ER, ERα36, GPER-1, HER-2, HER-3 and NRG-1 status and mutations predict breast cancer progression during endocrine treatment

Most breast cancers are driven by the oestrogen receptor (ER). Tamoxifen is an effective treatment for ER-positive (ER+ve) breast cancer. However, a subgroup of women presents with de novo or acquired endocrine therapy-resistant tumours. The ER, G protein-coupled oestrogen receptor 1 (GPER-1), human epidermal growth factor receptor 2 (HER-2), human epidermal growth factor receptor 3 (HER-3), and neuregulin 1 (NRG-1) have been associated with endocrine therapy-resistance. However, clinical data assessing survival based on the expression of these molecules has consistently shown mixed results. To that end, the prognostic value of the aforementioned molecules in the progression of breast cancer and endocrine resistance was investigated using three methodologies: metaanalysis with data from 51,945 breast cancer patients, laboratory work with two in vitro models of tamoxifen-resistant and -sensitive MCF-7 cell lines, and bioinformatic analysis with data from the Catalogue of Somatic Mutations in Cancer (COSMIC). For the first time, meta-analytical work showed the following in breast cancer patients. ER positivity was a favourable prognostic factor. GPER-1 expression was a favourable prognostic factor, but this effect reversed with plasma membrane localisation during tamoxifen treatment. HER-2 and HER-3 negativity were associated with greater survival. NRG-1 expression had no prognostic value. Results from in vitro models showed the tamoxifen-resistant cell line presented higher levels of total GPER-1 and ERα36 expression at the mRNA level, and lower levels of total ER and higher levels of HER-2 expression at the protein level. Bioinformatical analyses revealed mutation R233G in the ER may stimulate ER-mediated cell division. GPER-1 mutation L129M is likely to lower GPER-1-dependent apoptosis. Mutations W906C and W877C in HER-2 and HER-3, respectively, may increase proliferation. NRG-1 mutant L426H may lower NRG-1-mediated apoptosis. The novel results presented in this investigation suggest that an interplay between genetic alterations and expression levels of ER, ERα36, GPER-1, HER-2, HER-3 and NRG-1 may contribute to the tamoxifen-refractory phenotype. Overall, results presented in this thesis contribute to the understanding of the tamoxifen-refractory phenotype and provide the impetus to consider expression and mutation of these molecules prior to planning treatment schedules – thus paving the way for future clinical applications.