Ph.D., University of Texas-Houston MD Anderson Cancer Center, 2002

Our laboratory is interested in studying the role of FGF family growth factors and their receptors in regulating the normal development of mammary gland and how aberrant regulation of FGF ligands and their receptors is associated with breast cancer using mice as a model system. In mammals, the FGFs constitute a large family of more than 20 structurally homologous ligands, which transduce signals through a class of cell-surface tyrosine kinase receptors. The FGF receptors are encoded by four genes (FGFR1 to FGFR4) that give rise to seven prototype receptors because of alternative splicing. Upon binding of the ligand, FGF receptors homodimerize or heterodimerize to activate various intracellular signaling pathways. FGFs have been identified as oncogenes in murine mammary cancer and FGF receptor genes have been reported to be amplified in some human breast cancers (Theillet et al., 1993; Adnane et al., 1991). Our laboratory has successfully developed a novel, FGF-independent, drug-inducible model of mammary gland tumorigenesis to study the role of FGF receptors in breast cancer. The study of FGFR1 signaling using this inducible model indicated that acute FGFR1 activation resulted in loss of cell polarity and increased lateral budding in the mammary ductal epithelium, and that sustained activation induced alveolar hyperplasia, increased angiogenesis and invasive lesions (Welm et al., 2002). We hypothesize that normal mammary gland development is regulated by paracrine interactions of FGFs, such as FGF10, which are expressed in the stroma and activate signal transduction pathways important for branching morphogenesis and differentiation regulated by FGFR2 expressed on the mammary epithelium. One of the early steps in the breast cancer progression is a switch to an autocrine regulatory pathway in which FGFR1 is overexpressed in the mammary epithelium leading to an early loss in cell polarity, increased proliferation and cell survival and possibly activated by FGFs, such as FGF2 expressed in the epithelium. The ectopically expression of FGFR1 may also results in unregulated heterodimerization between FGFR1 and FGFR2 leading to tumorigenesis. This hypothesis predicts that there will be unique downstream signal transduction pathways activated by FGFR1 and FGFR2 homodimers, as well as FGFR1/2 heterodimers that cause distinct biological and pathological responses. To study the role of FGFR1 and FGFR2 heterodimer in mouse mammary gland normal development and tumorigenesis, we are in the process of establishing and characterizing an inducible FGFR1 and FGFR2 heterodimerization system in mammary epithelial cells and a transgenic mouse model. To identify the downstream effectors of FGFR1 and FGFR2 heterodimer, we will employ gene array analysis to screen for potential gene targets of FGFR1 and FGFR2 heterodimer signaling during tumor progression in mammary glands from the iFGFR1/R2 transgenic mice. We believe that a better understanding of these FGF regulated signaling pathways should help contribute to our understanding of breast cancer initiation and progression and may provide new targets for designing rational therapies targeting these pathways.

Schwertfeger K, Xian W, Burnett SH, Kaplan AM, Cohen DA, and Rosen JM
A Critical Role for the Inflammatory Response in a Mouse Model of Breast Cancer Progression.
Cancer Res. 2006; 66: (11) 5676-5685. [PDF] [Supp. Fig] [Sup. Table 1] [Sup. Table 2]

Kabotyanski EB, Hutter M, Xian W, Rijnkels M, and Rosen JM
Integration of prolactin and glucocorticoid signaling at the B-casein promoter and enhancer by ordered
recruitment of specific transcription factors and chromatin modifiers
Mol Endo. 2006; in press.

Behbod F, Xian W, Shaw CA, Hilsenbeck SG, Tsimelzon A and Rosen JM.
Transcriptional Profiling of Mammary Gland Side Population Cells
Stem Cells, 2006 [PDF] [Supp. Fig]

Xian W, Schwertfeger KL, Vargo-Gogola T, Rosen JM.
Pleiotropic effects of FGFR1 on cell proliferation, survival and migration in a 3D mammary epithelial cell model
J Cell Biol, 2005 Nov 21; 171(4): 663-673 [PDF]