ERβ Expression and Breast Cancer Risk Prediction for Women with Atypias

Abstract

Estrogen receptor beta (ERβ) is highly expressed in normal breast epithelium and a putative tumor suppressor. Atypical hyperplasia substantially increases breast cancer risk, but identification of biomarkers to further improve risk stratification is needed. We evaluated ERβ expression in breast tissues from women with atypical hyperplasia and association with subsequent breast cancer risk. ERβ expression was examined by immunohistochemistry in a well-characterized 171 women cohort with atypical hyperplasia diagnosed 1967–1991. Nuclear ERβ percent and intensity was scored in the atypia and adjacent normal lobules. An ERβ sum score (percent + intensity) was calculated and grouped as low, moderate or high. Competing risks regression was used to assess associations of ERβ expression with breast cancer risk. After 15 years median follow-up, 36 women developed breast cancer. ERβ expression was lower in atypia lobules than normal lobules, by percent staining and intensity (both p<0.001). Higher ERβ expression in the atypia or normal lobules, evaluated by percent staining, intensity or sum score, decreased the risk of subsequent breast cancer by 2 (p=0.04) and 2.5-fold (p=0.006). High normal lobule ERβ expression conferred the strongest protective effect in pre-menopausal women: the 20-year cumulative incidence of breast cancer was 0% for women <age 45 with high versus 31% for low-moderate ERβ expression (p=0.0008). High ERβ expression was associated with a significantly decreased risk of breast cancer in women with atypical hyperplasia. These data suggest ERβ may be a useful biomarker for risk stratification and a novel therapeutic target for breast cancer risk reduction.

Comprehensive assessment of estrogen receptor beta antibodies in cancer cell line models and tissue reveals critical limitations in reagent specificity

“…Contradictions between IHC findings and antibody-dependent molecular biology methods have contributed to this uncertainty, particularly the lack of clear consensus regarding correlation between tissue expression of ERβ and clinico-pathological parameters (Asgari and Morakabati, 2011, Attia and Ederveen, 2012, Bouchal et al., 2011, Dey et al., 2014, Esslimani-Sahla et al., 2004, Guo et al., 2014a, Guo et al., 2014b, Hieken et al., 2015, Horvath et al., 2001, Leav et al., 2001, Leygue and Murphy, 2013, Myers et al., 2004, Omoto et al., 2002, Risbridger et al., 2007, Roger et al., 2001, Umekita et al., 2006, Zellweger et al., 2013, Zhu et al., 2004). …”

“…However, it has also been reported that ERβ expression is high in bone and lymph node metastases (Bouchal et al., 2011, Zhu et al., 2004) and that high ERβ expression correlates with poor clinical prognosis (Horvath et al., 2001, Zellweger et al., 2013). In breast cancer, high ERβ expression has been described both as a poor (Guo et al., 2014a, Guo et al., 2014b) and favorable (Esslimani-Sahla et al., 2004, Gruvberger-Saal et al., 2007, Hieken et al., 2015, Leygue and Murphy, 2013, Myers et al., 2004, Omoto et al., 2002, Roger et al., 2001) prognostic marker, with others finding no association between clinico-pathological parameters and ERβ expression (Umekita et al., 2006). …”

“…Firstly, that when assessing an antibody by Western blotting in a cell line model, the factor of interest is expressed and secondly, when assessing an antibody's specificity by IHC in tissue, the tissue expression of the factor has been well characterized. In the case of ERβ, these assumptions are problematic, as its expression in commonly used cell line models and in tissues is not universally accepted (Al-Bader et al., 2011, Asgari and Morakabati, 2011, Attia and Ederveen, 2012, Bouchal et al., 2011, Dey et al., 2014, Gruvberger-Saal et al., 2007, Guo et al., 2014a, Guo et al., 2014b, Hieken et al., 2015, Holbeck et al., 2010, Horvath et al., 2001, Leav et al., 2001, Nakajima et al., 2011, Omoto et al., 2002, Risbridger et al., 2007, Shaaban et al., 2003, Skliris et al., 2002, Umekita et al., 2006, Zellweger et al., 2013, Zhou et al., 2012, Zhu et al., 2004). …”

Somatic loss of estrogen receptor beta and p53 synergize to induce breast tumorigenesis

“…Despite the controversy that exists over the clinical importance of ERβ in breast cancer, evidence from in-vitro and clinical studies points toward a role as a tumor suppressor in this malignancy. Loss of ERβ expression has been observed during the development and progression of breast cancer and increased levels of the receptor in normal gland with decreased risk of developing the disease [ 2 – 4 , 29 – 31 ]. Moreover, upregulation of ERβ in breast cancer cells is associated with enhanced apoptosis and decreased invasion [ 5 , 9 ].…”

Perspectives on Triple-Negative Breast Cancer: Current Treatment Strategies, Unmet Needs, and Potential Targets for Future Therapies

“…Estrogen receptor beta (ERβ) is highly expressed in normal mammary tissue [243][244][245]. ERβ expression level is gradually decreased or completely lost during mammary tumorigenesis in a variety of highly aggressive and malignant breast cancers [244,[246][247][248].…”