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Mutations in the estrogen receptor (ESR1) gene are common in ER-positive breast cancer patients who progress on endocrine therapies. Most mutations localise to just three residues at, or near, the C-terminal helix 12 of the hormone binding domain, at leucine-536, tyrosine-537 and aspartate-538. To investigate these mutations, we have used CRISPR-Cas9 mediated genome engineering to generate a comprehensive set of isogenic mutant breast cancer cell lines. Our results confirm that L536R, Y537C, Y537N, Y537S and D538G mutations confer estrogen-independent growth in breast cancer cells. Growth assays show mutation-specific reductions in sensitivities to drugs representing three classes of clinical anti-estrogens. These differential mutation- and drug-selectivity profiles have implications for treatment choices following clinical emergence of ER mutations. Our results further suggest that mutant expression levels may be determinants of the degree of resistance to some anti-estrogens. Differential gene expression analysis demonstrates up-regulation of estrogen-responsive genes, as expected, but also reveals that enrichment for interferon-regulated gene expression is a common feature of all mutations. Finally, a new gene signature developed from the gene expression profiles in ER mutant cells predicts clinical response in breast cancer patients with ER mutations.

Endocrine manifestations of cancer are usually paraneoplastic syndromes, (i.e. rare systemic manifestations of malignancy due to non-mass cancer effects). The pathobiology involves the production of hormone and related substances that act in an endocrine or paracrine manner, resulting in systemic manifestations. Two major mechanisms are observed: ectopic hormone production by non-endocrine organs and direct hormone secretion from endocrine malignancies. The commonest paraneoplastic syndromes include hypercalcaemia, Cushing's syndrome, and the syndrome of inappropriate antidiuretic hormone secretion. These may be the presenting feature of an underlying malignancy. Rarer syndromes result from ectopic production of less frequently observed bioactive proteins (e.g. growth hormone-releasing hormone, human chorionic gonadotropin, insulin-like growth factors, renin, and vasoactive intestinal peptide) and iatrogenic causes. Here, we review the spectrum of common and rare endocrine manifestations of malignancy.