Regular article
Tumorigenesis and neoplastic progression
Caveolin-1 and Accelerated Host Aging in the Breast Tumor Microenvironment: Chemoprevention with Rapamycin, an mTOR Inhibitor and Anti-Aging Drug

https://doi.org/10.1016/j.ajpath.2012.03.017Get rights and content
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Increasing 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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Supported by grants from the NIH/National Cancer Institute (R01-CA-80250, R01-CA-098779, and R01-CA-120876 to M.P.L.), the American Association for Cancer Research (M.P.L), the Department of Defense–Breast Cancer Research Program (Synergistic Idea Award) (M.P.L.), a grant from the Pennsylvania Department of Health (M.P.L.), a postdoctoral fellowship from the Susan G. Komen Breast Cancer Foundation (I.M.), and a career catalyst award from the Susan G. Komen Breast Cancer Foundation (J.-F.J.).

The Pennsylvania Department of Health disclaims responsibility for any analyses, interpretations, or conclusions.

A guest editor acted as editor-in-chief for this manuscript. No person at Thomas Jefferson University or Albert Einstein College of Medicine was involved in the peer review process or final disposition for this article.