title: Alterations of the HBP1 transcriptional repressor are associated with invasive breast cancer.
abstract: Invasive breast cancer has a high risk of recurrence to incurable disease and needs improved prognostic and therapeutic tools. Our work combines clinical and molecular analyses to show that the transcriptional repressor HBP1 may be a new target for invasive breast cancer. Previous work indicated that HBP1 regulated proliferation and senescence and inhibited Wnt signaling. Two of these functions have been associated with invasive breast cancer. In 76 breast tumors, we identified 10 HBP1 mutations/variants that were associated with fully invasive breast cancer. In a separate analysis, we found that a subset of invasive breast cancer specimens also had reduced HBP1 mRNA levels. These clinical correlations suggested that mutation or reduction of HBP1 occurs in invasive breast cancer and that HBP1 might regulate the proliferation and invasiveness of this breast cancer type. Analysis of the HBP1 mutants showed they were functionally defective for suppressing Wnt signaling. To test the consequences of reduced HBP1 levels, we used RNA interference to knock down HBP1 and observed increased Wnt signaling, tumorigenic proliferation, and invasiveness in cell and animal breast cancer models. Lastly, statistical analysis of a breast cancer patient database linked reduced HBP1 expression to breast cancer recurrence. In considering two-gene criteria for relapse potential, reduced expression of HBP1 and SFRP1, which is another Wnt inhibitor that was recently linked to invasive breast cancer, strikingly correlated with recurrence. Together, these data indicate that HBP1 may be a molecularly and clinically relevant regulator of breast cancer transitions that eventually lead to poor prognosis.
authors.affiliation: Department of Biochemistry and Program in Genetics, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: K Eric
authors.initials: KE
authors.lastname: Paulson
authors.forename: Kimberly
authors.initials: K
authors.lastname: Rieger-Christ
authors.forename: Michael A
authors.initials: MA
authors.lastname: McDevitt
authors.forename: Charlotte
authors.initials: C
authors.lastname: Kuperwasser
authors.forename: Jiyoung
authors.initials: J
authors.lastname: Kim
authors.forename: Vincent E
authors.initials: VE
authors.lastname: Unanue
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zhang
authors.forename: Maowen
authors.initials: M
authors.lastname: Hu
authors.forename: Robin
authors.initials: R
authors.lastname: Ruthazer
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Berasi
authors.forename: Chun-Yin
authors.initials: CY
authors.lastname: Huang
authors.forename: Dilip
authors.initials: D
authors.lastname: Giri
authors.forename: Seth
authors.initials: S
authors.lastname: Kaufman
authors.forename: John M
authors.initials: JM
authors.lastname: Dugan
authors.forename: Joanne
authors.initials: J
authors.lastname: Blum
authors.forename: Georges
authors.initials: G
authors.lastname: Netto
authors.forename: David E
authors.initials: DE
authors.lastname: Wazer
authors.forename: Ian C
authors.initials: IC
authors.lastname: Summerhayes
authors.forename: Amy S
authors.initials: AS
authors.lastname: Yee
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006609:High Mobility Group Proteins / Q000096:biosynthesis* / Q000235:genetics*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics*; D014158:Transcription, Genetic; D016896:Treatment Outcome
chemical_list: C486328:HBP1 protein, human; D006609:High Mobility Group Proteins; D012097:Repressor Proteins