A New Player in an Old Story: FBXO16 Prevents Breast Cancer Tumorigenesis through Disrupting Cellular Function of Nuclear ?-Catenin

22 β-Catenin is the central modulator of the canonical Wnt signaling pathway. Upon Wnt on state, β-Catenin is translocated to the nucleus and function as a transcription coactivator for several oncogenes. In Wnt off state, β-catenin is mostly localized in the cytoplasm and sequestered by the destruction complex, the negative regulator of β-catenin expression [2,3]. This destruction complex is composed of adenomatous polyposis coli (APC), casein kinase 1α (CK1α), glycogen synthase kinase 3α/β (GSK-3α/β), and AXIN1 [4-8]. CK1α initiates the degradation process of β-Catenin by phosphorylating it at Ser45, which is subsequently phosphorylated at Thr41, Ser37, and Ser33 by GSK3β [9]. The phosphorylated β-catenin is then polyubiquitinated by SCFβ-TrCP to promote its proteasomal degradation. In contrast, in the case of Wnt on state, β-catenin is released from the destruction complex and translocate to the nucleus. It is also reported that Norrin and R-Spondin activate Wnt signaling in stem cells and this activation is Wnt ligand independent [10-12]. They bind to LRP5/6 receptor and prevent the inactivation of LRP function by Rnf43/Znrf3. LRP5/6 functions as a coreceptor of Frizzled receptor and helps to separate Axin from the destruction complex. Thus, they help to translocate β-catenin in the nucleus through sequestration of Axin in the membrane. In the nucleus, β-catenin functions as a transcriptional coactivator to relate plethora of genes. Destruction complex-mediated sequestration of β-catenin is efficient to prevent cancer. However, it is ineffective in most of the cancers because of either mutation in the components of the destruction complex [13,14] or in the β-Catenin itself [15,16]. Among the components of destruction complex, loss of APC is main driver for constitutive translocation of β-catenin in colorectal cancer [17]. APC is mutated in almost 49% of colorectal cancers [18]. However, β-Catenin is predominantly mutated in hepatocellular carcinoma, endometrial cancer, and pancreatic cancer [19-21]. In addition to APC inactivation and β-catenin mutation, mutation in R-spondin/LRP5/ RNF43 plays crucial role in Wnt-dependent colorectal cancer. RNF43 is mutated in approximately 19% of colorectal cancer. Similarly, R-spondin is mutated in 10% of colorectal cancer. Interestingly, irrespective of the type of breast cancer, canonical Wnt signaling is activated in almost 50% of breast cancer and is closely associated with reduced overall survival of the breast cancer patients [22]. It is important to note that in most of the breast cancer patients, expression of Wnt ligands and receptors are elevated, whereas antagonists are silence.