Journal of Cellular Biochemistry 85:180±184 2002) DOI 10.1002/jcb.10126 .................... Soluble Fragment of P-Cadherin Adhesion Protein Found in Human Milk Alejandro Peralta Soler, 1 Jose Russo, 2 Irma H. Russo, 2 and Karen A. Knudsen 1 * 1 The Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, Pennsylvania 19096 2 Fox Chase Cancer Center, Breast Cancer Research Laboratory, 7701 Burholme Avenue, Philadelphia, Pennsylvania 19111 Abstract Classical cadherins such as E- and P-cadherin are transmembrane proteins that mediate speci®c cell-to- cell adhesion and are important to tissue development and function. Cadherin function can be modulated by various means, including proteolytic cleavage of the extracellular adhesion domain from the cells' surface, yielding large soluble fragments termed soluble) sE- or sP-cadherin. In people with certain carcinomas, sE-cadherin can be detected at elevatedlevelsintheserumandsometimescanserveasaprognosticmarker.SolubleE-cadherinalsoisfoundinurineof patients with bladder cancer. In addition to being present in bodily ¯uids of cancer patients, sE- and sP-cadherin are present in the serum of healthy people, suggesting that shedding of cadherins is a normal event. Here, we report high levels of 80 kDa sP-cadherin in human milk. In the lactating mammary gland tissue, P-cadherin appears to be a protein secreted by epithelial cells, rather than an adhesion protein. This is in contrast to the non-lactating mammary gland where P-cadherin is restricted to myoepithelial cells, and is present at sites of cell±cell contact. J. Cell. Biochem. 85: 180±184, 2002. ß 2002 Wiley-Liss, Inc. Key words: metalloproteinase; Listeria; epithelial cells; mammary gland; myoepithelial cells; protein in serum and urine Cadherins constitute a family of adhesion proteins [see Takeichi, 1991]. E-cadherin 120kDa)isexpressedbymostepithelialcells, whereas P-cadherin 118 kDa) is restricted to basal cell layers, including basal cells of skin and prostate, and myoepithelial cells of the mammary gland [Shimoyama et al., 1989]. Cadherins are transmembrane proteins that interact intracellularly with catenins and the actin cytoskeleton to promote strong cell±cell adhesion [see Wheelock et al., 1996]. They appear to serve as signaling molecules to regulate cell behavior [see Knudsen et al., 1998]. Cadherin activity is regulated by multi- ple mechanisms, including interaction with catenins,phosphorylationevents,andshedding oftheextracellulardomain. A soluble 80-kDa fragment representing most of the E-cadherin extracellular domain sE-cadherin) was originally found in condi- tioned medium from cultured epithelial cells [Wheelock et al., 1987]. E-cadherin shedding alsooccursinvivo,andsolubleE-cadherinsE- cadherin) is present in both serum [Katayama et al., 1994, Shirahama et al., 1996] and urine [Banks et al., 1995]. An elevated level of sE- cadherincorrelateswiththepresenceofcertain cancers,andhasbeenshowntobeaprognostic markerforsomecancers[Katayamaetal.,1994; Grif®ths et al., 1996; Gofuku et al., 1998; Velikova et al., 1998; Chan et al., 2001]. In additiontosE-cadherin,an80-kDafragmentof P-cadherin sP-cadherin) is present in serum of individuals with or without breast cancer, althoughitsconcentrationis20-foldlowerthan thatofE-cadherin[Knudsenetal.,2000]. Here we report that high concentrations of sP-cadherin are present in human milk. In examiningtheexpressionpatternofP-cadherin inlactatingmammarytissue,weobservedthat P-cadherin appears as protein secreted by luminalepithelialcells,ratherthanacell±cell adhesionprotein.Thisisinstarkcontrasttothe ß 2002 Wiley-Liss, Inc. Grantsponsor:JohnS.SharpeResearchFoundationofthe Bryn Mawr Hospital to K.A.K., A.P.S.); Grant sponsor: NIHtoJ.R.);Grantnumbers:U01CA6277,R21CA87230. *Correspondence to: Karen A. Knudsen, Ph.D., Lankenau InstituteforMedicalResearch,100LancasterAve,Wynne- wood, PA 19096. E-mail: knudsenk@mlhs.org Received 16 October 2001; Accepted 3 January 2002