Estrogen receptor alpha and beta in health and disease

Purpose The clinicopathologic importance of a second estrogen receptor (ER), ER-β, in breast cancers has been intensely studied; however, there is still no real consensus regarding the clinical utility of an ER-β assay, probably because of the lack of standardized methodology, the presence of several ER-β isotypes (ER-β1-5, and so on), and, more importantly, the lack of convincing data on whether the ER-β status provides clinically useful information over what is already provided by the traditional ER-α/progesterone receptor (PR) assay. A large and systematic study is needed to address these important issues. Patients and Methods Archival materials of 442 invasive breast cancers from women treated with adjuvant tamoxifen monotherapy and with a long follow-up period (median, 11.1 years) were subjected to immunohistochemical study using three commercially available anti–ER-β antibodies that detect ER-β1-3 (ER-βN), ER-β1, and ER-βcx (ER-β2). Results Positive staining for ER-βN or ER-β1 was associated with si...

Clinical Importance of Estrogen Receptor-β Evaluation in Breast Cancer Patients Treated With Adjuvant Tamoxifen Therapy

X-box binding protein 1 (XBP-1) is stimulated by endoplasmic reticulum stress as part of the unfolded protein response (UPR), which can promote apoptosis or cell survival. Non-conventional splicing, stimulated during the UPR, converts mRNA for "unspliced" XBP-1U to "spliced" XBP-1S mRNA. XBP-1 mRNA is oestrogen-responsive, but XBP-1S confers oestrogen independence and anti-oestrogen resistance to breast cancer cell lines. We therefore evaluated XBP-1 mRNA splicing as a factor in response of breast cancer patients to endocrine treatment. XBP-1 isoforms were measured by quantitative RT-PCR in 100 primary breast cancer patients treated with adjuvant tamoxifen (including 30 ER alpha-negative cases). In ER alpha-positive cases, levels of XBP-1U mRNA correlated with ER alpha mRNA levels and were lower in grade 3 tumors. Higher levels of XBP-1U mRNA were significantly associated with breast cancer survival (Log-rank p = 0.002; Cox hazard ratio (HR) 0.2, p = 0.005), independent of grade, size, nodal status and progesterone receptor status. However, in the full cohort, higher ratios of XBP-1S/XBP-1U mRNA (indicating enhanced splicing) were associated with poor survival (Log-rank p = 0.03; Cox HR 2.3, p = 0.03) and related factors: ER alpha-negative status, progesterone receptor negative status, grade 3 tumors and greater proliferation. Significant associations with poor outcome were also seen for XBP-1 splicing in ER alpha-positive cases. Our findings, that XBP-1 isoforms are differently associated with outcome of endocrine therapy for patients, can be explained by higher levels of dominant-negative XBP-1U favouring apoptosis of tumor cells and higher levels of XBP-1S increasing tumor survival.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.23479

Expression and splicing of the unfolded protein response gene XBP-1 are significantly associated with clinical outcome of endocrine-treated breast cancer.

ERβ in Breast Cancer – Onlooker, Passive Player, or Active Protector?

Estrogen receptors in breast carcinogenesis and endocrine therapy

This study has tested the hypothesis that comparison of protein and mRNA expression for ERalpha and ERbeta1 by human breast cancers provides novel information relating to the clinical and pathological characteristics of human breast cancers. Expression of ERalpha and ERbeta1 was identified in 167 invasive cancers from postmenopausal women treated only with endocrine therapy. The cohort included 143 cases receiving only adjuvant Tamoxifen following surgery. ERalpha and ERbeta1 expression was analysed by immunohistochemistry and reverse transcription RT-PCR and compared with clinical progression of individual cancers. ERalpha protein was closely associated with the corresponding RNA detected by RT-PCR (Chi-square, P<0.001). In contrast, ERbeta1 protein and mRNA were inconsistent. Although an association was identified between ERalpha and ERbeta mRNAs (Chi-square, P<0.001) and between ERalpha protein and ERbeta1 mRNA (Chi-square, P<0.027), no association was identified for the ERalpha and ERbeta1 proteins detected by immunohistochemistry. ERbeta1 was not associated with outcome. However, in the absence of ERalpha, ERbeta1 protein expression was associated with elevated cell proliferation. There was a trend for the ERbeta1 protein-positive cases to have a worse outcome, both within the group as a whole as well as within the ERalpha-positive Tamoxifen-treated cases. This study has confirmed the hypothesis that expression of ERalpha is an important determinant of breast cancer progression, and has further demonstrated that ERbeta1 may play a role in the response of breast cancers to endocrine therapy.

/pdf/wild-type-oestrogen-receptor-beta-erb1-mrna-and-protein-j4d44wdvfu.pdf

Wild-type oestrogen receptor beta (ERβ1) mRNA and protein expression in Tamoxifen-treated post-menopausal breast cancers

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Wild-type oestrogen receptor beta (ERβ1) mRNA and protein expression in Tamoxifen-treated post-menopausal breast cancers