Role of COX-2 in epithelial–stromal cell interactions and progression of ductal carcinoma in situ of the breast

Abstract

Epithelial-stromal cell interactions have an important role in breast tumor progression, but the molecular mechanisms underlying these effects are just beginning to be understood. We previously described that fibroblasts promote, whereas normal myoepithelial cells inhibit, the progression of ductal carcinoma in situ (DCIS) to invasive breast carcinomas by using a xenograft model of human DCIS. Here, we report that the tumor growth and progression-promoting effects of fibroblasts are at least in part due to increased COX-2 expression in tumor epithelial cells provoked by their interaction with fibroblasts. Up-regulation of COX-2 in DCIS xenografts resulted in increased VEGF and MMP14 expression, which may contribute to the larger weight and invasive histology of COX-2-expressing tumors. Administration of celecoxib, a selective COX-2 inhibitor, to tumor-bearing mice decreased xenograft tumor weight and inhibited progression to invasion. Coculture of fibroblasts with DCIS epithelial cells enhanced their motility and invasion, and this change was associated with increased MMP14 expression and MMP9 protease activity. We identified the NF-B pathway as one of the mediators of stromal fibroblast-derived signals regulating COX-2 expression in tumor epithelial cells. Inhibition of NF-B and COX-2 activity and down-regulation of MMP9 expression attenuated the invasion-promoting effects of fibroblasts. These findings support a role for COX-2 in promoting the progression of DCIS to invasive breast carcinomas, and suggest that therapeutic targeting of the NF-B and prostaglandin signaling pathways might be used for the treatment and prevention of breast cancer.breast cancer ͉ stroma ͉ tumor progression ͉ DCIS ͉ celecoxib

Role of cancer-associated fibroblasts in breast cancer development and prognosis

“…Loss of TGF-b type II receptor in fibroblasts cotransplanted with mammary carcinoma cells into mammary fat pad promoted tumor growth, invasion and metastasis (Cheng et al, 2005). In other studies using tumor xenograft models, CAFs were shown to accelerate the growth rate of tumors and enhanced tumor angiogenesis through mobilization and recruitment of endothelial cells (Hu et al, 2009;Orimo et al, 2005). Together, these results provide clear evidence on the active role of myofibroblasts on various steps of breast carcinogenesis.…”

“…In addition, fibroblasts were shown to promote breast cancer cell invasion by upregulating MMP9 production (Wang et al, 2002). Recently, Hu et al, have shown that fibroblast MMP9 promotes breast cancer cells invasion in a coculture in vitro model (Hu et al, 2009). This indicates that MMP9 plays an important role in the cross-talk between breast tumors and their milieu.…”

Cyclooxygenase-2–dependent lymphangiogenesis promotes nodal metastasis of postpartum breast cancer

“…MCF10DCIS.COM-GFP (and shRNA derivatives) were obtained from K. Polyak (Harvard University, Cambridge, Massachusetts, USA), and 66cl4-luciferase cells (54) were obtained from H. Ford (University of Colorado, Boulder, Colorado, USA). Cells were cultured as described previously (1,31,55). Human dermal LECs (HDLECs) were obtained from PromoCell and maintained according to manufacturer's protocol with the following modifications: for routine culturing, plates were coated with 10 μg/ml Matrigel.…”

Does Microenvironment Contribute to the Etiology of Estrogen Receptor–Negative Breast Cancer?

“…Arguably, aspirin may prove to be the prototype of low-cost, low-risk therapy that provides benefit via its effect on the microenvironment rather than the target epithelium. The prominent COX-2 involvement in progression of ductal carcinoma in situ has prompted the suggestion that its pharmaceutical inhibition could be beneficial (17,84).…”