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Protein 4.1B Expression Is Induced in Mammary Epithelial Cells During Pregnancy and Regulates Their Proliferation

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Protein 4.1B Expression Is Induced in Mammary Epithelial Cells During Pregnancy and Regulates Their Proliferation Oncogene (2005) 24, 6502–6515 & 2005 Nature Publishing Group All rights reserved 0950-9232/05 $30.00 www.nature.com/onc Protein 4.1B expression is induced in mammary epithelial cells during pregnancy and regulates their proliferation Robin Kuns1,2, Joseph L Kissil3, Irene F Newsham4, Tyler Jacks5, David H Gutmann6 and Larry S Sherman*,1 1Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Ave., Beaverton, OR 97006, USA; 2Department of Cell Biology, Neurobiology & Anatomy, University of Cincinnati School of Medicine, Cincinnati, OH 45267, USA; 3Molecular and Cellular Oncogenomics Program, The Wistar Institute, Philadelphia, PA 19104, USA; 4Department of Neurosurgery, David and Doreen Hermelin Laboratory of Molecular Oncogenetics, Hermelin Brain Tumor Center, Henry Ford Hospital, Detroit, MI 48202, USA; 5Department of Biology and Center for Cancer Research, and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; 6Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, USA 4.1B is a member of the protein 4.1 superfamily of erythrocytes (Tyler et al., 1979). This superfamily proteins that link transmembrane proteins to the actin consists of five subgroups, including the 4.1 proteins cytoskeleton. The 4.1B gene localizes to chromosome (4.1R, 4.1N, 4.1G, 4.1O, and 4.1B) and the ERM 18p11.3, which undergoes loss of heterozygosity in proteins (ezrin, radixin, moesin, and merlin). All 4.1 mammary tumors. Here, we examine the expression of family members are characterized by the presence of a 4.1B in murine mammary epithelium and find that 4.1B is conserved N-terminal membrane-association FERM dramatically upregulated in mammary epithelial cells (Fourpoint-one, Ezrin, Radixin, Moesin) domain during pregnancy when there is extensive cell prolifera- (Chishti et al., 1998). In addition, most 4.1 proteins tion. In contrast, 4.1B is not expressed in virgin, lactating, can associate with the spectrin–actin cytoskeleton by or involuting mammary epithelium. To examine the virtue of an actin-binding domain (Parra et al., 2000; consequence of 4.1B loss on mammary epithelial cell Gimm et al., 2002). Both 4.1 and ERM proteins can act proliferation, we analysed mammary glands in 4.1B-null as structural proteins that link the plasma membrane to mice. 4.1B loss results in a significant increase in the actin cytoskeleton (Tsukita et al., 1994). mammary epithelial cell proliferation during pregnancy, A number of signaling functions have been attributed to but has no effect on mammary epithelial cell proliferation, 4.1 family members. In particular, growth suppressive in virgin or involuting mice. Furthermore, we show that functions have been identified for protein 4.1R and the 4.1B inhibits the proliferation of mammary epithelial cell merlin tumor suppressor protein, as overexpression of these lines by inducing a G1 cell cycle arrest, characterized by proteins results in decreased cell proliferation (Lutchman decreased cyclin A expression and reduced Rb phosphor- and Rouleau, 1995; Robb et al., 2003). Loss or inactivation ylation, and accompanied by reduced erbB2 phosphoryla- of merlin, which shares high homology with ezrin, radixin, tion. This cell cycle arrest does not involve alterations in and moesin, is linked to neurofibromatosis type 2 (NF2), a the activities of MAPK, JNK, or Akt. Collectively, our disease characterized by the development of multiple findings demonstrate that 4.1B regulates mammary nervous system tumors including schwannomas and epithelial cell proliferation during pregnancy and suggest meningiomas (Rouleau et al., 1993; Trofatter et al., 1993). that its loss may influence mammary carcinoma patho- Several lines of evidence suggest that protein 4.1B may genesis in multiparous women. also function as a tumor suppressor. Protein 4.1B is a Oncogene (2005) 24, 6502–6515. doi:10.1038/sj.onc.1208813; brain-enriched ortholog of 4.1R that localizes to points published online 20 June 2005 of cell–cell contact at the plasma membrane (Peters et al., 1998; Parra et al., 2000). Several studies have indicated Keywords: protein 4.1B; erbB2; mammary epithelial that 4.1B expression is lost or reduced in numerous cells; pregnancy; mammary carcinoma malignant and benign tumors, including 54% of non- small cell lung carcinomas (NSCLC) (Tran et al., 1999). 4.1B is also reduced in 60% of sporadic meningiomas Introduction and 30% of ependymomas (Gutmann et al., 2000; Singh et al., 2002). The 4.1B gene is located on band 18p11.3, a Members of the protein 4.1 superfamily of proteins chromosomal region that has been shown to undergo share structural homology with band 4.1R, a spectrin- frequent loss of heterozygosity (LOH) in these tumors binding protein that was originally isolated from human (Tran et al., 1999; Gutmann et al., 2000; Singh et al., 2002). Re-expression of 4.1B in NSCLC and meningio- ma cell lines causes in growth suppression, further *Correspondence: LS Sherman; E-mail: [email protected] Received 22 January 2005; revised 8 April 2005; accepted 2 May 2005; supporting the possibility that 4.1B acts as a tumor published online 20 June 2005 suppressor (Tran et al., 1999; Gutmann et al., 2001). 4.1B regulates mammary epithelial proliferation R Kuns et al 6503 4.1B has also been implicated as a tumor suppressor sion is lost in breast cancers (Tran et al., 1998; protein in mammary carcinomas, which also frequently Kittiniyom et al., 2001; Charboneau et al., 2002). develop LOH at band 18p11.3 (Tran et al., 1999; However, the role of 4.1B in normal mammary Kittiniyom et al., 2004). Because loss of this region epithelium had not been previously tested. We there- occurs with relatively high frequency in ductal carcino- fore examined the expression of 4.1B in mammary mas in situ (56%), it has been proposed to be an early glands from prepubertal virgin (day 16, data not event in tumor progression in the breast (Kittiniyom shown), mature virgin (week 8), pregnant (13.5 days et al., 2001). Furthermore, re-introduction of the postcoitum (dpc)), lactating (9 days postpartum (dpp)), minimal growth inhibitory domain of 4.1B, called and involuting (1 day postweaning (dpw), data DAL-1 (differentially expressed in adenocarcinoma of not shown, and 5 dpw) C57BL/6 mice to determine the lung), results in growth suppression in a number of whether 4.1B expression changes in mammary epithelial mammary carcinoma cell lines (Charboneau et al., 2002). cells that are quiescent, proliferating, fully differen- In order to elucidate the role of 4.1B in the normal tiated, or undergoing apoptosis. Immunohistochemistry mammary gland and how its loss might contribute to of paraffin-embedded sections revealed that 4.1B mammary tumorigenesis, we examined the expression expression is virtually absent from epithelial cells in pattern of 4.1B during postpubertal mammary gland the mammary glands of virgin mice, but is dramatically development. Because the mammary gland is a dynamic induced in these cells during pregnancy (compare Figure tissue that undergoes extensive remodeling during its 1a and b). By midlactation, however, 4.1B expression postpubertal development, it is an excellent model is significantly reduced or absent from these cells system in which to study a protein involved in growth (Figure 1c) and is absent from the epithelial cells in regulation (Daniel and Smith, 1999). The mature virgin involuting glands (Figure 1d). Nearly all epithelial mammary gland consists of a ductal tree that is cells examined during pregnancy (12.5–14.5 dpc) were comprised of generally quiescent epithelial cells that positive for 4.1B expression, indicating that the upregu- surround a central lumen, with some of these ductal lation of this protein occurs throughout mammary branches ending in rudimentary alveolar buds. During gland epithelium. Specific labeling of 4.1B by the pregnancy, the epithelial cells undergo a massive burst antibody used in these experiments was confirmed of proliferation in order to form more alveolar buds and by staining mammary gland sections from pregnant differentiated alveoli that ultimately fill nearly the entire (13.5 dpc) 4.1B-null mice (Figure 1b, inset). Using this fat pad. During late pregnancy and lactation, these 4.1B antibody, weak immunoreactivity was detected alveoli become fully differentiated and begin to secrete in the lumen of some acini of both wild-type and 4.1B- milk. Upon weaning, the mammary gland enters null mice, indicating that this luminal staining was involution, a stage in which the secretory epithelial cells nonspecific (data not shown). Immunofluorescence of of the alveoli undergo apoptosis and the entire gland is the wild-type pregnant (13.5 dpc) gland for 4.1B remodeled so that it resembles the virgin gland (Richert (Figure 1e) and E-cadherin (Figure 1f) and their overlay et al., 2000). Although the epithelium of the mammary (Figure 1g) shows that 4.1B localizes predominantly to gland undergoes a proliferative phase during pregnancy, regions of cell–cell contact (Figure 1g, arrows) as well the proliferation that occurs is tightly controlled and as at apical membranes, with some limited cytoplasmic lasts for a defined period of time. expression. In this report, we show that 4.1B is not expressed in We next quantified the changes in 4.1B expression the epithelium of the virgin mouse mammary gland, but during different phases of mammary development. is dramatically upregulated during pregnancy and then The specificity of the 4.1B antibody was further downregulated again in the lactating and involuting verified by Western blot analysis of mammary gland glands. Exogenous expression of 4.1B in both mammary lysates from wild-type and 4.1B-null mice at 13.5 dpc. epithelial and carcinoma cell lines causes a significant Major bands with the predicted sizes of 4.1B isoforms inhibition of proliferation that results in a G1 cell cycle were detected in the wild-type but not the 4.1B-null arrest.
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