Estrogen receptor (ER) α mutations in breast cancer: hidden in plain sight

Abstract

The idea that somatic ERα mutations could play an important role in the evolution of hormone-dependent breast cancers was proposed some years ago (Fuqua J Mammary Gland Biol Neoplasia 6(4):407-417, 2001; Dasgupta et al. Annu Rev Med 65:279-292, 2013), but has remained controversial until recently. A significant amount of new data has confirmed these initial observations and shown their significance, along with much additional work relevant to the treatment of breast cancer. Thus, it is the purpose of this review to summarize the research to date on the existence and clinical consequences of ERα mutations in primary and metastatic breast cancer.

Fig. 1

The progression of invasive breast cancer (IBC). Approximately 50% of primary breast tumors have already metastasized to the axillary lymph nodes upon presentation. Of these axillary node-positive (N+) patients, 65-75% will eventually develop distant metastasis, while only 25% of axillary node-negative (N-) patients will metastasize. We hypothesize that up-regulation of ER expression, and clonal selection of ER mutants are involved in the progression and metastasis of many breast tumors. Reprinted with kind permission from Springer Science+Business Media: Journal of Mammary Gland Biology and Neoplasia, The Role of Estrogen Receptors in Breast Cancer Metastasis, volume 6, 2001, page 409, Suzanne A.W. Fuqua, Figure 1.

Fig. 2

Detection of the K303R ER mutation requires optimized primer extension sequencing technology. Panel A shows primer extension sequencing (SnapShotTM) technology applied to high molecular weight DNA isolated from a frozen invasive breast tumor. Panel B shows the same DNA which had been sheared to approximately 200 bp which allows resolution of the mutation. Panel C shows enhanced detection of the mutation in sheared DNA from Panel B and the use of optimized primer size.

Fig. 3

Current schemata of ER (ESR1 mutations) placed alongside their genomic locations and ER genomic structure. Hormone-independent activity is contained within the activation function 1 (AF-1) domain and hormone-dependent activity is contained within the activation function 2 (AF-2) domain. Mutations within AF-2 can cause hormone-independent activity. The hormone binding domain (HBD), hinge domain (HD), and ligand binding domain (LBD) locations are indicated. Amino acid resides are indicated. as well as functional A-E domains. References include [30,61,62,27,28,26,63,64,29,65,66,49,55,53,50,22,51,44].

Fig. 4

Clinical implications of ER mutations in both primary and metastatic breast cancers, and strategies to utilize mutations for clinical therapeutic decisions.