CD44 Attenuates Metastatic Invasion during Breast Cancer Progression

Abstract

Metastatic invasion is the primary cause of breast cancer mortality, and adhesion receptors, such as CD44, are believed to be critical in this process. Historically, primary breast tumor epithelium has been investigated in isolation from other tissue components, leading to the common interpretation that CD44 and its primary ligand, hyaluronan, promote invasion. Here, we provide in vivo evidence showing CD44 antagonism to breast cancer metastasis. In a mouse model of spontaneously metastasizing breast cancer (MMTV-PyV mT), we found that loss of CD44 promotes metastasis to the lung. Localization studies, in combination with a novel hyaluronan synthase-GFP transgenic mouse, show a restricted pattern of expression for CD44 and hyaluronan. Whereas CD44 is expressed in tumor epithelium, hyaluronan synthase expression is restricted to stromal-associated cells. This distinct CD44 and hyaluronan pattern of distribution suggests a role for epithelial-stromal interaction in CD44 function. To define the relevance of this spatial regulation, we developed an in vitro invasion assay to emulate invasion into the extracellular matrix. Invasion of CD44-positive tumor cells was inhibited in hyaluronan-containing matrices, whereas blocking CD44-hyaluronan association increased invasion. Collectively, these data show that during breast cancer progression, hyaluronan-CD44 dynamics occurring through epithelialstromal interactions are protective against metastasis. (Cancer Res 2005; 65(15): 6755-63)

Membrane and membrane‐associated proteins involved in the aggressive phenotype displayed by highly invasive cancer cells

“…Lopez et al reported that invasion of CD44-positive tumour cells was inhibited in hyaluronancontaining matrices, whereas blocking CD44-hyaluronan association increased invasion. Collectively, this data shows that during breast cancer progression, hyaluronan-CD44 dynamics occurring through epithelial-stromal interactions are protective against metastasis [33].…”

CD44 Promotes Epithelial Mammary Gland Development and Exhibits Altered Localization during Cancer Progression

“…We have previously shown that in the MMTV-PyV MT model of breast cancer, CD44 is protective against lung metastasis when lost throughout tumor progression but is strongly expressed throughout the tumor epithelium of invasive tumors. 17 This is in contrast to the loss of CD44 in a mutant p53 model of osteosarcoma, where CD44 loss prevented lung and liver metastasis. 31 These data suggest that myoepithelial-specific expression may regulate its tumor-suppressive function, while expression in epithelium of carcinoma may account for its tumor-promoting function.…”

“…Research of CD44 in breast and prostate cancer has shown that it both promotes metastatic signaling and acts as a putative tumor suppressor. [15][16][17][18][19] In vitro studies using prostate cancer cell lines demonstrate that CD44 has been implicated in prostate cancer cell proliferation, migration, and in vivo invasion and metastatic dissemination. 20,21 Correspondingly, purified CD44-positive prostate cancer cells from xenograft tumors and CD44-positive cells from primary breast tumors have characteristics associated with increased invasiveness and progenitor capacity.…”

“…27 We have previously demonstrated that the loss of CD44 in the MMTVPyV MT mouse model of breast cancer leads to a 6-fold increase in metastasis, supporting evidence that CD44 inhibits breast cancer progression, although CD44 is highly expressed in the primary tumor epithelium in this model. 17 To better understand the role of CD44 in cancer, we began by examining its function during normal mammary gland development, as processes that occur in development mirror cancer progression and rely on conserved signaling pathways, making it a powerful model system to understand cancer progression. Here, we report that CD44 is expressed early during pubertal mammary gland development and that it regulates ductal outgrowth and terminal end bud morphology.…”

Modeling Metastatic Breast Cancer in Mice

“…Finally, metastatic potential appears to be independent of hormonal fluctuations with a reproducible progression rate [67]. Several labs have employed the MMTV-PyMT model to define and substantiate a role for genes that have been implicated in tumor progression and metastasis, such as CD44 [68], uPA (69), Irs1 [70] and Plg [71] (Table 3). Also, overexpression of the blood vessel angiogenic factor VEGF-A in MMTV-PyMT mice resulted in accelerated formation of lung metastasis, not only by promoting tumor angiogenesis but also by sustaining tumor proliferation and survival [72].…”