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  • br Introduction br The claudins are a

    2022-09-08


    Introduction
    The claudins are a family of integral membrane proteins central to the formation of the tight junctions (TJs) of epithelial cells [1–4]. These TJ proteins are directly involved in the paracellular sealing between adjacent cells [1–4] where they provide a “fence” and a “barrier” function, facilitating the Z-VAD-FMK of small ions and nutrients between these cells [5]. As well, TJ proteins are also considered key players in maintaining apical and basolateral polarity across the plasma domains [6–11, for review: 12–14]. Claudin 1, the first of 24 members of this family of proteins to be identified [1,2], forms the backbone of the TJ in epithelial cells [15] and plays a vital role in regulating epithelial barrier function. Claudin 1–deficient mice die within 1 day of birth [15]. 
    Address all correspondence to: Yvonne Myal, Department of Pathology, University of Manitoba, 401 Brodie Centre, 727 McDermot Ave., Winnipeg, Manitoba, Canada, R3E 3P5. E-mail: [email protected]
    1 Funding: This study was supported by a grant from the Canadian Breast Cancer Foundation and CancerCare Manitoba Foundation. The funding institutions had no role in the design of the study; collection, analysis, and interpretation of data; and writing the manuscript.
    Currently, there exists a wealth of accumulating evidence which shows that some members of the claudin family, in particular claudin 1, exhibit abnormal gene expression and are associated with the cellular dysregulation and progression in human cancers [13,14,16–22]. During cancer progression, the upregulation of claudin 1 has been shown to lead to the promotion of epithelial mesenchymal transition, EMT [23–25], cellular invasion and migration [21,24–30], as well as an accumulation or mislocalization of the claudin 1 protein in the cytoplasm [21,24,25,28,29,31–33]. The more recent observation that some aggressive breast cancers are associated with low levels of claudin protein family members, 3, 4, 5, and 7 has now led to the consensus to define a new molecular subtype of breast cancers, the “claudin low” subtype [34,35]. These claudin low breast tumors were generally derived from patients diagnosed with poor prognoses [36]. Conversely, high levels of claudin 1 have also been identified in, and associated with, the aggressive breast cancer phenotype. Original studies from our laboratory [31,37,38] and later others [39] identified an association between high claudin 1 expression/levels and breast cancer invasiveness. In a large cohort of human breast cancers of mixed pathologies, we found a significant correlation between high claudin 1 levels and the basal-like subtype, an aggressive form of breast cancer [31,37]. High levels of claudin 1 have also been identified in the BRCA1 breast cancers, a tumor type that is linked to poor prognosis [40]. Additionally, tumors of the luminal subtype have been reported to exhibit high claudin 1 levels [39]. Whether these tumors are yet another new subtype of breast cancer warrants further investigations. Thus, the role of claudin 1 in breast cancer appears to be quite complex, and the range of levels reported among the different subtypes suggest that other mitigating factors, including the interaction with mediators in signaling pathways, such as the protein kinases, that play a role in cancer, may also impact the role of claudin 1 during breast cancer progression.
    The multi-isomer protein kinase C (PKC) family of serine-threonine kinases, 12 identified to date [41,42], plays regulatory roles in normal tissue as well as cancer. The most studied conventional isomers are PKCα, PKCδ, PKCε, and PKCγ, which, in healthy tissues, have been shown to be important in regulating epithelial barrier function and mammary gland development [43–45; for review, 46]. Among the PKC isomers, much variation exists in terms of expression profile and mechanism of action [47,48]. As well, many PKC isomers have also been shown to be involved in cancer progression and metastasis [49–51; for review, 52] and play roles in both tumor suppression and/or promotion [53–55]. Notably, aberrant kinase activity to date has been linked to nearly 25% of all cancers [52].