An estrogen receptor genetic polymorphism and a history of spontaneous abortion — Correlation in women with estrogen receptor positive breast cancer but not in women with estrogen receptor negative breast cancer or in women without cancer

Summary We previously identified a polymorphism in the human estrogen receptor gene. In a preliminary study on women with estrogen receptor positive (ER⁺) breast tumors, we found that the presence of the rarer of the two alleles, the B' allele, is correlated with a history of spontaneous abortion. Because that study evaluated only women with estrogen receptor positive (ER⁺) breast cancer, it was unknown whether the observed correlation was restricted to the cancer group or was independent of breast cancer. We have now extended our analysis to include not only additional women with ER⁺ breast cancer, but also those with estrogen receptor negative (ER^–) breast cancer and women without cancer. Results of the current study continue to show an association between the B' allele and a history of spontaneous abortion in the ER⁺ breast cancer group. There was no such correlation either in the ER^– breast cancer group or in the group without cancer. Also, we continue to observe, in the ER⁺ breast cancer group, a significantly higher concentration of ER protein in tumors from homozygous wild type women (genotype BB), than in the tumors from women who are heterozygous for the rarer allele (genotype BB'). We conclude that the combination of spontaneous abortion and the BB' ER genotype may be a marker for breast cancer susceptibility.     

Transferrin receptor is inversely correlated with estrogen receptor in breast cancer

Summary The transferrin receptor (TfR) has been identified as a marker for proliferation in cells in culture and can be accurately quantitated by specific radioimmunoassay. This study directly quantifies levels of TfR and compares them to levels of estrogen receptor (ER) and progesterone receptor (PgR) in biopsy material obtained from patients with infiltrating ductal carcinoma of the breast. A comparison of ER and TfR levels displayed an exponential distribution which was log-normalized to yield a linear inverse relationship (r = –.44). Although ER was strongly correlated with PgR, there was no correlation pattern between TfR and PgR. Multiple regression analysis indicated that 73% of ER levels could be predicted by a combination of the other two markers, PgR (representing degree of differentiation) and TfR (representing growth rate). Transferrin receptor levels were also found to be correlated (p<.05) with menopausal status, with tumors from premenopausal patients exhibiting higher levels, whereas the opposite pattern was shown for estrogen receptor levels (p<.02). Neither steroid receptor nor transferrin receptor levels were correlated to stage of disease or presence of nodal involvement. Addition of TfR level as an independent marker for proliferation may facilitate the decision-making process in the treatment of individual cases of carcinoma of the breast.     

Differences in estrogen receptor subtype according to family history of breast cancer among Hispanic, but not non-Hispanic White women

BACKGROUND: Pathologic differences have been reported among breast tumors when comparing ethnic populations. Limited research has been done to evaluate the ethnic-specific relationships between breast cancer risk factors and the pathologic features of breast tumors. METHODS: Given that genetic variation may contribute to ethnic-related etiologic differences in breast cancer, we hypothesized that tumor characteristics differ according to family history of breast cancer among Hispanic and non-Hispanic White (NHW) women. Logistic regression models were used to compute odds ratios (OR) and 95% confidence intervals (95% CI) to assess this relationship in the population-based, case-control 4-Corners Breast Cancer Study (1,537 cases and 2,452 controls). RESULTS: Among Hispanic women, having a family history was associated with a 2.7-fold increased risk of estrogen receptor (ER) negative (95% CI, 1.59-4.44), but not ER positive tumors (OR, 1.04; 95% CI, 0.71-1.54) when compared with women without breast cancer. In contrast, there was an increased risk for ER positive (OR, 1.89; 95% CI, 1.50-2.38) and a marginally significant increased risk for ER negative tumors (OR, 1.41; 95% CI, 0.92-2.17) among NHW women. When comparing tumor characteristics among invasive cases, those with a family history also had a significantly higher proportion of ER negative tumors among Hispanics (39.2% versus 25.8%; P=0.02), but not among NHWs (16.3% versus 21.1%; P=0.13). CONCLUSIONS: These results may reflect ethnic-specific predisposing genetic factors that promote the development of specific breast tumor subtypes, and emphasize the importance of evaluating the relationship between breast cancer risk factors and breast tumor subtypes among different ethnic populations.     

SGK3 is associated with estrogen receptor expression in breast cancer

While breast cancer mortality rate has seen a steady decline in the last few decades, advances in better treatment and diagnostic tools remain important as we come into the age of personalized therapy. In this report, we describe our studies of SGK3's role in breast cancer. SGK3 (also known as CISK) is a member of the AGC family of kinases. Our previous work indicates that SGK3 functions downstream of the PI 3-kinase cascade and shares molecular and biochemical similarities with Akt. Here, we show that SGK3 expression is linked to estrogen receptor (ER) both in breast caner cell lines and in primary tumor samples. Our analysis also indicated a positive correlation between SGK3 expression and tumor prognosis. Importantly, our immunochemistry analysis of human tumor samples established a clinical link between SGK3 expression and ER+ tumors. These findings implicate SGK3 as an additional component to a complex and heterogeneous disease, and point to the potential benefits of incorporating SGK3 into the process of breast cancer diagnosis and treatment.     

Progesterone receptor is involved in 2,3,7,8-tetrachlorodibenzo-p-dioxin-stimulated breast cancer cells proliferation

Sex hormones are pivotal for both normal and neoplastic development of breast tissues. TCDD, with sex hormonal activity, executes multiple biological activities primarily through AhR. However, the detailed mechanisms how TCDD affects human breast cell are mostly unexplored. We analyzed the biological effects and underlying mechanisms of TCDD on MCF-7 cells. PR, other than AhR, was involved in TCDD-stimulated MCF-7 cell proliferation. TCDD inactivated Akt–FoxO3a pathway, increased cdc25C/cdc2 activity, decreased P21/P27 activity, and enriched G2/M phase, in a PR- and AhR-dependent manner. In conclusion, our study demonstrated for the first time that PR was involved in TCDD-stimulated breast cell proliferation.     

Methylation of estrogen receptor 1 in colorectal adenomas is not age-dependent, but is correlated with K-ras mutation

The promoter region of estrogen receptor 1 ( ESR1 ) has been shown to be methylated in normal colorectal mucosa in an age-dependent manner. However, the methylation of this region in colorectal tumors has not sufficiently been investigated. The methylation status of ESR1 in 105 colorectal adenoma tissues was examined by MethyLight and presented as the percentage of methylated references (PMR). Factors that affect the PMR of ESR1 in adenomas were determined using parameters including patient age, sex, past history of malignancy, family history of colorectal cancer, smoking and drinking habits, clinical characteristics of adenomas (location, size, macroscopic appearance, and histology), and K-ras mutation. Multiple linear regression revealed that the PMR was not correlated with patient age. K-ras mutation was significantly correlated with the higher methylation status of ESR1 in adenoma ( t -value = 3.21, P  = 0.0018), whereas alcohol exposure was significantly correlated with lower methylation status ( t -value = –2.37, P  = 0.02). Because methylation of O⁶-methylguanine DNA methyltransferase ( MGMT ) has been reported to be correlated with K-ras G-to-A transition, methylation of ESR1 was compared with that of MGMT with regard to K-ras mutation. Contrary to expectations, methylation of MGMT was not significantly correlated with K-ras G-to-A transition, but that of ESR1 was strongly correlated with K-ras G-to-A transition. Thus, the methylation status of ESR1 in adenomas was not correlated with patient age, but was associated with K-ras mutation, suggesting that methylation of ESR1 in tumors functions differently from that in normal colon mucosa. ( Cancer Sci 2009; 100: 1005–1011)     

Expression of coxsackie-adenovirus receptor is related to estrogen sensitivity in breast cancer

This study analyzes the relationship between coxsackie-adenovirus receptor (CAR) expression (transmembrane and soluble isoforms) and hormone sensitivity in 95 breast cancers. Furthermore, prognostic significance of the expression of the various CAR isoforms was investigated. In addition, inducibility of CAR expression by estradiol and tamoxifen was assessed in various breast cancer cell lines. Expression of transmembrane CAR (hCAR) highly correlated with estrogen receptivity, but was independent of the expression of progesterone receptor (PR). Furthermore, hCAR expression was significantly higher in tumors with low-grade malignancy. However, no relationship between hCAR expression and tumor size, lymph node status, or survival was revealed. In the hormone receptor-positive breast cancer cell line T47-D expression of hCAR and its soluble isoforms was increased by treatment with estradiol and tamoxifen. In contrast, no induction of either CAR isoform was achieved in receptor-negative cell lines. Furthermore, enhancement of hCAR expression was significantly greater when cells were treated with the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) than when treated with estradiol or tamoxifen. Moreover, sensitivity to TSA induction of hCAR was considerably greater in receptor-positive than in receptor-negative cell lines. No additive effect on CAR expression was found when TSA was combined with either estradiol or tamoxifen. In conclusion, the so far undescribed association between estrogen receptivity and the expression of hCAR in breast cancer seems to not only reflect a phenotype of low malignancy, but expression of hCAR may also be directly influenced by ER-specific ligands.     

In situ aromatase expression in primary tumor is associated with estrogen receptor expression but is not predictive of response to endocrine therapy in advanced breast cancer

Background  

New, third-generation aromatase inhibitors (AIs) have proven comparable or superior to the anti-estrogen tamoxifen for treatment of estrogen receptor (ER) and/or progesterone receptor (PR) positive breast cancer. AIs suppress total body and intratumoral estrogen levels. It is unclear whether in situ carcinoma cell aromatization is the primary source of estrogen production for tumor growth and whether the aromatase expression is predictive of response to endocrine therapy. Due to methodological difficulties in the determination of the aromatase protein, COX-2, an enzyme involved in the synthesis of aromatase, has been suggested as a surrogate marker for aromatase expression.