Mammary epithelial cells are embedded in a unique extracellular environment to which adipocytes and other stromal cells contribute. Mammary epithelial cells are critically dependent on this milieu for survival. However, it remains unknown which adipocyte-secreted factors are required for the survival of the mammary epithelia and what role these adipokines play in the process of ductal carcinoma tumorigenesis. Here, we take a systematic molecular approach to investigate the multiple ways adipocytes and adipokines can uniquely influence the characteristics and phenotypic behavior of malignant breast ductal epithelial cells. Microarray analysis and luciferase reporter assays indicate that adipokines specifically induce several transcriptional programs involved in promoting tumorigenesis, including increased cell proliferation (IGF2, FOS, JUN, cyclin D1), invasive potential (MMP1, ATF3), survival (A20, NFκB), and angiogenesis. One of the key changes in the transformed ductal epithelial cells associated with the cell cycle involves the induction of NFκB (five-fold) and cyclin D1 (three-fold). We show that by regulating the transcription of these molecules, the synergistic activity of adipocyte-derived factors can potentiate MCF-7 cell proliferation. Furthermore, compared to other stromal cell-secreted factors, the full complement of adipokines shows an unparalleled ability to promote increased cell motility, migration, and the capacity for angiogenesis. Adipocyte-secreted factors can affect tumorigenesis by increasing the stabilization of pro-oncogenic factors such as β-catenin and CDK6 as a result of a reduction in the gene expression of their inhibitors (ie p18). An in vivo coinjection system using 3T3-L1 adipocytes and SUM159PT cells effectively recapitulates the host–tumor interactions in primary tumors. Type VI collagen, a soluble extracellular matrix protein abundantly expressed in adipocytes, is further upregulated in adipocytes during tumorigenesis. It promotes GSK3β phosphorylation, β-catenin stabilization, and increased β-catenin activity in breast cancer cells and may critically contribute towards tumorigenesis when not counterbalanced by other factors.