Project description:The transcriptome changes of breast cancer cell SUM1315, with or without co-culture with bone marrow stroma cells, upon cisplatin (CDDP) treatment.
Project description:Transcription profiling of mouse bone marrow macrophages (BMM) compared to BMM co-cultured with 4T1.2 breast cancer cells, treated with tumour cell supernatant, or RAW macrophage cell line
Project description:Chemotherapy resistance presents a major hurdle for cancer treatment. We proposed to identify the molecular changes through which breast cancer cells evolve resistance to conventional treatment, here cisplatin, so targeted therapy can be developed. Candidate approach RNAi screening was combined with cisplatin treatment in order to identify molecular pathways conferring survival advantages. The screening identified ATP7A, a copper transport ATPase responsible for the intercellular movement and sequestering of cisplatin, as a therapeutic target. Copper chelation with tetrathiomolybdate (TM) targets ATP7A. TM in combination with cisplatin sensitized drug-resistant breast cancer cells. Allograft and xenograft models in aythymic mice treated with TM/cisplatin combination therapy inhibited tumor growth and increased survival compared with monotreated mice. Examination of the molecular effects of TM on cisplatin efficacy in drug-resistant tumors revealed reduced levels of APT7A, reduced cisplatin sequestering by ATP7A and increased nuclear availability of cisplatin. Further, we showed that TM treatment combined with cisplatin reduced the half-life of ATP7A in human breast cancer cell lines. This finding offered the potential to combat drug platinum-resistant tumors and sensitize patients to conventional breast cancer treatments by identifying and targeting resistant tumors’ unique molecular adaptations.
Project description:Transcription profiling by array of human breast epithelium and stroma in normal reduction mammoplasty and invasive breast cancer patients
Project description:Transcription profiling by high throughput sequencing of murine bone marrow endothelial cells and bone marrow stroma, in vitro and in vivo, with and without hematopoietic stem cells co-culture