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dc.contributor.authorDumont, Nancy
dc.contributor.authorCrawford, Yongping
dc.contributor.authorSigaroudinia, Mahvash
dc.contributor.authorNagrani, Shefali
dc.contributor.authorWilson, Matthew
dc.contributor.authorBuehring, Gertrude
dc.contributor.authorTurashvili, Gulisa
dc.contributor.authorAparicio, Samuel
dc.contributor.authorGauthier, Mona
dc.contributor.authorFordyce, Colleen
dc.contributor.authorMcDermott, Kimberly
dc.contributor.authorTlsty, Thea
dc.date.accessioned2016-05-20T08:58:53Z
dc.date.available2016-05-20T08:58:53Z
dc.date.issued2009en
dc.identifier.citationBreast Cancer Research 2009, 11:R87 (doi:10.1186/bcr2457)en
dc.identifier.doi10.1186/bcr2457en
dc.identifier.urihttp://hdl.handle.net/10150/610113
dc.description.abstractINTRODUCTION:We have previously identified a rare subpopulation of variant human mammary epithelial cells (vHMEC) with repressed p16INK4A that exist in disease-free women yet display premalignant properties, suggesting that they have engaged the process of malignant transformation. In order to gain insight into the molecular alterations required for vHMEC to progress to malignancy, and to characterize the epigenetic events associated with early progression, we examined the effect of oncogenic stress on the behavior of these cells.METHODS:HMEC that express p16INK4A and vHMEC that do not, were transduced with constitutively active Ha-rasV12 and subsequently exposed to serum to determine whether signals from the cellular microenvironment could cooperate with ras to promote the malignant transformation of vHMEC. Epigenetic alterations were assessed using methylation-specific polymerase chain reaction (PCR).RESULTS:vHMEC expressing Ha-rasV12 (vHMEC-ras) bypassed the classic proliferative arrest that has been previously documented in normal fibroblasts following oncogenic stress, and that we also observe here in normal HMEC. Moreover, vHMEC-ras cells exhibited many additional alterations that are observed during progression to malignancy such as the generation of chromosomal abnormalities, upregulation of telomerase activity, immortalization following exposure to serum, and anchorage-independent growth, but they did not form tumors following orthotopic injection in vivo. Associated with their early progression to malignancy was an increase in the number of genes methylated, two of which (RASSF1A and SFRP1) were also methylated in other immortalized mammary cell lines as well as in breast cancer cells and tissues.CONCLUSIONS:We have characterized a mammary progression model that recapitulates molecular and methylation alterations observed in many breast cancers. Our data suggest that concomitant methylation of RASSF1A and SFRP1 marks an early event in mammary transformation and may thus have prognostic potential.
dc.language.isoenen
dc.publisherBioMed Centralen
dc.relation.urlhttp://breast-cancer-research.com/content/11/6/R87en
dc.rights© 2009 Dumont et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0)en
dc.titleHuman mammary cancer progression model recapitulates methylation events associated with breast premalignancyen
dc.typeArticleen
dc.identifier.eissn1465-542Xen
dc.contributor.departmentDepartment of Pathology and Comprehensive Cancer Center, University of California at San Francisco, 513 Parnassus Avenue, San Francisco, California, 94143-0511, USAen
dc.contributor.departmentDivision of Infectious Diseases and Vaccinology, School of Public Health, University of California at Berkeley, Berkeley, California, 94720-7354, USAen
dc.contributor.departmentDepartment of Molecular Oncology, B.C. Cancer Research Centre, 675 West 10th Avenue, Vancouver, British Columbia, V5Z 1L3, Canadaen
dc.contributor.departmentCurrent address: ES Cell Culture, Genentech, Inc. 1 DNA Way, South San Francisco, California, 94080, USAen
dc.contributor.departmentNational Science Foundation, 4201 Wilson Boulevard, Suite 1220, Arlington, Virginia, 22230, USAen
dc.contributor.departmentDepartment of Medical Biophysics, University of Toronto, Campbell Family Institute for Breast Cancer Research, 620 University Avenue, Toronto, Ontario, M5G 2C1, Canadaen
dc.contributor.departmentDepartment of Cell Biology and Anatomy, University of Arizona, 1515 Campbell Avenue, Tucson, Arizona, 85724, USAen
dc.identifier.journalBreast Cancer Researchen
dc.description.collectioninformationThis item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu.en
dc.eprint.versionFinal published versionen
refterms.dateFOA2018-08-15T07:04:10Z
html.description.abstractINTRODUCTION:We have previously identified a rare subpopulation of variant human mammary epithelial cells (vHMEC) with repressed p16INK4A that exist in disease-free women yet display premalignant properties, suggesting that they have engaged the process of malignant transformation. In order to gain insight into the molecular alterations required for vHMEC to progress to malignancy, and to characterize the epigenetic events associated with early progression, we examined the effect of oncogenic stress on the behavior of these cells.METHODS:HMEC that express p16INK4A and vHMEC that do not, were transduced with constitutively active Ha-rasV12 and subsequently exposed to serum to determine whether signals from the cellular microenvironment could cooperate with ras to promote the malignant transformation of vHMEC. Epigenetic alterations were assessed using methylation-specific polymerase chain reaction (PCR).RESULTS:vHMEC expressing Ha-rasV12 (vHMEC-ras) bypassed the classic proliferative arrest that has been previously documented in normal fibroblasts following oncogenic stress, and that we also observe here in normal HMEC. Moreover, vHMEC-ras cells exhibited many additional alterations that are observed during progression to malignancy such as the generation of chromosomal abnormalities, upregulation of telomerase activity, immortalization following exposure to serum, and anchorage-independent growth, but they did not form tumors following orthotopic injection in vivo. Associated with their early progression to malignancy was an increase in the number of genes methylated, two of which (RASSF1A and SFRP1) were also methylated in other immortalized mammary cell lines as well as in breast cancer cells and tissues.CONCLUSIONS:We have characterized a mammary progression model that recapitulates molecular and methylation alterations observed in many breast cancers. Our data suggest that concomitant methylation of RASSF1A and SFRP1 marks an early event in mammary transformation and may thus have prognostic potential.


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