Breast cancer is the most common malignant disease in women. The worldwide incidence of breast cancer continues to rise, and has become a leading cause of cancer deaths. There is an urgent need to discover new biomarkers for early detection as well as to identify new pathways or targets for drug therapy. More than 90% of breast cancers are sporadic or acquired somatic mutations. It is believed that genomic instability might promote the accumulation of genetic changes in apparently normal breast tissue, even before histological abnormalities are detectable. Although genomic instability is commonly found in invasive carcinomas, little is known about the timing of critical changes in early tumorigenesis or changes associated with the transition from normal cells to invasive breast carcinoma. We have recently identified mobile DNA elements, L1 retrotransposons that are differentially expressed in normal and breast cancer tissue. In normal healthy tissues, L1 proteins are completely absent throughout the cell cycle. In contrast, L1 retrotransposon is overexpressed in several clinically relevant breast cancer tissues. The unchecked L1 activity would create havoc in the human genome, initially through insertional mutations and later by genomic instability through high levels of double-strand DNA breaks, deletions, and genomic rearrangements. Although the mechanistic pathways that activate L1 expression are not known, its expression and its effect on genomic instability have given rise to suggestion that it may serve as useful biomarkers in the early diagnosis of breast cancer or in the prediction of cancer onset. Specifically, L1 biomarker is useful in the prediction of genetic changes associated with the transition from normal to hyperplasia to insitu breast carcinoma to invasive breast cancer. With collaboration of the ACT Pathology, Canberra Hospital, we are currently testing this L1 biomarker using a panel of archived breast cancer tissues and confirming the association of L1 expression with clinical and morphological features of breast cancer samples.
Given the deleterious nature of retrotransposon activity and genomic instability in breast cancer development, we are interested in the mechanisms by which the L1 retrotransposon is regulated in normal healthy cells, but not in cancer cells. Using deep-sequencing technology combined with microarray analysis, we have recently identified a class of small non-coding endo-siRNAs as a key regulator of L1 retrotransposons in the human genome. Currently, we are testing the epigenetic role of endo-siRNAs including DNA methylation, packaging retrotransposons into inactive heterochromatin structures, and RNAi-mediated silencing pathways. This research project will shed new light into how and why disease states arise in breast tissues and how the altered expressions of L1 retrotransposons activate the process of breast cancer development. Unravelling the relationship between small regulatory endo-siRNAs and DNA methylation in the development of cancers may provide new strategies for future therapeutic and diagnostic approaches.