title: BCCIP suppresses tumor initiation but is required for tumor progression.
abstract: Dysfunctions of genome caretaker genes contribute to genomic instability and tumor initiation. Because many of the caretaker genes are also essential for cell viability, permanent loss of function of these genes would prohibit further tumor progression. How essential caretaker genes contribute to tumorigenesis is not fully understood. Here, we report a "hit-and-run" mode of action for an essential caretaker gene in tumorigenesis. Using a BRCA2-interacting protein BCCIP as the platform, we found that a conditional BCCIP knockdown and concomitant p53 deletion caused rapid development of medulloblastomas, which bear a wide spectrum of alterations involving the Sonic Hedgehog (Shh) pathway, consistent with a caretaker responsibility of BCCIP on genomic integrity. Surprisingly, the progressed tumors have spontaneously lost the transgenic BCCIP knockdown cassette and restored BCCIP expression. Thus, a transient downregulation of BCCIP, but not necessarily a permanent mutation, is sufficient to initiate tumorigenesis. After the malignant transformation has been accomplished and autonomous cancer growth has been established, BCCIP reverses its role from a tumor-initiation suppressor to become a requisite for progression. This exemplifies a new type of tumor suppressor, which is distinct from the classical tumor suppressors that are often permanently abrogated during tumorigenesis. It has major implications on how a nonmutagenic or transient regulation of essential caretaker gene contributes to tumorigenesis. We further suggest that BCCIP represents a paradoxical class of modulators for tumorigenesis as a suppressor for initiation but a requisite for progression (SIRP).
authors.affiliation: Authors' Affiliation: Rutgers Cancer Institute of New Jersey, Department of Radiation Oncology, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, New Jersey.
authors.forename: Yi-Yuan
authors.initials: YY
authors.lastname: Huang
authors.forename: Li
authors.initials: L
authors.lastname: Dai
authors.forename: Dakim
authors.initials: D
authors.lastname: Gaines
authors.forename: Roberto
authors.initials: R
authors.lastname: Droz-Rosario
authors.forename: Huimei
authors.initials: H
authors.lastname: Lu
authors.forename: Jingmei
authors.initials: J
authors.lastname: Liu
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Shen
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000502:physiology*; D063646:Carcinogenesis / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000502:physiology*; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000473:pathology; D018450:Disease Progression; D016147:Genes, Tumor Suppressor / Q000502:physiology; D053823:Hedgehog Proteins / Q000502:physiology; D008297:Male; D008527:Medulloblastoma / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D055495:Neurogenesis / Q000235:genetics; D009687:Nuclear Proteins / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: C415366:BCCIP protein, human; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D053823:Hedgehog Proteins; D009687:Nuclear Proteins