CCN5/WISP-2: A micromanager of breast cancer progression

Abstract

The gain of plasticity by a subset of cancer cells is a unique but common sequence of cancer progression from epithelial phenotype to mesenchymal phenotype (EMT) that is followed by migration, invasion and metastasis to a distant organ, and drug resistance. Despite multiple studies, it is still unclear how cancer cells regulate plasticity. Recent studies from our laboratory and others' proposed that CCN5/WISP-2, which is found intracellularly (in the nucleus and cytoplasm) and extracellularly, plays a negative regulator of plasticity. It prevents the EMT process in breast cancer cells as well as pancreatic cancer cells. Multiple genetic insults, including the gain of p53 mutations that accumulate over the time, may perturb CCN5 expression in non-invasive breast cancer cells, which ultimately helps cells to gain invasive phenotypes. Moreover, emerging evidence indicates that several oncogenic lesions such as miR-10b upregulation and activation of TGF-β-signaling can accumulate during CCN5 crisis in breast cancer cells. Collectively, these studies indicate that loss of CCN5 activity may promote breast cancer progression; application of CCN5 protein may represent a novel therapeutic intervention in breast cancer and possibly pancreatic cancer.

Fig. 1

Modular structures of WISP-subfamily of CCN family growth factors. There are three genes under WISP (Wnt-1-induced signaling protein) sub-family. These include WISP-1/CCN4, WISP-2/CCN5 and WISP-3/CCN6. The modular domains of WISP-subfamily are analogous except in their C-terminal domains, which is absent in the CCN5/WISP-2 gene

Fig. 2

Pathobiological implication of CCN5/WISP-2. CCN5/WISP-2 is differentially expressed in different cellular environments of normal breast and breast cancer samples. CCN5/WISP-2 expression in undetected or minimally detected in normal breast epithelial and its expression is predominantly in the nucleus. CCN5/WISP-2 over expressed in non-invasive breast cancer cells and its expression gradually disappears as the disease progressed from non-invasive to invasive cancers with or without ER-α positivity. Highly aggressive cells show no expression of CCN5/WISP-2

Fig. 3

Regulation of CCN5/WISP-2 by estrogen. Estrogen up regulates CCN5/WISP-2 expression through both genomic and none genomic signaling pathways. Constitutively expressed CCN5 in breast cancer epithelial cells shows no effect on proliferation. In contrast, estrogen-induced upregulation of CCN5/WISP-2 is associated with the estrogen-induced proliferation of ER-positive breast cancer cells. mER-α: membrane estrogen receptor-α; ER-α: nuclear ER-α; ERE: estrogen-response element

Fig. 4

CCN5/WISP-2 plays critical roles in EGF and IGF-1-induced cell proliferation and migration and invasion. EGF and IGF-1 growth factors regulate breast cancer cell proliferation or migration and invasion under two different micro-environments. In ER-α − CCN5 positive microenvironment, EGF and IGF-1 induce cell proliferation, while in CCN5 negative microenvironment they help breast cancer cells migrate to and invade the distant places

Fig. 5

EMT is regulated by CCN5/WISP-2 through the modulation of multiple signaling pathways in breast cancer cells. CCN5/WISP-2 is a negative regulator of EMT. It blocks miR-10b expression and TGF-β-signaling in breast cancer cells, which are prime regulators of EMT in breast cancer cells. The mutant p53 proteins, which are also EMT inducers, activate the EMT event in breast cancer cells through the down regulation of CCN5/WISP-2