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Functions of the APC tumor suppressor protein dependent and independent of canonical WNT signaling: implications for therapeutic targeting

Journal

CANCER AND METASTASIS REVIEWS
Volume 37, Issue 1, Pages 159-172

Publisher

SPRINGER
DOI: 10.1007/s10555-017-9725-6

Keywords

APC; Canonical WNT signaling; WNT-independent; Colorectal cancer; Therapeutics

Categories

Funding

  1. NIH [R01CA063507, UL1TR001070, F31CA174260]
  2. HHMI MED into GRAD
  3. Pelotonia Fellowship Program
  4. NATIONAL CANCER INSTITUTE [R01CA063507, P30CA016058, F31CA174260] Funding Source: NIH RePORTER
  5. NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UL1TR001070] Funding Source: NIH RePORTER

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The acquisition of biallelic mutations in the APC gene is a rate-limiting step in the development of most colorectal cancers and occurs in the earliest lesions. APC encodes a 312-kDa protein that localizes to multiple subcellular compartments and performs diverse functions. APC participates in a cytoplasmic complex that promotes the destruction of the transcriptional licensing factor beta-catenin; APC mutations that abolish this function trigger constitutive activation of the canonical WNT signaling pathway, a characteristic found in almost all colorectal cancers. By negatively regulating canonical WNT signaling, APC counteracts proliferation, promotes differentiation, facilitates apoptosis, and suppresses invasion and tumor progression. APC further antagonizes canonical WNT signaling by interacting with and counteracting beta-catenin in the nucleus. APC also suppresses tumor initiation and progression in the colorectal epithelium through functions that are independent of canonical WNT signaling. APC regulates the mitotic spindle to facilitate proper chromosome segregation, localizes to the cell periphery and cell protrusions to establish cell polarity and appropriate directional migration, and inhibits DNA replication by interacting directly with DNA. Mutations in APC are often frameshifts, insertions, or deletions that introduce premature stop codons and lead to the production of truncated APC proteins that lack its normal functions and possess tumorigenic properties. Therapeutic approaches in development for the treatment of APC-deficient tumors are focused on the inhibition of canonical WNT signaling, especially through targets downstream of APC in the pathway, or on the restoration of wild-type APC expression.

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