Abstract
The development of multidrug resistance greatly impedes effective cancer therapy. Recent advances in cancer research have demonstrated that acquisition of multidrug resistance by cancer cells is usually accompanied by enhanced cell invasiveness. Several lines of evidence indicated that cross activation of other signaling pathways during development of drug resistance may increase invasive potential of multidrug-resistant (MDR) cancer cells. However, the accurate mechanism of this process is largely undefined. In this study, to better understand the associated molecular pathways responsible for cancer progression induced by drug resistance, a MDR human breast cancer cell line SK-BR-3/EPR with P-glycoprotein overexpression was established using stepwise long-term exposure to increasing concentration of epirubicin. The SK-BR-3/EPR cell line exhibited decreased cell proliferative activity, but enhanced cell invasive capacity. We showed that the expression of metastasis-related matrix metalloproteinase (MMP)-2/9 was elevated in SK-BR-3/EPR cells. Moreover, SK-BR-3/EPR cells showed elevated activation of STAT3. Activation of STAT3 signaling is responsible for enhanced invasiveness of SK-BR-3/EPR cells through upregulation of MMP-2/9. STAT3 is a well-known oncogene and is frequently implicated in tumorigenesis and chemotherapeutic resistance. Our findings augment insight into the mechanism underlying the functional association between MDR and cancer invasiveness.
Highlights
Breast cancer remains the major cause of cancer death among females in spite of advances in breast cancer therapy in the past three decades [1]
We further provide evidence that activation of STAT3 signaling was responsible for enhanced invasiveness of SK-BR-3/EPR cells through upregulation of matrix metalloproteinase (MMP)-2/9
SK-BR-3 is frequently used for studies on breast cancer cell biology and anticancer therapy, but induction of drug resistance in this well-known cell line has not been explored
Summary
Breast cancer remains the major cause of cancer death among females in spite of advances in breast cancer therapy in the past three decades [1]. Multidrug resistance promotes tumor relapse and cancer metastasis clinically [21,22,29,30,31,32] These results suggest a functional relationship between drug resistance and cancer cell invasion and metastasis. Several lines of evidence indicate that cross-activation of other signaling pathways during acquisition of drug resistance may increase the invasiveness potential of MDR cancer cells [9,10,23,33,34,35,36]. We showed that SK-BR-3/EPR cells exhibited enhanced cell invasiveness along with upregulated expression of metastasis-related matrix metalloproteinase (MMP)-2/9. Our findings suggest a novel plausible mechanism employed by MDR cancer cells to promote their invasiveness
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