Relationship Between Plasma Estradiol Levels and Estrogen-Responsive Gene Expression in Estrogen Receptor–Positive Breast Cancer in Postmenopausal Women

Abstract

A B S T R A C T PurposeTo determine whether plasma estradiol (E2) levels are related to gene expression in estrogen receptor (ER)-positive breast cancers in postmenopausal women. Materials and MethodsGenome-wide RNA profiles were obtained from pretreatment core-cut tumor biopsies from 104 postmenopausal patients with primary ER-positive breast cancer treated with neoadjuvant anastrozole. Pretreatment plasma E2 levels were determined by highly sensitive radioimmunoassay. Genes were identified for which expression was correlated with pretreatment plasma E2 levels. Validation was performed in an independent set of 73 ER-positive breast cancers. ResultsThe expression of many known estrogen-responsive genes and gene sets was highly significantly associated with plasma E2 levels (eg, TFF1/pS2, GREB1, PDZK1 and PGR; P Ͻ .005). Plasma E2 explained 27% of the average expression of these four average estrogen-responsive genes (ie, AvERG; r ϭ 0.51; P Ͻ .0001), and a standardized mean of plasma E2 levels and ER transcript levels explained 37% (r, 0.61). These observations were validated in an independent set of 73 ER-positive tumors. Exploratory analysis suggested that addition of the nuclear coregulators in a multivariable analysis with ER and E2 levels might additionally improve the relationship with the AvERG. Plasma E2 and the standardized mean of E2 and ER were both significantly correlated with 2-week Ki67, a surrogate marker of clinical outcome (r ϭ Ϫ0.179; P ϭ .05; and r ϭ Ϫ0.389; P ϭ .0005, respectively). ConclusionPlasma E2 levels are significantly associated with gene expression of ER-positive breast cancers and should be considered in future genomic studies of ER-positive breast cancer. The AvERG is a new experimental tool for the study of putative estrogenic stimuli of breast cancer.

Differential expression of progesterone receptor, FOXA1, GATA3, and p53 between pre- and postmenopausal women with estrogen receptor-positive breast cancer

“…We have shown that expression levels of PgR and TFF1 in breast cancer tissues were significantly higher in premenopausal women than in postmenopausal women. TFF1, originally known as pS2, was the gene which correlated most significantly with plasma estradiol concentration in postmenopausal ER-positive breast cancer tissues [13]. It was also reported that expression levels of TFF1, similar to PgR, in ER-positive breast tumors differed across the menstrual cycle in premenopausal women, although expression of proliferation genes, such as Ki67, did not differ during the cycle [12].…”

“…We previously analyzed genetic and environmental predictors, endogenous hormones and growth factors, and risk of ER-positive breast cancer, and demonstrated that risk factors differed between women of different menopausal status [24]. It has been reported that plasma estradiol levels are significantly associated with estrogen-responsive gene expression of ER-positive breast cancers in both pre-and postmenopausal women [12,13].…”

“…PgR is one of the estrogen-responsive genes, and it has been reported that plasma estradiol levels are related to expression levels of estrogen-responsive genes, such as PGR and trefoil factor 1 (TFF1)/pS2, in ER-positive breast cancer in both preand postmenopausal women [12,13]. We previously showed that the incidence of ER-positive, PgR-negative breast cancer in women aged 50 years or younger and in those older than 50 years were 6% and 15%, respectively, whereas for ER-positive, PgR-positive tumors, incidences were 81% and 64%, respectively [14].…”

Correlation between PDZK1, Cdc37, Akt and Breast Cancer Malignancy: The Role of PDZK1 in Cell Growth through Akt Stabilization by Increasing and Interacting with Cdc37

“…The PDZK1 gene was initially reported to be estrogen-responsive in the breast cancer cell line MCF-7 (15). Additionally, a significant association between plasma 17β-estradiol (E 2 ) levels and PDZK1 mRNA expression levels in estrogen receptor (ER)-α(+) human breast cancer was established (16), strengthening the relationship between ER-α and PDZK1. In a recent investigation (17), we conducted a series of studies in which we found that E 2 -induced PDZK1 mRNA expression was slow and was blocked upon inhibition of protein synthesis.…”

GREB1 (growth regulation by estrogen in breast cancer 1)

“…This positive correlation of GREB1 expression with ERα expression is validated in clinical cohorts (Ghosh et al, 2000). Another cohort of ER positive breast cancers in postmenopausal women (n=104) has shown a strong correlation of GREB-1 gene expression with plasma E 2 levels (Dunbier et al, 2010). In a cohort of breast cancer patients (n=64) compared to healthy women (n=79) GREB-1 gene expression correlated positively with serum E 2 levels (Haakensen et al, 2011).…”