STAT3-RANTES Autocrine Signaling Is Essential for Tamoxifen Resistance in Human Breast Cancer Cells

Abstract

The acquisition of tamoxifen resistance is a major therapeutic problem in breast cancer. We developed a tamoxifen-resistant MCF-7 (TRM-7) cell line to elucidate the molecular mechanisms and factors associated with acquisition of such resistance. We showed that phosphorylation of STAT3 at tyrosine 705 (Y705) and RANTES expression are increased in response to tamoxifen in human breast cancer cells. On the basis of these results, we hypothesize that upregulated STAT3 phosphorylation and RANTES may be correlated with the development of drug resistance. Here, we showed that STAT3 and RANTES contribute to the maintenance of drug resistance. STAT3 phosphorylation is constitutively retained via a RANTES autocrine loop, which in turn upregulates antiapoptotic signals in TRM-7 cells. STAT3-RANTES autocrine signaling affected expression of anti-apoptotic BCL-2 family genes and prevented TRM-7 cells from undergoing programmed cell death by inhibiting PARP and caspase-9 cleavage. Subsequently, blockade of STAT3 and RANTES in TRM-7 cells resulted in reduction of antiapoptotic signals, which was rescued by exogenous RANTES treatment; drug resistance was also restored. Taken together, our results suggested that STAT3-RANTES autocrine signaling is essential for maintenance of drug resistance and inhibition of programmed cell death. These mechanisms of STAT3-RANTES autocrine signaling suggest a novel strategy for management of patients with tamoxifen-resistant tumors. Mol Cancer Res; 11(1); 31-42. Ó2012 AACR. IntroductionBreast cancer is the second most common cancer worldwide after lung cancer, the fifth most common cause of cancer death, and the leading cause of cancer death in women. The global burden of breast cancer exceeds that of all other cancers, and its incidence is increasing (1). In women younger than 50 years with breast cancer, chemotherapy increases the 15-year survival rate by 10%,

Cisplatin-induced CCL5 secretion from CAFs promotes cisplatin-resistance in ovarian cancer via regulation of the STAT3 and PI3K/Akt signaling pathways

“…Here, we investigated the role of cisplatin-induced CCL5 secretion from CAFs in ovarian cancer cell resistance to cisplatin. CCL5, also known as RANTES, is a member of the CC-chemokine family and plays a critical role in tumor progression and prognosis (3). A previous study demonstrated that CCL5 could be used as a prognostic indicator for breast and cervical cancer (6).…”

“…Mice were housed under specific pathogen-free conditions and all animal experiments were carried out in accordance with the Guide for the Care and Use of Laboratory Animals of Tongji Hospital in Wuhan, China. When tumors reached a mean size of 50 mm 3 , the mice were randomly assigned into two groups with 6 mice per group. The experiment group was treated with DDP 5 mg/kg intraperitoneally once a week for four weeks.…”

“…Furthermore, a previous study demonstrated that using small molecule inhibitors or interference RNA could rescue the inherent and acquired chemoresistance of ovarian cancer cells (18). Moreover, the STAT3-CCL5 signaling pathway has been shown to play an important role in tamoxifen resistance in human breast cancer cells (3). The PI3K/Akt signaling pathway also plays a lead role in tumor progression and chemotherapy resistance and this signaling pathway can be activated by CCL5 (19).…”

“…CCL5 (also known as RANTES), is a member of the CC-chemokine family and plays a crucial role in chemotherapy resistance, relapse, metastasis and migration in human malignancy (3). Many studies have demonstrated that altered CCL5 expression in patients with breast tumors, melanoma, lung, prostate, cervical and pancreatic cancer is significantly correlated with disease progression, poor prognosis and tumor cell chemotherapy resistance (4-7).…”

CCL5/RANTES is important for inducing osteogenesis of human mesenchymal stem cells and is regulated by dexamethasone

“…Moreover, CCL5 can promote osteogenesis as revealed by increasing ALP activity and elevating ALP, DLX5, and BSP gene expression. CCL5 has been shown to associate with STAT3 in an autocrine-loop in breast cancer cells (20), and STAT3 was also shown to be involved in osteogenesis (21). Therefore, our future studies will examine whether there is an association between STAT3 and CCL5 that is crucial for osteogenesis of hMSCs.…”