Endocrine therapy has become one of most effective forms of targeted adjuvant therapy for hormone-sensitive breast cancer and may be given after surgery or radiotherapy, and also prior, or subsequent to chemotherapy. Current commonly used drugs for adjuvant endocrine therapy can be divided into following three classes: selective estrogen receptor modulators, aromatase inhibitors and selective estrogen receptor downregulators. Tumor cells can develop resistance to endocrine therapy, a major obstacle limiting the success of breast cancer treatment. The complicated crosstalk, both genomic and nongenomic, between estrogen receptors and growth factors was considered to be a crucial factor contributing to endocrine resistance. However, resistance to this therapy is thought to be a progressive, step-wise process, and the underlying mechanism remains unclear. In this review, we summarize the possible biological and molecular mechanisms that underlie endocrine resistance, and discuss some novel strategies to overcoming these issues.

It is a therapeutic strategy for cancers including pancreatic to inhibit proteasome activity. Disulfiram (DSF) may bind copper (Cu) to form a DSF-Cu complex. DSF-Cu is capable of inducing apoptosis in cancer cells by inhibiting proteasome activity. DSF is rapidly converted to diethyldithiocarbamate (DDTC) within bodies. Copper(II) absorbed by bodies is reduced to copper(I) when it enters cells. We found that DDTC and copper(I) could form a binuclear complex which might be entitled DDTC-Cu(I), and it had been synthesized by us in the laboratory. This study is to investigate the anticancer potential of this complex on pancreatic cancer and the possible mechanism. Pancreatic cancer cell lines, SW1990, PANC-1 and BXPC-3 were used for in vitro assays. Female athymic nude mice grown SW1990 xenografts were used as animal models. Cell counting kit-8 (cck-8) assay and flow cytometry were used for analyzing apoptosis in cells. A 20S proteasome assay kit was used in proteasome activity analysis. Western blot (WB) and immunohistochemistry (IHC) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays were used in tumor sample analysis. The results suggest that DDTC-Cu(I) inhibit pancreatic cancer cell proliferation and proteasome activity in vitro and in vivo. Accumulation of ubiquitinated proteins, and increased p27 as well as decreased NF-κB expression were detected in tumor tissues of DDTC-Cu(I)-treated group. Our data indicates that DDTC-Cu(I) is an effective proteasome activity inhibitor with the potential to be explored as a drug for pancreatic cancer.

Bone marrow-derived mesenchymal stem cells (MSC) have been shown to home into tumor tissues, where they promote tumor growth and suppress immune rejection. In this study, we tested whether MSCs engineered to express the immune stimulating factor LIGHT, a member of the TNF superfamily, could induce tumor regression. Using in vitro and in vivo migration assays, we found that LIGHT-expressing MSCs (MSC-L) displayed a strong tropism for tumor tissues. MSC-L treatment activated the LIGHT-signaling pathway, effectively organizing a potent antitumor immune response that stimulated an influx of T cells and inhibited tumor growth in vivo. CD4 T cells were found to play a role in the induction phase of the immune response, and CD8 T cells were shown to be essential for the effector phase. Together, our findings indicate that MSCs can effectively home into and deliver immune stimulating molecules to tumor tissues, thereby reversing the immune-suppressive environment, promoting antitumor immunity, and inhibiting tumor growth. Cancer Res; 72(12); 2980-9. Ó2012 AACR.