Review Understanding the Dual Nature of CD44 in Breast Cancer Progression Jeanne M.V. Louderbough and Joyce A. Schroeder Abstract CD44 has been the subject of extensive research for more than 3 decades because of its role in breast cancer, in addition to many physiological processes, but interestingly, conflicting data implicate CD44 in both tumor suppression and tumor promotion. CD44 has been shown to promote protumorigenic signaling and advance the metastatic cascade. On the other hand, CD44 has been shown to suppress growth and metastasis. Histopathological studies of human breast cancer have correlated CD44 expression with both favorable and unfavorable clinical outcomes. In recent years, CD44 has garnered significant attention because of its utility as a stem cell marker and has surfaced as a potential therapeutic target, necessitating a greater understanding of CD44 in breast cancer. In this review, we attempt to unify the literature implicating CD44 in both tumor promotion and suppression, and explain its dualistic nature. Mol Cancer Res; 9(12); 1573–86. Ó2011 AACR. Introduction CD44 is a member of a large family of cell adhesion molecules that is responsible for mediating communica- tion and adhesion between adjacent cells and between cells and the extracellular matrix (ECM). Cell adhesion mol- ecule–mediated organization is a basic feature of normal breast histology and is essential for maintaining tissue integrity. Disruption or misregulation of these adhesive relationships causes a loss of tissue architecture and is a feature of neoplastic transformation. In addition to its role in cellular adhesion, CD44 can direct intracellular signal- ing for growth and motility, and thus it is involved in many types of cancers, including breast, lung, prostate, ovarian, cervical, and colorectal cancers and neuroblasto- ma (1). In prostate cancer and neuroblastoma, CD44 has been dubbed a metastasis suppressor gene (2, 3), although it was recently shown to promote prostate cancer growth and metastasis in a xenograft model (4). Its role in breast cancer, however, is unclear and controversial. CD44 expression in breast cancer has been correlated with both poor and favorable outcomes. It mediates both pro- and antitumoral signaling in vitro, and it can inhibit and promote metastatic progression in vivo. Although researchers often focus on one or another aspect of CD44-mediated biology, it is important to understand its dualistic nature if it is to be used as a diagnostic and therapeutic tool. Here we review the pro- and antitumoral signaling events that are mediated by CD44, and we discuss its expression in human breast cancer and its use as a therapeutic target. CD44 has been examined in many cancer types; however, we will focus primarily on evidence derived from breast cancer. Furthermore, although CD44 is used as a stem cell marker in breast cancer (5), its role in that context is beyond the scope of this review, and the reader is directed to previous excellent reviews for an evaluation of this topic (6, 7). CD44 Structure CD44 is encoded by a single, highly conserved gene, spanning 50 kilobases. It is located on chromosome 11 in humans and chromosome 2 in mice, and it encodes a group of proteins ranging from 80 to 200 kDa in size. The heterogeneity of this group is due to posttranscriptional regulation, including alternative splicing and protein modification (8). The CD44 gene contains 20 exons, which encode 20 CD44 isoforms (9). Exons 1–5 and 16–18 are constant, whereas exons 6–15 and 19–20 are variants and inserted by alternative splicing (ref. 10; Fig. 1A). The nonvariant standard isoform, denoted CD44s, is encoded by the constant exons, is the smallest and most widely expressed isoform, and is present on the surface of most vertebrate cells (8). Inclusion of the variant exons lengthens the extracellular membrane-proximal stem structure of CD44 (11), creating larger isoforms and exposing binding sites for additional posttranslational modifications and ligand-binding sites. Variant expression is regulated by tissue and environment-specific factors, and oncogenic pathways such as the Ras-MAPK cascade Authors' Affiliation: Department of Molecular and Cellular Biology, Arizona Cancer Center, and the BIO5 Institute, University of Arizona, Tucson, Arizona Corresponding Author: Joyce A. Schroeder, Department of Molecular and Cellular Biology, Arizona Cancer Center, 1515 N. Campbell Ave., P.O. Box 245024, Tucson, AZ 85724. Phone: 520-626-1384; Fax: 520-626-3764; E-mail: jschroeder@azcc.arizona.edu doi: 10.1158/1541-7786.MCR-11-0156 Ó2011 American Association for Cancer Research. Molecular Cancer Research www.aacrjournals.org 1573 on May 22, 2020. © 2011 American Association for Cancer Research. mcr.aacrjournals.org Downloaded from Published OnlineFirst October 4, 2011; DOI: 10.1158/1541-7786.MCR-11-0156