Ethanol‐induced in vitro invasion of breast cancer cells: The contribution of MMP‐2 by fibroblasts

Abstract

Ethanol is a tumor promoter and may promote metastasis of breast cancer. However, the underlying cellular/molecular mechanisms remain unknown. Overexpression and high activity of matrix metalloproteinase-2 (MMP-2) are frequently associated with metastatic breast cancers and serve as a prognostic indicator of clinical outcome. MMP-2 is predominantly expressed in stromal fibroblasts and plays a pivotal role in regulating the invasive behavior of breast tumor cells. We hypothesized that ethanol may enhance the invasion of breast tumor cells by modulating the activity of fibroblastic MMP-2. With in vitro models (HS68 and CCD1056SK human fibroblasts), we showed that ethanol at physiologically relevant concentrations (50 -200 mg/dl) activated MMP-2; conversely, at a higher concentration (400 mg/dl), it inhibited the MMP-2 activity. Consistently, conditioned medium collected from ethanol ( Key words: alcohol; ErbB; metastasis; proteinases; signal transductionBreast cancer is a leading cause of morbidity and mortality in women. 1 The endogenous and environmental factors that contribute to its etiology remain elusive. Despite being responsive to hormonal manipulation and chemotherapy, relapse after treatment is common, particularly in patients presenting with metastatic disease. 2 The metastatic process involves the degradation of different macromolecular components of the extracellular matrix (ECM) and basement membranes and is regulated by intrinsic properties of the tumor cells as well as microenvironmental factors. Alcohol is a tumor promoter; there is a positive correlation between alcohol intake and the risk of several human cancers, including mouth/oropharyngeal cancer, oesophageal cancer, liver cancer and breast cancer. [3][4][5][6][7][8][9][10][11] Epidemiologic studies indicate that alcohol consumption is associated with advanced and invasive breast tumors, [12][13][14] suggesting that alcohol may enhance tumor development and metastasis. These epidemiologic results are supported by experimental studies using animal models and cell culture systems, which show that ethanol promotes mammary tumorigenesis and stimulates proliferation as well as invasion of breast cancer cells. [15][16][17][18][19][20][21] The molecular mechanisms underlying ethanol action, however, remain to be determined.Abnormal communication between the mammary epithelium and stromal cells promotes tumorigenesis and development of breast carcinomas. 22 Cancer-stroma interaction is mediated at least in part through the matrix metalloproteinases (MMPs). MMPs are a family of zinc-dependent endopeptidases that collectively are capable of degrading all components of the ECM. MMPs have been implicated in normal matrix remodeling events such as development of the mammary gland 23 and in pathologic conditions, including tumor invasion and metastasis. 24 Coupled with their function in metastasis, the MMPs also have a role in carcinogenesis. 25,26 High levels of MMP-2 and MMP-9 have been found to correlate with enhanced metastasis and poor prognosis in ...

Matrix Metalloproteinase 2 (MMP2) and MMP9 Secreted by Erythropoietin-Activated Endothelial Cells Promote Neural Progenitor Cell Migration

“…Therefore, in stroke brain, rhEPO-enhanced angiogenesis could attract neural progenitor cells via increased MMP2 and MMP9, which may partially explain in vivo findings that rhEPO increases the number of new neurons around the ischemic boundary . Although the MMP inhibitor used in the present study has been shown to block MMP2 activity (Liao et al, 2003;Aye et al, 2004), our results cannot rule out a role for MMP9 in mediating neural progenitor cell migration, and additional studies are warranted.…”

Ethanol stimulates the secretion of matrix metalloproteinases 2 and 9 in MCF-7 human breast cancer cells

“…For our part, we have postulated that an increase in metalloproteinase expression could be involved in the stimulation of migration observed in breast cancer cells following ethanol exposure. Indeed, it has been recently shown in fibroblasts that ethanol stimulates the secretion of MMP-2 (29), which plays a critical role, together with MMP-9, in extracellular matrix degradation and tumor cell invasion in breast cancer (15,17). Moreover, ethanol activates the estrogen signaling pathway in breast cancer cells (14,21), and some studies show that estrogens are able to stimulate the secretion of MMP-2 and -9 (18,19).…”

“…Interestingly, a recent study shows that, in fibroblasts, ethanol increases MMP-2 secretion by the protein kinase C pathway (PKC) (29). Nevertheless, TPA, a PKC activator, stimulated the secretion of MMP-9 while it did not change the level of MMP-2 in MCF-7 cells and in organotypic cultures of human breast cancer tissue (35,36).…”

Latest research progress in the correlation between baicalein and breast cancer invasion and metastasis

“…The initial step of breast cancer cell metastasis is characterized by the breakdown of the basement membrane, a process known to be dependent on type IV collagen-degrading enzymes, predominantly MMP-2 and MMP-9 (28). The expression of MMPs, particularly the gelatinases (MMP-2 and MMP-9), has been associated with a high potential of metastasis in several human carcinomas, including breast cancer (29,30 …”