Dwek, Miriam Victoria; (1998) Mapping oligosaccharides of aggressive breast cancer. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Virtually all deaths from breast cancer result from the growth of metastases and increasing evidence suggests that cancer cell oligosaccharides may be involved in the metastatic process. We have investigated oligosaccharides as potential biochemical markers for metastasis and survival after breast cancer. We set out to map oligosaccharides from breast cancers that were rapidly fatal and compare them with cancers that did not form clinical metastases. To do this, it was necessary to use tissues removed from patients who were followed-up for at least 5-10 years. Initially, we developed methods for the release of intact oligosaccharides from archival fixed tissues. The methods proved to be sufficiently sensitive to enable the detection of, typically, 50 different oligosaccharides from single pathology sections. To seek new markers for the clinical behaviour of breast cancer, oligosaccharides were extracted from 76 specimens, with different clinical outcomes and 5-10 years follow- up. The heterogeneous mixture of oligosaccharides from the different breast cancer specimens was separated using normal-phase high performance liquid chromatography. Pilot studies had previously identified a number of oligosaccharides that appeared related to aggressive breast cancer behaviour. The levels of these in the oligosaccharide pool from the 76 breast cancer specimens were compared, by multivariate analysis, to time to first recurrence and breast cancer death. Some of the oligosaccharides were found to be independent markers of poor prognosis. The expression of one oligosaccharide correlated with cancer tissue staining using the lectin from the snail Helixpomatia. This lectin has previously been shown to detect breast cancers associated with poor prognosis. As a result of this work, flirther studies will be undertaken, in the first instance, to sequence the oligosaccharide structures which we have found to be associated with aggressive, clinically metastatic, breast cancer.

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