Abstract
High expression of Rac small GTPases in invasive breast ductal carcinoma is associated with poor prognosis, but its therapeutic value in human cancers is not clear. The aim of the current study was to determine the response of human primary breast cancers to Rac-based drug treatments ex vivo. Three-dimensional organotypic cultures were used to assess candidate therapeutic avenues in invasive breast cancers. Uniquely, in these primary cultures, the tumour is not disaggregated, with both epithelial and mesenchymal components maintained within a 3-dimensional matrix of type I collagen. EHT 1864, a small molecule inhibitor of Rac GTPases, prevents spread of breast cancers in this setting, and also reduces proliferation at the invading edge. Rac1+ epithelial cells in breast tumours also contain high levels of the phosphorylated form of the transcription factor STAT3. The small molecule Stattic inhibits activation of STAT3 and induces effects similar to those seen with EHT 1864. Pan-Rac inhibition of proliferation precedes down-regulation of STAT3 activity, defining it as the last step in Rac activation during human breast cancer invasion. Our data highlights the potential use of Rac and STAT3 inhibition in treatment of invasive human breast cancer and the benefit of studying novel cancer treatments using 3-dimensional primary tumour tissue explant cultures.
Highlights
In recent years there has been a growing appreciation that developing new effective treatments may be facilitated by experimental systems that replicate the multi-component tumour environment [1, 2]
We show that Rac and Signal Transducer and Activator of Transcription-3 (STAT3) inhibition regimens are effective at blocking tumour invasion ex vivo, independently of known clinical biomarkers such as histological grade and ER status
Rac1 is over-expressed in invasive human breast cancer
Summary
In recent years there has been a growing appreciation that developing new effective treatments may be facilitated by experimental systems that replicate the multi-component tumour environment [1, 2]. We have developed a threedimensional culture system that allows maintenance of complex breast cancer specimens explanted ex vivo for up to four weeks after surgical resection in a supporting matrix of exogenous stromal type I collagen [4, 5] These ex vivo cultures offer a relatively rapid and quantitative avenue to explore mechanisms of tumour spread and evaluate new treatments. The ability of Rac to induce metastasis has been closely linked to mesenchymal type motility in cancer cell lines [7,8,9] This is likely to be due to Rac activity near the cell leading edge and subsequent disruption of cellular organization [10, 11]. Rac activity must be tightly regulated in order to maintain normal epithelial cell junction formation, polarization and proliferation [12,13,14]
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