The Cytoskeletal Protein Cyclase-Associated Protein 1 (CAP1) in Breast Cancer: Context-Dependent Roles in Both the Invasiveness and Proliferation of Cancer Cells and Underlying Cell Signals

Abstract

As a conserved actin-regulating protein, CAP (adenylyl Cyclase-Associated Protein) functions to facilitate the rearrangement of the actin cytoskeleton. The ubiquitously expressed isoform CAP1 drives mammalian cell migration, and accordingly, most studies on the involvement of CAP1 in human cancers have largely been based on the rationale that up-regulated CAP1 will stimulate cancer cell migration and invasiveness. While findings from some studies reported so far support this case, lines of evidence largely from our recent studies point to a more complex and profound role for CAP1 in the invasiveness of cancer cells, where the potential activation of cell adhesion signaling is believed to play a key role. Moreover, CAP1 was also found to control proliferation in breast cancer cells, through the regulation of ERK (External signal-Regulated Kinase). Alterations in the activities of FAK (Focal Adhesion Kinase) and ERK from CAP1 depletion that are consistent to the opposite adhesion and proliferation phenotypes were detected in the metastatic and non-metastatic breast cancer cells. In this review, we begin with the overview of the literature on CAP, by highlighting the molecular functions of mammalian CAP1 in regulating the actin cytoskeleton and cell adhesion. We will next discuss the role of the FAK/ERK axis, and possibly Rap1, in mediating CAP1 signals to control breast cancer cell adhesion, invasiveness, and proliferation, largely based on our latest findings. Finally, we will discuss the relevance of these novel mechanistic insights to ultimately realizing the translational potential of CAP1 in targeted therapeutics for breast cancer.

Persistent Infection of Simian Foamy Virus Derived from the Japanese Macaque Leads to the High-Level Expression of microRNA that Resembles the miR-1 microRNA Precursor Family

“…It is interesting to note that the expression level of hsa-miR-1, which shares a seed sequence with SFVmfu-miR-S7-5p, was down-regulated in various types of cancers (Liu et al, 2015;Han et al, 2017;Korde et al, 2017). The upregulation of CAP1 has been observed in several solid tumors, such as ovarian cancer, breast cancer (Xie et al, 2014;Hua et al, 2015;Hasan and Zhou, 2019), and rhabdomyosarcoma from which the TE671 cell line is derived (Rao et al, 2010). Rhabdomyosarcoma is also known to have a reduced expression level of hsa-miR-1, which suppresses CAP1 expression (Vinther et al, 2006;Rao et al, 2010).…”

Oligomerization Affects the Ability of Human Cyclase-Associated Proteins 1 and 2 to Promote Actin Severing by Cofilins

“…Elevated expression of both human CAP isoforms (CAP1 and CAP2) is linked to poor prognosis in multiple different metastatic cancers [45,55]. High invasiveness of cancer cells overexpressing CAP1 and CAP2 correlates with their roles in stimulating the turnover of actin filaments, which is essential for cell motility via promoted formation and turnover of pro-migratory structures such as filopodia and lamellipodia, leading to metastasis [45].…”

“…Elevated expression of both human CAP isoforms (CAP1 and CAP2) is linked to poor prognosis in multiple different metastatic cancers [45,55]. High invasiveness of cancer cells overexpressing CAP1 and CAP2 correlates with their roles in stimulating the turnover of actin filaments, which is essential for cell motility via promoted formation and turnover of pro-migratory structures such as filopodia and lamellipodia, leading to metastasis [45]. Since cancer-related mutations in both CAP1 and CAP2 are more prevalent in the N-terminal part of the CAP isoforms, we compared the biochemical properties of the N-terminal region of both isoforms, which are recognized to bind F-actin and enhance cofilin-mediated filament disassembly.…”

“…Both human CAP isoforms have recently emerged as markers of invasive tumors. Thus, CAP1 has been implicated in breast, lung, pancreatic, and ovarian cancers along with glioma, hepatocellular, and head and neck squamous cell carcinomas [43,44,45,46]. CAP2 is overproduced in hepatocellular carcinoma, malignant melanoma, breast, and gastric cancers [47,48], and its expression is associated with poor clinical outcomes [44,49].…”

“…CAP2 is also overproduced by bladder, colon, kidney, and thyroid tumors [41], making it a common marker for various tumors. However, the exact role of CAPs in tumorigenesis is ambiguous, and anti-oncogenic action of the CAP1 and 2 isoforms for other tumors has also been proposed [45]. Interestingly, cancer-linked mutations in both CAP1 and CAP2 are enriched in the N-terminal domain, with the hot spot mutations in CAP1 are located at the Arg-29 residue [44], which is not conserved between the two isoforms.…”