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 miR10b 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. Keywords Breast cancer . Cell signaling . Invasion and apoptosis Human breast cancer: an overviewBreast cancer, a genetically heterogeneous disease (Lichy et al. 2000;Polyak 2011), is the most commonly identified malignant disease in Western women after nonmelanocytic skin cancer. It attacks one in eight women (~12%), impacting nearly every family worldwide. It is estimated that more than 1 in 4 cancers are breast cancer. Approximately 30% of these women will develop the invasive form of the disease, which is ultimately incurable. Therefore, it is a major health issue for women. Incidence of breast cancer generally increases with age. Women approaching or at menopause have an increased risk of breast cancer. In addition to age, several other factors (i.e., personal and environmental) are associated with the development of this disease. Fortunately, the breast cancer related death rate has been reduced recently due, in part, to early diagnosis and decreased intake of carcinogenic hormones or other unknown factors. However, our current therapeutic options for advanced stages of breast cancer are still fairly limited and ineffective. Thus, there is a need to better understand the molecular basis of the genesis of breast cancer and its progression in order to design targeted, molecularly based therapies.Like other cancers, the genesis of ductal carcinoma in the breast is the result of unprogrammed genetic and epigenetic changes, which lead to mal-regulation of cellular growth.

Human pancreatic cancer progression: an anarchy among CCN-siblings

“…4). Like colon and breast cancers, the CCN5 protein is overexpressed in normal and preneoplastic cells, but is mostly undetected or minimally detected in various pancreatic cancer cell lines and tissue samples (Banerjee and Banerjee 2012;Dhar et al 2007;Russo and Castellot 2010;Sabbah et al 2011;Saxena et al 2001). Functional studies demonstrate that the exposure of pancreatic cancer cells to CCN5 recombinant protein reverses the EMT process (Dhar et al 2007), thereby suggesting that CCN5 silencing may promote tumor progression and drug resistance in PDAC.…”

“…The molecular skeleton of the CCN family and their biological significance CCN is a small family of matricellular proteins with different homologs in different vertebrate species (Banerjee and Banerjee 2012;Brigstock 2003;Jun and Lau 2011;Lau 2016;Perbal 2001;Perbal 2004). In human, these siblings are Cyr61/ CCN1 (Cysteine rich 61), CTGF/CCN2 (Connective tissue growth Factor), CCN3, WISP-1/CCN4 (WNT1 inducible signaling protein 1), WISP-2/CCN5 (WNT1 inducible signaling protein 2) and WISP-3/CCN6 (WNT1 inducible signaling protein 3) with various synonyms (Li et al 2015).…”

“…In human, these siblings are Cyr61/ CCN1 (Cysteine rich 61), CTGF/CCN2 (Connective tissue growth Factor), CCN3, WISP-1/CCN4 (WNT1 inducible signaling protein 1), WISP-2/CCN5 (WNT1 inducible signaling protein 2) and WISP-3/CCN6 (WNT1 inducible signaling protein 3) with various synonyms (Li et al 2015). The CCNsiblings share four conserved, multimodular domains in all except CCN5, in which the C-terminal Cysteine-knot (CT) domain is absent (Banerjee and Banerjee 2012) (Fig. 1).…”

“…The biological significances of CCN-siblings are multifaceted and can be mediated through their cognate receptors integrins with various combinations (Banerjee and Banerjee 2012;Haque et al 2012;Jun and Lau 2011;Lau 2012). The CCN-siblings are either positive or negative regulators of various biological and pathobiological events, depending on the cellular context (Perbal 2001;Perbal 2004).…”

“…The CCN-siblings are either positive or negative regulators of various biological and pathobiological events, depending on the cellular context (Perbal 2001;Perbal 2004). These contexts include cell proliferation, differentiation, migration, angiogenesis, wound-healing and cancers (Banerjee and Banerjee 2012;Brigstock 1999;Brigstock 2002;Brigstock 2003;Ji et al 2014;Lake and Castellot 2003;Leask 2010;Lin et al 2003;Perbal 2001;Perbal 2004). The unique biology of CCN-siblings now places them in an area of great interest in understanding the mechanisms of disease-progression and aiding in the development of mechanism-driven biomarkers that may lead to the discovery of new drug designs.…”