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dc.contributor.authorMercier, I
dc.contributor.authorCamacho, J
dc.contributor.authorTitchen, K
dc.contributor.authorGonzales, D
dc.contributor.authorQuann, K
dc.contributor.authorBryant, K
dc.contributor.authorMolchansky, A
dc.contributor.authorMilliman, J
dc.contributor.authorWhitaker-Menezes, D
dc.contributor.authorSotgia, Federica
dc.contributor.authorJasmin, J
dc.contributor.authorSchwarting, R
dc.contributor.authorPestell, R
dc.contributor.authorBlagosklonny, M
dc.contributor.authorLisanti, Michael P
dc.date.accessioned2012-12-05T18:05:39Z
dc.date.available2012-12-05T18:05:39Z
dc.date.issued2012-07
dc.identifier.citationCaveolin-1 and accelerated host aging in the breast tumor microenvironment: chemoprevention with rapamycin, an mTOR inhibitor and anti-aging drug. 2012, 181 (1):278-93 Am J Patholen_GB
dc.identifier.issn1525-2191
dc.identifier.pmid22698676
dc.identifier.doi10.1016/j.ajpath.2012.03.017
dc.identifier.urihttp://hdl.handle.net/10541/254652
dc.description.abstractIncreasing chronological age is the most significant risk factor for human cancer development. To examine the effects of host aging on mammary tumor growth, we used caveolin (Cav)-1 knockout mice as a bona fide model of accelerated host aging. Mammary tumor cells were orthotopically implanted into these distinct microenvironments (Cav-1(+/+) versus Cav-1(-/-) age-matched young female mice). Mammary tumors grown in a Cav-1-deficient tumor microenvironment have an increased stromal content, with vimentin-positive myofibroblasts (a marker associated with oxidative stress) that are also positive for S6-kinase activation (a marker associated with aging). Mammary tumors grown in a Cav-1-deficient tumor microenvironment were more than fivefold larger than tumors grown in a wild-type microenvironment. Thus, a Cav-1-deficient tumor microenvironment provides a fertile soil for breast cancer tumor growth. Interestingly, the mammary tumor-promoting effects of a Cav-1-deficient microenvironment were estrogen and progesterone independent. In this context, chemoprevention was achieved by using the mammalian target of rapamycin (mTOR) inhibitor and anti-aging drug, rapamycin. Systemic rapamycin treatment of mammary tumors grown in a Cav-1-deficient microenvironment significantly inhibited their tumor growth, decreased their stromal content, and reduced the levels of both vimentin and phospho-S6 in Cav-1-deficient cancer-associated fibroblasts. Since stromal loss of Cav-1 is a marker of a lethal tumor microenvironment in breast tumors, these high-risk patients might benefit from treatment with mTOR inhibitors, such as rapamycin or other rapamycin-related compounds (rapalogues).
dc.language.isoenen
dc.rightsArchived with thanks to The American journal of pathologyen_GB
dc.subject.meshAging
dc.subject.meshAnimals
dc.subject.meshAnticarcinogenic Agents
dc.subject.meshAntigens, CD31
dc.subject.meshCaveolin 1
dc.subject.meshFemale
dc.subject.meshMammary Neoplasms, Animal
dc.subject.meshMice
dc.subject.meshMice, Knockout
dc.subject.meshNeoplasm Transplantation
dc.subject.meshNeovascularization, Pathologic
dc.subject.meshOvariectomy
dc.subject.meshSignal Transduction
dc.subject.meshSirolimus
dc.subject.meshStromal Cells
dc.subject.meshTOR Serine-Threonine Kinases
dc.subject.meshTumor Microenvironment
dc.subject.meshXenograft Model Antitumor Assays
dc.titleCaveolin-1 and accelerated host aging in the breast tumor microenvironment: chemoprevention with rapamycin, an mTOR inhibitor and anti-aging drug.en
dc.typeArticleen
dc.contributor.departmentDepartment of Stem Cell Biology and Regenerative Medicine, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.en_GB
dc.identifier.journalAmerican Journal of Pathologyen_GB
html.description.abstractIncreasing chronological age is the most significant risk factor for human cancer development. To examine the effects of host aging on mammary tumor growth, we used caveolin (Cav)-1 knockout mice as a bona fide model of accelerated host aging. Mammary tumor cells were orthotopically implanted into these distinct microenvironments (Cav-1(+/+) versus Cav-1(-/-) age-matched young female mice). Mammary tumors grown in a Cav-1-deficient tumor microenvironment have an increased stromal content, with vimentin-positive myofibroblasts (a marker associated with oxidative stress) that are also positive for S6-kinase activation (a marker associated with aging). Mammary tumors grown in a Cav-1-deficient tumor microenvironment were more than fivefold larger than tumors grown in a wild-type microenvironment. Thus, a Cav-1-deficient tumor microenvironment provides a fertile soil for breast cancer tumor growth. Interestingly, the mammary tumor-promoting effects of a Cav-1-deficient microenvironment were estrogen and progesterone independent. In this context, chemoprevention was achieved by using the mammalian target of rapamycin (mTOR) inhibitor and anti-aging drug, rapamycin. Systemic rapamycin treatment of mammary tumors grown in a Cav-1-deficient microenvironment significantly inhibited their tumor growth, decreased their stromal content, and reduced the levels of both vimentin and phospho-S6 in Cav-1-deficient cancer-associated fibroblasts. Since stromal loss of Cav-1 is a marker of a lethal tumor microenvironment in breast tumors, these high-risk patients might benefit from treatment with mTOR inhibitors, such as rapamycin or other rapamycin-related compounds (rapalogues).


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