Oestrogen receptor: a stable phenotype in breast cancer

Abstract

Summary Oestrogen receptor (ER) expression in breast cancer is regarded as a phenotype that may change during the natural history of the disease or during endocrine therapy. It has been suggested that in up to 70% of tumours that show acquired resistance the mechanism may be changed in ER status from positive to negative. This paper proposes an alternative hypothesis that ER expression is a stable phenotype in breast cancer. The paper reviews the literature on ER expression during the natural history of breast cancer in patients and also presents data on the effect of endocrine therapy on ER expression. If the alternative hypothesis is true it has important implications for treatment from chemoprevention to acquired endocrine resistance in advanced disease. Equally, if the hypothesis is true, attempts to develop laboratory models of endocrine resistance where ER-positive tumours become ER negative need to be re-evaluated.Keywords: breast cancer; oestrogen receptor; stable phenotypeThe oestrogen receptor (ER) is a 65 kDa oestrogen-binding protein expressed by 46-77% of breast cancers (Walt et al., 1976;Knight et al., 1977; Maynard et al., 1978;Brooks et al., 1980;Osborne et al., 1980; Croton et al., 1981;Howell et al., 1984;Hawkins et al.,1987a;Williams et al., 1987;Clarke and McGuire, 1988). It is a generally held view that ER expression is not a permanent phenotype in breast cancer cells Moolgavakar et al., 1980; Encarnacion et al., 1993; Morrow and Jordon, 1993;Nomura et al., 1985;Jordan, 1994;Paik et al., 1994). One reason for this view is the belief that patients with ER-positive primary breast tumours often develop ER-negative metastases in regional lymph nodes or distant sites. This has been interpreted to show that ER negativity correlates with more aggressive tumour biology and loss of cellular control. A second reason is the strong correlation between ER and therapeutic response to primary endocrine therapy (Samaan et al., 1981;Howell et al., 1984;Williams et al., 1987), which formed the basis for early hypotheses of endocrine sensitivity and resistance. Up to 60% of ER-positive tumours respond to hormone therapy (e.g. Tamoxifen), while for ER-negative tumours the figure is around 10% Samaan et al., 1981;Williams et al., 1987). Therapeutic response to endocrine therapy is not permanent and eventually all such tumours progress. As ER negativity is strongly associated with primary resistance to endocrine therapy it is generally accepted that when responding tumours subsequently progress that in the majority of tumours this is due to loss of ER expression by the tumour Moolgavakar et al., 1980;Nomura et al., 1985; Encarnacion et al., 1993;Morrow and Jordan, 1993;Jordan, 1994;Paik et al., 1994). This paper proposes the alternative hypothesis that ER is a stable phenotype in breast cancer cells.The discovery of monoclonal antibodies (Kohler and Milstein, 1975) subsequently led to specific antibodies being raised to ER (Green and Jensen, 1982 . The ER-ICA allowed assessment of tumour tissue sections (King ...

Effect of dietary GLA+/?tamoxifen on the growth, ER expression and fatty acid profile of ER positive human breast cancer xenografts

“…The partial oestrogen antagonist tamoxifen and the newer pure anti-oestrogens are known to down-regulate the expression of ER and ER-regulated gene-products in human breast carcinomas. 12,13,31 In previous work from this unit we have shown a greater extent of ER downregulation to be associated with better quality and longer duration of clinical response on primary tamoxifen. 15 Given the experimental capacity for EFAs to modulate the structure and function of steroid hormone receptors we wished to examine the effect of GLAϩ/Ϫ tamoxifen on the expression of ER in this xenograft model of ERϩve breast cancer.…”

“…Tamoxifen and other anti-oestrogens are known to down-regulate ER. [12][13][14] Our own group has also recently shown that a greater extent of ER down-regulation was correlated with better clinical response on primary tamoxifen. 15 EFAs have previously been reported to modulate the structure and function of steroid hormone receptors, including the ER.…”

Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure

“…Hormone ablation therapy, using ER antagonists, are currently a common first-line therapy for ER-positive breast cancers and function by eliciting cell-cycle arrest in hormone-dependant breast cancer cells (Sutherland et al, 1983;Jensen and Jordan, 2003). Although these anti-estrogen therapies are initially effective, B50% of ER-positive patients develop resistance within their lifetime, ultimately leading to therapeutic failure (Encarnacion et al, 1993;Robertson, 1996;Barker, 2003;Ariazi et al, 2006). As such, a significant fraction of patients with ER-positive disease require adjuvant therapies.…”

Gene expression profiles in breast tumors regarding the presence or absence of estrogen and progesterone receptors

“…17,18 However, the ER expression is gradually lost during tumor progression, leading to a more undifferentiated state. 19 The majority of ER ϩ tumors are diploid, well differentiated, more common in postmenopausal women and less aggressive than ER Ϫ breast tumors. 15,20 However, the plethora of genes that might be associated with each tumor phenotype remains to be fully explored.…”