Relationship of coregulator and oestrogen receptor isoform expression to de novo tamoxifen resistance in human breast cancer

Murphy, Leigh C.; Leygue, Etienne; Niu, Yue; Snell, Linda; Sm, Ho; Watson, Peter H.

doi:10.1038/sj.bjc.6600654

Cited by 65 publications

(61 citation statements)

References 30 publications

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“…Although there is a general consensus that the presence of ERa predicts response to tamoxifen (ERa-negative tumours rarely respond), the literature relating to ERb and response to tamoxifen is confusing and conflicting. In part, this is because studies have been performed in two different settings, giving tamoxifen either as an adjuvant to surgery and measuring recurrence rates/times (Murphy et al, 2002;Davies et al, 2004;Esslimani-Sahla et al, 2004;Hopp et al, 2004;O'Neill et al, 2004) or as neoadjuvant treatment and monitoring changes in the size of the primary tumours. In general, the latter studies are more applicable to tumour sensitivity to therapy, as recurrence in the adjuvant setting is determined not only by response to systemic treatment but also by the extent of micrometastatic disease and inherent aggressiveness of the tumour.…”

Section: Discussionmentioning

confidence: 99%

Oestrogen receptor β and neoadjuvant therapy with tamoxifen: prediction of response and effects of treatment

et al. 2006

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In order to elucidate the relative importance of oestrogen receptor (ER)a, ERb and an ERb variant (ERb2/bcx) in the response of breast cancers to tamoxifen, tumour levels of each receptor were assessed in 36 patients before and after 3 months of neoadjuvant treatment with tamoxifen (20 mg daily). All patients were postmenopausal women presenting with large ERa-positive breast cancers. Clinical response to treatment was assessed by tumour volume changes as determined from sequential ultrasounds and pathological response by comparison of the tumour morphology before and after treatment. Of 33 cases, 23 (70%) were classified as having a clinical response and 16 (48%) as having a response pathologically. All tumours stained positively for ERa and ERb and 15 out of 33 (45%) for ERb2/bcx. There were no significant differences in quantitative expression of any receptor between tumours that subsequently responded and that did not, whether response was assessed clinically or pathologically. Tamoxifen treatment was associated with a decrease in ERa, but an increase was the most frequent change (17 out of 33) in ERb, and no consistent change was evident in staining of the ERb2/bcx variant. In summary, ERb1 and ERb2/bcx variant protein are detected in ERa-positive breast tumours but their expression is not associated with a response to tamoxifen. Differential changes in ERa and ERb were seen with treatment.

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Section: Discussionmentioning

confidence: 99%

Oestrogen receptor β and neoadjuvant therapy with tamoxifen: prediction of response and effects of treatment

et al. 2006

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“…In patients treated with chemotherapy as well as TAM, ERβ expression also significantly correlates with increased OS [97,105] and DFS [94,97,104,105]. Higher ERβ expression is observed more frequently in TAM-sensitive breast tumors than in TAM-resistant tumors [113], and lower ERβ is associated with TAM resistance [107,113,114]. One study analyzing 138 postmenopausal patients with invasive cancer observed a trend toward worse outcome in ERβ+ patients treated with TAM, although it was not statistically significant and only seventeen ERβ− tumors were used in this comparison.…”

Section: Clinical Correlations Between Erβ Expression and Response Tomentioning

confidence: 96%

“…Iwase et al have reported that patients with ERβ+ tumors tend to have a better response to endocrine therapy than those with ERβ− tumors [112]. In breast cancer patients treated with adjuvant TAM, high ERβ expression significantly correlates with increased overall [86,107] and disease-free survival [107], no disease progression [113], or no relapse within five years [93,114]. In patients treated with chemotherapy as well as TAM, ERβ expression also significantly correlates with increased OS [97,105] and DFS [94,97,104,105].…”

Section: Clinical Correlations Between Erβ Expression and Response Tomentioning

confidence: 99%

“…We found fifteen studies investigating ERβ expression and response to endocrine therapy. Of these, thirteen examined ERβ protein expression using primarily IHC [82,86,87,93,94,97,104,105,107,[111][112][113][114]. Only three of these studies [82,97,107] separate ERβ tumor populations based on ERα status, although the majority of tumors typically contain both subtypes.…”

Section: Clinical Correlations Between Erβ Expression and Response Tomentioning

confidence: 99%

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ERβ in breast cancer—Onlooker, passive player, or active protector?

2008

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The role of estrogen exposure in breast cancer risk is well-documented, and both estrogen synthesis and actions through the estrogen receptor (ER) have been targeted by therapies to control hormonedependent breast cancer. The discovery of a second ER form and its therapeutic implications sparked great interest. Both the original ERα and the more recently identified ERβ subtypes bind and respond similarly to many physiological and pharmacological ligands. However, differences in phytoestrogen binding have been noted, and subtype-specific ligands have been developed. Cell-based assays show that ERβ and its variants are generally less active on gene transcription than ERα, and may influence ERα activity; however, both gene-and cell-specific responses occur, and nongenomic activities are less well explored. Specific ligands, and methods to disrupt or eliminate receptor subtype expression in animal and cell models, demonstrate that the ERs have both overlapping and distinct biological functions. Overall, in cell-based studies, ERα appears to play a predominant role in cell proliferation, and ERβ is suggested to be antiproliferative.The potential for distinct populations of breast tumors to be identified based on ER subtype expression, and to exhibit distinct clinical behaviors, is of greatest interest. Several studies suggest that the majority of ER-positive tumors contain both subtypes, but that some tumors contain only ERβ and may have distinct clinical behaviors and responses. Expression of ERβ together with ERα favors positive responses to endocrine therapy in most studies, and additional studies to determine if the addition of ERβ to ERα as a tumor marker is of clinical benefit are warranted. In contrast, the positive association between ERβ and HER2 expression in high-grade ERα-negative breast cancer does not favor positive responses to endocrine therapy. Expression of ERβ in specific clinical subpopulations, and the potential for therapies targeting ERβ specifically, is discussed.

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“…There is little consensus however as to the direction of these changes. Steroid receptor coactivator 1 and AIB1 mRNA levels have been associated with tumour progression; however, studies investigating coactivator RNA expression and resistance to ER modulators failed to demonstrate a significant association (Murphy et al, 2000(Murphy et al, , 2002. Recent studies have reported positive associations between AIB1 protein expression, high tumour grade and coexpression with the coactivators p300/ CBP (Hudelist et al, 2003).…”

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confidence: 99%

Inverse relationship between ER-β and SRC-1 predicts outcome in endocrine-resistant breast cancer

et al. 2004

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The oestrogen receptor (ER) interacts with coactivator proteins to modulate genes central to breast tumour progression. Oestrogen receptor is encoded for by two genes, ER-a and ER-b. Although ER-a has been well characterized, the role of ER-b as a prognostic indicator remains unresolved. To determine isoform-specific expression of ER and coexpression with activator proteins, we examined the expression and localisation of ER-a, ER-b and the coactivator protein steroid receptor coactivator 1 (SRC-1) by immunohistochemistry and immunofluorescence in a cohort of human breast cancer patients (n ¼ 150). Relative levels of SRC-1 in primary breast cultures derived from patient tumours in the presence of b-oestradiol and tamoxifen was assessed using Western blotting (n ¼ 14). Oestrogen receptor-b protein expression was associated with disease-free survival (DFS) and inversely associated with the expression of HER2 (P ¼ 0.0008 and Po0.0001, respectively), whereas SRC-1 was negatively associated with DFS and positively correlated with HER2 (Po0.0001 and Po0.0001, respectively). Steroid receptor coactivator 1 protein expression was regulated in response to b-oestradiol or tamoxifen in 57% of the primary tumour cell cultures. Protein expression of ER-b and SRC-1 was inversely associated (P ¼ 0.0001). The association of ER-b protein expression with increased DFS and its inverse relationship with SRC-1 suggests a role for these proteins in predicting outcome in breast cancer.

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Relationship of coregulator and oestrogen receptor isoform expression to de novo tamoxifen resistance in human breast cancer

Cited by 65 publications

References 30 publications

Oestrogen receptor β and neoadjuvant therapy with tamoxifen: prediction of response and effects of treatment

Oestrogen receptor β and neoadjuvant therapy with tamoxifen: prediction of response and effects of treatment

ERβ in breast cancer—Onlooker, passive player, or active protector?

Inverse relationship between ER-β and SRC-1 predicts outcome in endocrine-resistant breast cancer

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