title: Biological responses to TGF-β in the mammary epithelium show a complex dependency on Smad3 gene dosage with important implications for tumor progression.
abstract: TGF-β plays a dual role in epithelial carcinogenesis with the potential to either suppress or promote tumor progression. We found that levels of Smad3 mRNA, a critical mediator of TGF-β signaling, are reduced by approximately 60% in human breast cancer. We therefore used conditionally immortalized mammary epithelial cells (IMEC) of differing Smad3 genotypes to quantitatively address the Smad3 requirement for different biologic responses to TGF-β. We found that a two-fold reduction in Smad3 gene dosage led to complex effects on TGF-β responses; the growth-inhibitory response was retained, the pro-apoptotic response was lost, the migratory response was reduced, and the invasion response was enhanced. Loss of the pro-apoptotic response in the Smad3(+/-) IMECs correlated with loss of Smad3 binding to the Bcl-2 locus, whereas retention of the growth-inhibitory response in Smad3 IMECs correlated with retention of Smad3 binding to the c-Myc locus. Addressing the integrated outcome of these changes in vivo, we showed that reduced Smad3 levels enhanced metastasis in two independent models of metastatic breast cancer. Our results suggest that different biologic responses to TGF-β in the mammary epithelium are differentially affected by Smad3 dosage and that a mere two-fold reduction in Smad3 is sufficient to promote metastasis.
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: Ethan A
authors.initials: EA
authors.lastname: Kohn
authors.forename: Yu-an
authors.initials: YA
authors.lastname: Yang
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Du
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Nagano
authors.forename: Catherine M H
authors.initials: CM
authors.lastname: Van Schyndle
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Herrmann
authors.forename: Madeleine
authors.initials: M
authors.lastname: Heldman
authors.forename: Jin-Qiu
authors.initials: JQ
authors.lastname: Chen
authors.forename: Christina H
authors.initials: CH
authors.lastname: Stuelten
authors.forename: Kathleen C
authors.initials: KC
authors.lastname: Flanders
authors.forename: Lalage M
authors.initials: LM
authors.lastname: Wakefield
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D018450:Disease Progression; D004742:Enhancer Elements, Genetic / Q000235:genetics; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005260:Female; D018628:Gene Dosage / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D042361:Mammary Glands, Human / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; C497790:SMAD3 protein, human; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta