Leptin regulates cyclin D1 in luminal epithelial cells of mouse MMTV-Wnt-1 mammary tumors

J Cancer Res Clin Oncol. 2012 Sep;138(9):1607-12. doi: 10.1007/s00432-012-1252-9. Epub 2012 Jun 13.

Abstract

Purpose: Leptin, an adipose secreted cytokine, is implicated in mammary cancer stem cell self-renewal and tumor growth in murine mammary tumor virus (MMTV)-Wnt-1 transgenic mice. In vitro studies indicate that leptin induces expression of cyclin D1, a cell-cycle control protein necessary for mammary tumor development. The aim of the present study was to assess cyclin D1 expression in spontaneous tumors that develop in the MMTV-Wnt-1 transgenic mice and interrogate the in vivo effect of leptin.

Materials and methods: Cells derived from spontaneous MMTV-Wnt-1 tumors were orthotopically transplanted into wild-type, leptin-deficient, and hyperleptinemic mice. After 6 weeks, tumors were collected and formalin fixed. Immunoflurescence staining was used to assess cyclin D1, keratin 8, α-SMA, phospho-AKT expression.

Results: Cyclin D1 is expressed exclusively in luminal keratin 8 immunoreactive tumor cells and is dependent on the adipose secreted hormone leptin. Tumor cell transplant into leptin-deficient mice resulted in approximately an 80 % reduction of cyclin D1 immunoreactivity in keratin 8 luminal epithelial cells, and this was independent of Akt activation.

Conclusions: These data and our previous findings indicate that inhibition of leptin signaling provides an excellent therapeutic target for breast cancer. The current data indicate that in luminal mammary tumors, leptin antagonists would potentially inhibit growth in a cyclin D1-dependent mechanism. In contrast, in basal mammary tumors, leptin antagonists would inhibit growth in an Akt-dependent manner leading to reduction in cancer stem cell self-renewal. Thus, leptin therapeutics may inhibit breast cancer via distinct mechanisms related to tumor type.

Publication types

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

MeSH terms

  • Actins / metabolism
  • Animals
  • Cyclin D1 / metabolism*
  • Epithelial Cells / metabolism*
  • Female
  • Fluorescent Antibody Technique
  • Keratin-8 / metabolism
  • Leptin / deficiency
  • Leptin / genetics
  • Leptin / physiology*
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / metabolism*
  • Mammary Tumor Virus, Mouse / genetics
  • Mammary Tumor Virus, Mouse / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Muscle, Smooth / chemistry
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / physiology
  • Wnt1 Protein / genetics
  • Wnt1 Protein / metabolism

Substances

  • Actins
  • Keratin-8
  • Leptin
  • Wnt1 Protein
  • Cyclin D1
  • Proto-Oncogene Proteins c-akt