Caveolin-1 and Accelerated Host Aging in the Breast Tumor Microenvironment: Chemoprevention With Rapamycin, an mTOR Inhibitor and Anti-Aging Drug

Am J Pathol. 2012 Jul;181(1):278-93. doi: 10.1016/j.ajpath.2012.03.017. Epub 2012 Jun 13.


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).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aging / physiology*
  • Animals
  • Anticarcinogenic Agents / therapeutic use*
  • Caveolin 1 / deficiency
  • Caveolin 1 / physiology*
  • Female
  • Mammary Neoplasms, Animal / blood supply
  • Mammary Neoplasms, Animal / pathology
  • Mammary Neoplasms, Animal / physiopathology
  • Mammary Neoplasms, Animal / prevention & control*
  • Mice
  • Mice, Knockout
  • Neoplasm Transplantation
  • Neovascularization, Pathologic / metabolism
  • Ovariectomy
  • Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
  • Signal Transduction / physiology
  • Sirolimus / therapeutic use*
  • Stromal Cells / pathology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • Tumor Microenvironment / physiology
  • Xenograft Model Antitumor Assays


  • Anticarcinogenic Agents
  • Caveolin 1
  • Platelet Endothelial Cell Adhesion Molecule-1
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Sirolimus