title: Estrogen expands breast cancer stem-like cells through paracrine FGF/Tbx3 signaling.
abstract: Many tumors contain heterogeneous populations of cells, only some of which exhibit increased tumorigenicity and resistance to anticancer therapies. Evidence suggests that these aggressive cancer cells, often termed "cancer stem cells" or "cancer stem-like cells" (CSCs), rely upon developmental signaling pathways that are important for survival and expansion of normal stem cells. Here we report that, in analogy to embryonic mammary epithelial biology, estrogen signaling expands the pool of functional breast CSCs through a paracrine FGF/FGFR/Tbx3 signaling pathway. Estrogen or FGF9 pretreatment induced CSC properties of breast cancer cell lines and freshly isolated breast cancer cells, whereas cotreatment of cells with tamoxifen or a small molecule inhibitor of FGFR signaling was sufficient to prevent the estrogen-induced expansion of CSCs. Furthermore, reduction of FGFR or Tbx3 gene expression was able to abrogate tumorsphere formation, whereas ectopic Tbx3 expression increased tumor seeding potential by 100-fold. These findings demonstrate that breast CSCs are stimulated by estrogen through a signaling pathway that similarly controls normal mammary epithelial stem cell biology.
authors.affiliation: Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Fillmore
authors.forename: Piyush B
authors.initials: PB
authors.lastname: Gupta
authors.forename: Jenny A
authors.initials: JA
authors.lastname: Rudnick
authors.forename: Silvia
authors.initials: S
authors.lastname: Caballero
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Keller
authors.forename: Eric S
authors.initials: ES
authors.lastname: Lander
authors.forename: Charlotte
authors.initials: C
authors.lastname: Kuperwasser
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D051525:Fibroblast Growth Factor 9 / Q000235:genetics / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000502:physiology; D019899:Paracrine Communication; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D004967:Estrogens; C496459:FGF9 protein, human; D051525:Fibroblast Growth Factor 9; D020825:T-Box Domain Proteins; C106884:TBX3 protein, human; D005346:Fibroblast Growth Factors; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3