Leptin regulates cyclin D1 in luminal epithelial cells of mouse MMTV-Wnt-1 mammary tumors.
Summary of "Leptin regulates cyclin D1 in luminal epithelial cells of mouse MMTV-Wnt-1 mammary tumors."
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.
Affiliation
Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, NC10, Cleveland, OH, 44195, USA, zhengq@ccf.org.
Journal Details
This article was published in the following journal.
Name: Journal of cancer research and clinical oncology
ISSN: 1432-1335
Pages:
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/22692856
- DOI: http://dx.doi.org/10.1007/s00432-012-1252-9
Medical and Biotech [MESH] Definitions
Leptin
A 16-kDa peptide hormone secreted from WHITE ADIPOCYTES. Leptin serves as a feedback signal from fat cells to the CENTRAL NERVOUS SYSTEM in regulation of food intake, energy balance, and fat storage.
Cyclin-dependent Kinase Inhibitor P27
A cyclin-dependent kinase inhibitor that coordinates the activation of CYCLIN and CYCLIN-DEPENDENT KINASES during the CELL CYCLE. It interacts with active CYCLIN D complexed to CYCLIN-DEPENDENT KINASE 4 in proliferating cells, while in arrested cells it binds and inhibits CYCLIN E complexed to CYCLIN-DEPENDENT KINASE 2.
Receptors, Leptin
Cell surface receptors for obesity factor (LEPTIN), a hormone secreted by the WHITE ADIPOCYTES. Upon leptin-receptor interaction, the signal is mediated through the JAK2/STAT3 pathway to regulate food intake, energy balance and fat storage.
Cyclin G2
An unusual cyclin subtype that is found highly expressed in terminally differentiated cells. Unlike conventional cyclins increased expression of cyclin G2 is believed to cause a withdrawal of cells from the CELL CYCLE.
Enterocytes
Absorptive cells in the lining of the INTESTINAL MUCOSA. They are differentiated EPITHELIAL CELLS with apical MICROVILLI facing the intestinal lumen. Enterocytes are more abundant in the SMALL INTESTINE than in the LARGE INTESTINE. Their microvilli greatly increase the luminal surface area of the cell by 14- to 40 fold.
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