration and metastasis were enhanced by the sequestration of the tumor suppressor p63 into a ternary complex containing the mutant p53 and the intracellular TGF-β signaling mediators Smad2/3. The phosphorylation of mutant p53 at Ser6/Ser9 by Ras/MAPK signaling was essential for the formation of the ternary complex and appeared to be a crucial hallmark for the switch of TGF-β to be a tumor promoter. To better understand the molecular mechanism driving the switch of TGF-β pathway to become a tumor promoter, we performed a study using spontaneously immortalized and non-tumorigenic human mammary epithelial MCF-10A cell line (10A). We found that ectopic expression of both oncogenic H-RasV12 and mutant p53 (R175H) in 10A enhanced phosphorylation of p53 (P-p53) at Ser6/9 and TGF-β-induced formation of p53/P-Smad2 complex. Additionally, the cellular migration of those transformed 10A was more sensitive to TGF-β when compared with 10A expressing H-RasV12 alone. These results indicate that mutant p53 may induce TGF-β to become a tumor promoter in our model derived from 10A. Notably, we found there might be a PI3K/AKT signaling-dependent fashion for the switch of TGF-β to become a tumor promoter as 10A with ectopic expression of Simian virus 40 T antigens also expressed a high level of P-p53 at Ser6/9 with active PI3K/AKT signaling in contrast to active MAPK signaling. Furthermore, the level of P-p53 at Ser9 was elevated in the 10A and the p53-null PC-3 prostate cancer cells with ectopic expression of both constitutively active AKT (*AKT) and mutant p53 R175H. Importantly, TGF-β-induced interaction among p63, p53 R175H and P-Smad2 was significantly increased in the absence of a strong MAPK signaling activity in those transformed cells. Taken together, our studies may provide a novel mechanism for switching TGF-β to play the oncogenic role. In addition, we can use the model systems with key molecular alterations such as mutant p53 together with oncogenic Ras or *AKT to test the efficacy of TGF-β inhibitors as a novel cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3968.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-3968
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 5
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    Abstract 542: TGF-β inhibitors enhance chemotherapeutic efficacy via abrogation of autocrine and paracrine signaling in a triple negative breast cancer model
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 542-542
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 542-542
    Abstract: Triple negative breast cancer (TNBC) accounts for approximately 15-20% of total invasive breast cancers. This subtype of cancer is often correlated with poor prognosis, visceral metastases and relapse. Molecular characterization reveals that these tumors are negative for hormone receptors and they often develop chemo resistance. Tumor microenvironment, among other factors, has emerged as a definite player in the progression of breast cancer and may also confer chemo resistance. In the current study, we demonstrate that MDA-MB-231 cells show greater resistance to paclitaxel in heterotypic culture with RMF/EG-hTERT (reduction mammary fibroblast with enhanced GFP) as compared to homotypic culture. Further, we show that RMF/EG-hTERT cells can enhance the motility of MDA-MB-231 cells in trans well migration assays, which could be attenuated by the TGF-β inhibitor sRIII (soluble receptor type III). TGF-β signaling was shown to activate pro-survival pathways like PI3K/Akt and MAPK/ERK pathways in mammary fibroblasts suggesting that they may mediate the paracrine tumor-promoting activity of TGF-β. Autocrine TGF-β signaling has been shown to promote EMT and cancer stem cell-like features in TNBC cells and appears to be a potential therapeutic target. We show that paclitaxel in combination with sRIII was more effective in inhibiting the growth of MDA-MB-231 cells than either agent alone. The combination of a TGF-β inhibitor with paclitaxel was also more effective in inhibiting tumor sphere formation than either agent alone. Our future research will be focused on the mechanisms of autocrine and paracrine TGF-β signaling in mediating chemo resistance and the tumor-promoting activity of mammary stromal cells. Our research will reveal the potential use of TGF-β inhibitors as novel therapeutics in combination with chemotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 542. doi:10.1158/1538-7445.AM2011-542
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-542
    RVK:
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    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 6
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    384 REDUCED EXPRESSION OF FUMARATE HYDRATASE IN CLEAR CELL RENAL CANCER PROMOTES HIF-2α ACCUMULATION, MIGRATION AND INVASION
    Ovid Technologies (Wolters Kluwer Health) ; 2011
    In:  Journal of Urology Vol. 185, No. 4S ( 2011-04)
    Details
    In: Journal of Urology, Ovid Technologies (Wolters Kluwer Health), Vol. 185, No. 4S ( 2011-04)
    Type of Medium: Online Resource
    ISSN: 0022-5347 , 1527-3792
    URL: Article
    DOI: 10.1016/j.juro.2011.02.472
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    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2011
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  • 7
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    Single‐cell analysis of circulating tumor cells identifies cumulative expression patterns of EMT‐related genes in metastatic prostate cancer
    Wiley ; 2013
    In:  The Prostate Vol. 73, No. 8 ( 2013-06), p. 813-826
    Details
    In: The Prostate, Wiley, Vol. 73, No. 8 ( 2013-06), p. 813-826
    Abstract: Prostate tumors shed circulating tumor cells (CTCs) into the blood stream. Increased evidence shows that CTCs are often present in metastatic prostate cancer and can be alternative sources for disease profiling and prognostication. Here we postulate that CTCs expressing genes related to epithelial–mesenchymal transition (EMT) are strong predictors of metastatic prostate cancer. METHODS A microfiltration system was used to trap CTCs from peripheral blood based on size selection of large epithelial‐like cells without CD45 leukocyte marker. These cells individually retrieved with a micromanipulator device were assessed for cell membrane physical properties using atomic force microscopy. Additionally, 38 CTCs from eight prostate cancer patients were used to determine expression profiles of 84 EMT‐related and reference genes using a microfluidics‐based PCR system. RESULTS Increased cell elasticity and membrane smoothness were found in CTCs compared to noncancerous cells, highlighting their potential invasiveness and mobility in the peripheral circulation. Despite heterogeneous expression patterns of individual CTCs, genes that promote mesenchymal transitioning into a more malignant state, including IGF1 , IGF2 , EGFR , FOXP3 , and TGFB3 , were commonly observed in these cells. An additional subset of EMT‐related genes (e.g., PTPRN2 , ALDH1 , ESR2 , and WNT5A ) were expressed in CTCs of castration‐resistant cancer, but less frequently in castration‐sensitive cancer. CONCLUSIONS The study suggests that an incremental expression of EMT‐related genes in CTCs is associated with metastatic castration‐resistant cancer. Although CTCs represent a group of highly heterogeneous cells, their unique EMT‐related gene signatures provide a new opportunity for personalized treatments with targeted inhibitors in advanced prostate cancer patients. Prostate 73: 813–826, 2013. © 2012 Wiley Periodicals, Inc.
    Type of Medium: Online Resource
    ISSN: 0270-4137 , 1097-0045
    URL: Issue
    URL: Article
    DOI: 10.1002/pros.v73.8
    DOI: 10.1002/pros.22625
    Language: English
    Publisher: Wiley
    Publication Date: 2013
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  • 8
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    TGF-β signalling is mediated by two autonomously functioning TβRI:TβRII pairs : TGF-β signals through autonomous TβRI:TβRII pairs
    Wiley ; 2011
    In:  The EMBO Journal Vol. 30, No. 7 ( 2011-04-06), p. 1263-1276
    Details
    In: The EMBO Journal, Wiley, Vol. 30, No. 7 ( 2011-04-06), p. 1263-1276
    Type of Medium: Online Resource
    ISSN: 0261-4189
    URL: Article
    DOI: 10.1038/emboj.2011.54
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    Language: English
    Publisher: Wiley
    Publication Date: 2011
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  • 9
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    Abstract LB-203: Aromatase expression promotes breast cancer tumorigenesis and bone metastasis
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. LB-203-LB-203
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. LB-203-LB-203
    Abstract: Aromatase P450 (CYP19) is the rate-limiting enzyme catalyzing the final step in estrogen biosynthesis, and an important target in breast cancer therapy. In post-menopausal women, ovaries cease to make estrogen, yet the incidence of breast cancer increases with age as aromatase present in breast adipose stroma and epithelium catalyzes local estrogen formation. The circulating estrogen level in postmenopausal women is very low and it reflects the sum of local estrogen biosynthesis in various sites. Although breast cancer cells have been shown to express aromatase prompting the hypothesis that intracrine action of estrogen in breast cancer cells may drive tumor progression, there has been little evidence in addressing the hypothesis. We stably transfected the ER positive (ER+) breast cancer ZR-75-1 cells with an human aromatase expression vector and obtained a few clones expressing a moderately higher level of aromatase in comparison with the control vector-transfected cells. One of the clones called ZR-75-1/Aro/Clone10 (Cl10) was selected for further study due to its increased intracellular estradiol (E2) concentration compared to other clones. The Cl10 cells formed tumors after being xenografted into the inguinal mammary fat pad of female athymic mice while the control cells were incapable of forming tumors without estrogen supplementation. Implantation of testosterone pellet further stimulated the growth of the tumor and a cell line, ZR-75-1/Aro/Clone10/TT1 (TT1) was established from the tumor. Both Cl10 and TT1 cells expressed similar levels of aromatase. Interestingly, the aromatase expression increased when the cells were cultured in suspension suggesting circulating ER+ breast cancer cells may up-regulate intracrine estrogen activity for survival after leaving the estrogen-rich adipose stroma at primary site. To investigate the importance of intracrine estrogen in promoting tumorigenesis and metastasis, we implanted the Cl10 and TT1 cells orthotopically and intracardiacally (I.C.) into female athymic mice. Notably, both cell lines generated orthotopic tumors with no estrogen supplementation after three weeks of inoculation. More interestingly, the mice with I.C. inoculated aromatase-expressing cells presented distant metastasis to bones in mandible and legs after two weeks of inoculation detected by whole mouse fluorescence and bioluminescence imaging as both cells were stably transfected with a luciferase and GFP expression vector. We will determine whether growth of the orthotopic tumors and bone metastases can be inhibited with systemic administration of an aromatase inhibitor and whether bone metastasis is osteoclastic or osteoblastic. Our studies show that a moderate expression of aromatase in breast cancer cells is sufficient to generate intracrine estrogenic action and promote tumorigenesis and skeletal metastasis in ER+ breast cancer cells. These aromatase-expressing models should be useful for future investigation on how ER+ breast cancer cells up-regulate aromatase expression in suspension and induces bone remodeling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-203.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-LB-203
    RVK:
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    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 10
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    Abstract 3469: Effect of age and mutagen on the enriched murine mammary epithelial stem and progenitor cell population
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 3469-3469
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 3469-3469
    Abstract: Epidemiological studies indicated that aging is a significant risk factor for breast cancer. Yet, there is insufficient knowledge on the mechanisms affecting breast cancer initiation and promotion in older women. Recent studies indicated epithelial stem/progenitor cell population, responsible for lifelong tissue maintenance and regeneration, as a target of transformation. It has been reported earlier by serial transplantation of murine mammary tissues that functional mammary outgrowths indicating stem cell function is unaffected by the age of the donor. But it is unclear that whether spontaneous or induced mutagenesis in the aging stem/progenitor cell population has the potential to impair stem/progenitor functions and/or to initiate tumorigenesis. In this study, first we have isolated lineage negative (CD31−CD45−Ter119−) mammary epithelial cells (Lin−MEC) from the thoracic/inguinal mammary glands of young (6 months, n=7) and old (28 months, n=6) mice by serial enzymatic dissociation followed by magnetic nanoparticle separation method (StemCell Technology). These cells were utilized to form mammospheres, representing mammary stem/early progenitor cells. Although the frequency of mammosphere formation remained the same, the number of larger mammospheres ( & gt;60µm) from old mice were significantly lower than the young mice, probably indicating decreased stem cell activity in the older population. To study the effect of mutagen in vivo, we treated two young and two old mice with methyl nitrosourea (MNU, 25mg/kg body weight) once a week for three consecutive weeks. Animals were sacrificed one week after the last treatment. Both total and larger mammospheres ( & gt;60µm) from the isolated Lin−MEC of the treated older mice were observed in significantly higher number than the treated younger mice. In a recent clinical study larger mammospheres ( & gt;50µm) obtained from metastatic breast cancer cells has been correlated to their ability to induce tumors. These Lin−MEC cells were also analyzed and compared for DNA damage by alkaline comet assay and a higher percentage of cells ( & gt;10%) with irreversible DNA damage in the older population were observed compared to younger population ( & lt;2%) indicating probable lower DNA repair capacity of the former cells. Thus, our preliminary study indicated that enriched stem/progenitor cells in the old mice with decreased in vitro stem cell activity might have the potential to be vulnerable to DNA damage by mutagens and subsequent tumorigenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3469.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-3469
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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