title: Leptin mediates tumor-stromal interactions that promote the invasive growth of breast cancer cells.
abstract: Obesity confers risks to cancer development and progression but the mechanisms underlying these risks remain unclear. In this study, we identify a role for the obesity cytokine leptin, which has been implicated previously in breast cancer development, as a determinant for the tumor-promoting activity of cancer-associated fibroblasts (CAF) in both wild-type (WT) and K303R mutant estrogen receptor-α (ERα)-expressing breast cancer cells. Human CAFs stimulated a greater increase in the proliferation and migration of breast cancer cells expressing the K303R-ERα hyperactive receptor than WT-ERα-expressing cells. A concomitant increase was seen in leptin receptor isoform expression and activation of the leptin signaling pathway in cells expressing K303R-ERα compared with WT-ERα, correlating with leptin effects on cell growth, motility, and invasiveness in mutant cells. Epidermal growth factor and other factors secreted by K303R-ERα cells stimulated CAF proliferation, migration, and subsequent leptin secretion. Moreover, K303R-ERα expression generated a leptin hypersensitive phenotype in vivo. Together, our results reveal a bidirectional cross-talk between breast cancer cells and "educated" CAFs that drives tumor progression via leptin signaling. In elucidating a mechanism that connects obesity and cancer, these findings reinforce the concept that blocking cancer-stromal cell communication may represent an effective strategy for targeted therapy of breast cancer.
authors.affiliation: Centro Sanitario, University of Calabria, Rende, Italy.
authors.forename: Ines
authors.initials: I
authors.lastname: Barone
authors.forename: Stefania
authors.initials: S
authors.lastname: Catalano
authors.forename: Luca
authors.initials: L
authors.lastname: Gelsomino
authors.forename: Stefania
authors.initials: S
authors.lastname: Marsico
authors.forename: Cinzia
authors.initials: C
authors.lastname: Giordano
authors.forename: Salvatore
authors.initials: S
authors.lastname: Panza
authors.forename: Daniela
authors.initials: D
authors.lastname: Bonofiglio
authors.forename: Gianluca
authors.initials: G
authors.lastname: Bossi
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Covington
authors.forename: Suzanne A W
authors.initials: SA
authors.lastname: Fuqua
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Andò
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology*; D002277:Carcinoma / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004815:Epidermal Growth Factor / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000032:analysis; D005260:Female; D005347:Fibroblasts / Q000502:physiology; D020869:Gene Expression Profiling; D006801:Humans; D020738:Leptin / Q000502:physiology*; D009361:Neoplasm Invasiveness; D054411:Receptors, Leptin / Q000032:analysis; D015398:Signal Transduction; D017154:Stromal Cells / Q000502:physiology
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D020738:Leptin; D054411:Receptors, Leptin; D004815:Epidermal Growth Factor