Survivin Is a Novel Target of CD44-Promoted Breast Tumor Invasion

Abstract

The hyaluronan (HA) receptor CD44 plays an essential role in cell-cell or cell-extracellular matrix communications and is a bioactive signal transmitter. Although a number of studies have described the function of CD44 in breast cancer (BC) metastasis, the underlying mechanisms have yet to be determined. By using a validated tetracycline-off-regulated CD44 expression system in the MCF-7 cell line combined with microarray analysis, we identified survivin (SVV) as a potential downstream transcriptional target of CD44. To test the hypothesis that SVV underpins CD44-promoted BC cell invasion, we combined molecular and pharmacologic approaches and showed that CD44 induction increased SVV expression levels, which in turn promotes BC cell invasion. Further, clinical analysis of breast tissue samples showed that SVV expression patterns paralleled those of the standard form of CD44 during breast tumor progression. More interestingly, we identified the PI3K/E2F1 pathway as a potential molecular link between HA/CD44 activation and SVV transcription. In addition to identifying SVV as a target for HA/CD44 signaling, this investigation provides a better understanding of the molecular mechanisms that underpin the novel function of SVV in breast cancer metastasis. Breast cancer (BC) is the most common cancer and the second most common cause of cancer-related deaths in women in the United States, with more than 175,000 women being diagnosed annually. 1,2 In the later stages of progression, BC cells metastasize from the original tumor site and travel through the vasculature to distant organs such as liver, lungs, brain, and bone. [2][3][4][5] Although the involvement of cell adhesion molecules in cancer development, progression, and metastasis has been established and discussed extensively in the literature, the mechanisms underlying their implication is still nascent. 6 -9 The hyaluronan (HA) receptor CD44, a multistructural and multifunctional cell adhesion molecule involved in cell-cell and cell-extracellular matrix interactions, functions as a bioactive signaling transmitter involved in a variety of cellular responses, including lymphocyte homing, hematopoiesis, inflammation, tumorigenesis, angiogenesis, and metastasis. 10 -13 The CD44 -HA complex initiates a series of intracellular signaling events that lead to migration, adhesion, invasion, proliferation, and differentiation of a variety of cells. The transduction of HA/CD44 signaling can occur through various mechanisms including the following: i) HA binding to CD44 can initiate the extracellular clustering of CD44, resulting in the activation of downstream kinases, 14 ii) CD44 can serve as a co-receptor physically associated with other cell signaling receptors, [15][16][17][18] iii) CD44 can serve as a docking protein for pericellular or cytoplasmic proteins, 19,20 and iv) the transmembrane domain of CD44 can be cleaved, allowing the translocation of the cytoplasmic domain to the nucleus, where it functions as a transcription factor regulating the expression of target gen...

TGF-β2: A Novel Target of CD44-Promoted Breast Cancer Invasion

“…Nevertheless, recent studies carried out in our laboratory and others provide strong evidence, using both in vitro and in vivo models, that CD44s-mediated adhesion and signaling are required for cell growth and the dissemination of breast-derived tumors5,17-19. In the present study we demonstrate a novel relationship between HA/CD44s signaling and the transcription of TGF- β2 in BC cells.…”

Association of survivin splice variants with prognosis and treatment of breast cancer

“…This correlated with a significant loss of breast cancer cell invasiveness. Simultaneous increased expression of both CD44 and survivin was detected in late-stage metastatic breast cancer cells, expression that was absent in normal breast tissue samples [38] . Recently, a group of small non-coding RNAs, known as microRNAs, attracted cancer researchers [39,40] .…”

Oncogenic role and therapeutic target of leptin signaling in breast cancer and cancer stem cells

“…Survivin is highly expressed during fetal development and cancer development, but it is rarely found in normal healthy adult tissues [239–240]. Recently, Survivin, was identified as a novel target of Notch [239–240] and CD44 genes [241]. Notch directly activates at least one RPB-Jκ site in the Survivin promoter [242].…”