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.