Investigation of the role of HMGB2 in endocrine resistant breast cancer

The high mobility group box 2 protein (HMGB2) is an abundant chromatin remodelling protein with an affinity for unusual DNA structures. It induces architectural modifications to DNA structure, thereby allowing easier access for transcriptional machinery to promoters of interest. Immunohistochemical staining of our patient tissue microarray revealed that patients who are positive for HMGB2 in their primary tumour have a reduced risk of breast cancer recurrence. This favourable outcome could be due to the interaction between the estrogen receptor α (ERα) and HMGB2, as ERα positive tumours promote the formation of a luminal type tumour, which are less aggressive in general. HMGB2 was identified as a steroid receptor coactivator 1 (SRC1) binding partner in an endocrine resistant cell model, but not the endocrine sensitive model. In contrast to HMGB2, SRC1 has previously been associated with a reduced disease free survival. It is possible that the role of HMGB2 changes as the tumour develops resistance to an endocrine therapy. This study demonstrates that HMGB2 increases the interaction between ERα and SRC1 in an endocrine resistance breast cancer cell line. We have shown that HMGB2 binds to the estrogen regulated breast cancer amplified sequence 3 (BCAS3) promoter in an endocrine resistant cell line. Furthermore, estrogen and tamoxifen treatment increase this level of binding. HMGB2 has also been shown to regulate protein expression of BCAS3 in endocrine resistance. A knock-down study of HMGB2 resulted in a decreased expression of BCAS3. Conversely, over-expressing HMGB2 resulted in increase in BCAS3 protein expression. The findings in this study suggest that a transcriptional complex of SRC1/ERα/HMGB2 regulate the transcriptional activity of BCAS3 in endocrine resistant breast cancer.