Oestrogen-receptor-positive breast cancer: towards bridging histopathological and molecular classifications

The oestrogen receptor (ER) pathway is key for survival and progression in a significant proportion of breast cancers. The ER can be activated by oestrogen or activated due to "crosstalk" with growth factor receptor pathways. Activated ER signals through transcriptional and non-transcriptional mechanisms. Immunohistochemistry (IHC), in spite of the shortcomings, remains the method of choice as it provides for in situ assessment of ER expression within the tumour cells. This capability is lost in tissue grinding methods that assess oestrogen-binding activity or messenger RNAs in tumours. IHC is also not influenced by the presence of non-tumoural cells or low amounts of tumour cells within samples examined. It is clear that ER-positive tumours do not represent a single entity. Irrespective of the terminology used, low-grade ER-positive (also known as luminal A) tumours need to be differentiated from high-grade/highly proliferative ER-positive tumours. This can be done in a variety of ways including but not limited to analysis of FOXA1 and GATA-3 by IHC, and limited molecular profiling by Oncotype DX, MGH2-gene signature, intrinsic gene signature or MapQuant Dx. Several areas of ER biology are still poorly understood; these include: its function in the cytoplasm/plasma membrane, its role in the differentiation to proliferation switch, and pathways associated with resistance to hormonal therapy. A detailed understanding of these areas will permit better classification and a personalised approach to management of ER-positive breast cancers.