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Brain metastasis of breast cancer profoundly affects the cognitive and sensory functions as well as morbidity of patients, and the 1 year survival rate among these patients remains less than 20%. However, the pathological mechanism of brain metastasis is as yet poorly understood. In this report, we found that metastatic breast tumour cells in the brain highly expressed IL-1β which then 'activated' surrounding astrocytes. This activation significantly augmented the expression of JAG1 in the astrocytes, and the direct interaction of the reactivated astrocytes and cancer stem-like cells (CSCs) significantly stimulated Notch signalling in CSCs. We also found that the activated Notch signalling in CSCs up-regulated HES5 followed by promoting self-renewal of CSCs. Furthermore, we have shown that the blood-brain barrier permeable Notch inhibitor, Compound E, can significantly suppress the brain metastasis in vivo. These results represent a novel paradigm for the understanding of how metastatic breast CSCs re-establish their niche for their self-renewal in a totally different microenvironment, which opens a new avenue to identify a novel and specific target for the brain metastatic disease., (Copyright © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.)

The molecular mechanisms that operate within the organ microenvironment to support metastatic progression remain unclear. Here, we report that upregulation of hyaluronan synthase 2 (HAS2) occurs in highly metastatic breast cancer stem-like cells (CSC) defined by CD44(+)/CD24(-)/ESA(+) phenotype, where it plays a critical role in the generation of a prometastatic microenvironment in breast cancer. HAS2 was critical for the interaction of CSCs with tumor-associated macrophages (TAM), leading to enhanced secretion of platelet-derived growth factor-BB from TAMs, which then activated stromal cells and enhanced CSC self-renewal. Loss of HAS2 in CSCs or treatment with 4-methylumbelliferone, an inhibitor of HAS, which blocks hyaluronan production, drastically reduced the incidence and growth of metastatic lesions in vitro or in vivo, respectively. Taken together, our findings show a critical role of HAS2 in the development of a prometastatic microenvironment and suggest that HAS2 inhibitors can act as antimetastatic agents that disrupt a paracrine growth factor loop within this microenvironment.

We report a case of a 52-year-old female with multiple skin metastases from breast cancer who responded to S-1. She underwent surgery of her right breast in March 2000 and the left in June 2006. Multiple skin metastases were later detected. As there was no hormone sensitivity, chemotherapy was selected. We started treatment with administration of S-1 at 120mg/day(4 weeks)and trastuzumab. Thoracic CT at the end of the three courses revealed the disappearance of the multiple skin metastases. No major side effects were seen. It was concluded from these findings that S-1 could be safely and effectively administered to advanced breast cancer patients.

We report an 83-year-old female with axillary node metastasis from breast cancer who responded to trastuzumab/ capecitabine combination therapy. In April 2007, she underwent surgery and at the same time axillary node metastasis was detected. As there was no hormone sensitivity, chemotherapy was selected, and administration of capecitabine at 1,800 mg/day(2 divided doses)and trastuzumab was initiated. Thoracic CT at the end of the six courses revealed the disappearance of the axillary node metastasis. No major side effects were produced. It was concluded from these findings that trastuzumab/capecitabine combination therapy could be safely and effectively administered to elderly advanced breast cancer patients.

We experienced a case of multi-drug resistant recurrent breast cancer with multiple bone metastases achieving a significant improvement by TS-1 and trastuzumab. The prior treatments including taxane or vinorelbine and trastuzumab were changed in the regimen to TS-1 and trastuzumab because of the progressive disease. TS-1 was administered orally at 100 mg/day everyday for 2 weeks, followed by a 1-week rest interval as 1 cycle, and trastuzumab was injected at 2 mg/kg/week for 4 weeks, followed by a 1-week rest interval as 1 cycle. After 3 cycles of the treatment, the level of tumor markers and tumor sizes of bone metastases became reduced. In conclusion, the combination treatment of TS-1 and trastuzumab is thought to be effective for multi-drug resistant recurrent breast cancer.