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.

Loss of WISP2/CCN5 in Estrogen-Dependent MCF7 Human Breast Cancer Cells Promotes a Stem-Like Cell Phenotype

“…Furthermore, recent data indicate that WISP2 can block expression of miR-10b [20], a non-coding RNA known to play a role in invasion and metastasis [21]. Taken together, these findings suggest that loss of WISP2 is associated with breast cancer progression [22].…”

Glucocorticoids induce CCN5/WISP-2 expression and attenuate invasion in oestrogen receptor-negative human breast cancer cells

“…Furthermore, in vivo studies have shown that CCN5 expression is mainly detected in preneoplastic disorders, such as non-invasive DCIS (ductal carcinoma in situ) and atypical ductal hyperplasia, whereas expression levels were either minimal or undetectable in invasive cancer cells [16,18]. These studies indicate that loss of CCN5 activity may promote breast cancer progression [19].…”

Decreased TIP30 expression predicts poor prognosis in pancreatic cancer patients

“…Tip30 mutant derived from HCC patient was able to upregulate N‐cadherin and downregulate E‐cadherin . Insulin‐like growth factor 1 and WNT1‐ inducible signaling pathway protein 2, two important regulators of EMT, were found increased in Tip30‐ null MECs . TIP30 was also found to be involved in Sorafenib‐induced EMT in HCC cells .…”

“…14 Insulin-like growth factor 1 and WNT1-inducible signaling pathway protein 2, two important regulators of EMT, were found increased in Tip30-null MECs. [45][46][47] TIP30 was also found to be involved in Sorafenibinduced EMT in HCC cells. 48 Our in vitro data confirm that decreased TIP30 is able to induce EMT in PDAC cells.…”