Upregulating MMP-1 in carcinoma-associated fibroblasts reduces the efficacy of Taxotere on breast cancer synergized by Collagen IV.

Abstract

Chemotherapy is an important comprehensive treatment for breast cancer, which targets micro-environment of tumors as well as their characterisitcs. A previous microarray analysis revealed that matrix metalloproteinase (MMP)-1 was highly upregulated in carcinoma-associated fibroblasts (CAFs) prior to and following treatment with Taxotere under co-culture conditions. However, whether the chemotherapeutic effects of Taxotere were influenced by the changes in MMP-1 remained unclear. The purpose of the present study was to investigate the impact and mechanism of CAFs in regulating the efficacy of Taxotere on breast cancer cells. CAFs isolated from primary invasive ductal human breast tumors following surgical resection, were used in co-culture with MDA-MB-231 cells to simulate the tumor micro-environment. Following the addition of Taxotere, changes in MMP-1 gene and protein expression were assessed by reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. Proliferation, invasion and apoptosis assays revealed that when MMP-1 was upregulated in CAFs, the therapeutic efficacy of Taxotere was reduced in breast cancer cells. Chemosensitivity was significantly increased when MMP-1 expression was inhibited by GM6001. In addition, Collagen IV was upregulated in CAFs following chemotherapy and protected breast cancer cells against chemotherapeutic side effects. Collagen IV expression significantly decreased, as well as MMP-1 expression when GM6001 was added. Proliferation and invasion assays demonstrated that the exogenous addition of Collagen IV weakend the chemotherapeutic effect of Taxotere on breast tumor cells. Overall, the results revealed that in CAFs, MMP-1 synergized with Collagen IV as a key gene in regulating the chemotherapeutic effect of Taxotere on breast tumor cells and served an important role in reducing the efficacy of Taxotere on breast cancer, potentially via the transforming growth factor-β signaling pathway. These fidings provide a theoretical basis for the mechanism of CAFs in reducing the chemotherapeutic effect of Taxotere on breast cancer cells and a novel approach for enhancing the chemosensitivity of tumors.