BCCIP Suppresses Tumor Initiation but is Required for Tumor Progression
Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels la protéine BCCIP joue initialement un rôle de suppresseur de tumeurs mais, après l'établissement d'une croissance tumorale autonome, s'avère nécessaire pour la progression de la maladie
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 a platform, we found that a conditional BCCIP knockdown and concomitant p53 deletion caused rapid development of medulloblastomas, which bear a wide spectrum of alternations 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 down-regulation of BCCIP, but not necessarily a permanent mutation, is sufficient to initiate tumorigenesis. Once 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 non-mutagenic 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).