Hormonal receptors in locally advanced breast cancer: Change with response to neoadjuvant chemotherapy?

Twenty-one cancers in 20 patients with locally advanced breast cancer were studied. Incisional biopsy was performed without using electrocautery. Tissue was obtained for histology and estrogen (ER) and progesterone (PR) receptors. Patients received chemotherapy after biopsy. All responded and had radical mastectomy performed. Tissue was removed from the mastectomy specimen to confirm residual tumor and for repeat receptor measurements. Initial receptor levels were negative in 13 cancers. Following chemotherapy, both ER and PR levels were unchanged in 11 cancers. Levels in one cancer changed from ER-PR- to ER+PR- and one changed from ER-PR- to ER+PR+. Six cancers were ER+PR+ at initial examination. Repeat receptor levels after chemotherapy were ER+PR+ in three. One ER+PR+ tumor became ER-PR+, one changed to ER+PR-, and one to ER-PR-. One ER+PR- cancer remained ER+PR- after treatment and an ER-PR+ cancer became ER-PR- after treatment. Chemotherapy dose not significantly alter hormonal levels in breast cancer tissue.     

Tumor variants by hormone receptor expression in white patients with node-negative breast cancer from the surveillance, epidemiology, and end results database.

PURPOSE: Hormone receptor expression (presence-positive or absence-negative) may reflect different stages of one disease or different breast cancer types. Determining whether hormone receptor expression represents one or more breast cancer phenotypes would have important paradigmatic and practical implications. METHODS: Breast cancer records were obtained from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database. The study included 19,541 non-Hispanic white women with node-negative breast cancer. Standard tumor cell characteristics and breast cancer-specific survival were analyzed by independent estrogen receptor (ER+ and ER-), independent progesterone receptor (PR+ and PR-), and joint ERPR expression (ER+PR+, ER+PR-, ER-PR+, and ER-PR-). RESULTS: Age frequency density plots by hormone receptor expression showed two overlapping breast cancer populations with early-onset and/or late-onset etiologies. Independent ER+ and PR+ phenotype were associated with smaller tumor sizes, better grade, and better cancer-specific survival than ER- and PR- breast cancer types. Joint ERPR phenotype exhibited biologic gradients for tumor size, grade, and cancer-specific survival, which ranked from good to worse for ER+PR+ to ER+PR- to ER-PR+ to ER-PR-. CONCLUSION: Variations of standard tumor cell characteristics and breast cancer-specific survival by hormone receptor expression in white patients with node-negative breast cancer suggested two breast cancer phenotypes with overlapping etiologies and distinct clinical features.     

Do Clinical Features and Survival of Single Hormone Receptor Positive Breast Cancers Differ from Double Hormone Receptor Positive Breast Cancers?

The significance of the single hormone receptor positive phenotype of breast cancer is still poorly understood.The use of hormone therapy has been found to be less effective for this type, which has a survival outcome midwaybetween double positive and double negative phenotypes. The aim of this study was to investigate differencesin patient and tumor characteristics and survival between double-receptor positive (ER+PR+), double receptornegative (ER-PR-) and single receptor positive (ER+PR- and ER-PR+) breast cancer in an Asian setting. Atotal of 1,992 patients with newly diagnosed stage I to IV breast cancer between 2003 and 2008, and whereinformation on ER and PR were available, were included in this study. The majority of patients had ER+PR+tumors (n=903: 45.3%), followed by 741 (37.2%) ER-PR-, 247 (12.4%) ER+PR-, and 101 (5.1%) ER-PR+ tumors.Using multivariate analysis, ER+PR- tumors were 2.4 times more likely to be grade 3 compared to ER+PR+tumors. ER+PR- and ER-PR+ tumors were 82% and 86% respectively less likely to be grade 3 compared withER-PR- tumors. ER-PR+ tumours were associated with younger age. There were no survival differences betweenpatients with ER+PR+ and ER-PR+ tumors. However, ER+PR- tumors have poorer survival compared withER+PR+ tumours. ER-PR- tumours had the worst survival. Adjuvant hormonal therapy with tamoxifen wasfound to have identical survival advantage in patients with ER+PR+ and ER-PR+ tumors whereas impact wasslightly lower in patients with ER+PR- tumors. In conclusion, we found ER+PR- tumors to be more aggressiveand have poorer survival when compared to ER+PR+ tumors, while patients with ER-PR+ tumours were younger,but had a similar survival to their counterparts with ER+PR+ tumours.     

Breast cancer risk factors according to joint estrogen receptor and progesterone receptor status

BACKGROUND: We investigated risk factor patterns for subtypes of breast cancer characterized by joint estrogen receptor (ER) and progesterone receptor (PR) status in a hospital-based case-control study. METHODS: ER and PR tumor status were determined immunohisotchemically. Risk factors of interest were entered into a multiple polychotomous logistic regression model simultaneously; odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Using this model, cases in the four tumor subtypes (ER+PR+, ER-PR-, ER+PR-, ER-PR+) were compared simultaneously to controls. A Wald test for heterogeneity across the four subtypes was conducted, as well as a case-case comparison between the two most biologically disparate subtypes, ER+PR+ and ER-PR-. RESULTS: The receptor status distribution was as follows: 33% ER+PR+, 34% ER-PR-, 20% ER+PR-, and 13% ER-PR+. Among 317 cases and 401 controls, we found significant heterogeneity across the four tumor subtypes for older age at first full-term pregnancy (p=0.04) and post-menopausal status (p=0.04). For older age at first full-term pregnancy, an elevated risk was found for the ER+PR- subtype (OR=2.5; 95% CI: 1.2-5.1). For post-menopausal status, elevated risks were found for both the ER+PR+ (OR=2.4; 95% CI: 1.1-4.9) and ER+PR- (OR=7.2; 95% CI: 2.4-21.7) subtypes. From the case-case comparisons, we found that cases, who had consumed alcohol for more than 1 year were 3.4 times more likely to have ER+PR+ tumors than ER-PR- tumors (95% CI: 1.4-8.4). CONCLUSIONS: Certain breast cancer risk factors may vary by ER and PR status, and joint ER/PR status should be taken into account in future studies of risk factor estimates.     

Estrogen and progesterone receptors in ovarian cancer

To determine whether steroid hormone receptor expression is clinically relevant in ovarian cancer, cytoplasmic and nuclear estrogen (ER) and progesterone (PR) receptor levels have been measured and their concentration calculated by Scatchard analysis. Of 89 samples from patients with non-pretreated epithelial ovarian cancer, 33% were ER-positive, PR-positive (ER+PR+) and 40% ER-negative, PR-negative (ER-PR-); 20% were ER+PR-, and 7% ER-PR+. There was no correlation between receptor status and patient age, menopausal status, or tumor grade, although serous tumors were more likely to be ER+. The incidence of PR+ tumors was highest in early disease and decreased with increasing International Federation of Gynecology and Obstetrics (FIGO) stage. Survival of patients with advanced disease (FIGO Stages IIC, III, or IV) was significantly prolonged by optimal initial cytoreductive surgery (P = 0.002), platinum therapy (P = 0.003), and tumor expression of PR (P = 0.009). On multivariate analysis, PR positivity was still associated with improved survival, although this did not retain statistical significance (P = 0.09).     

Frequency distributions of breast cancer characteristics classified by estrogen receptor and progesterone receptor status for eight racial/ethnic groups.

BACKGROUND: The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) cancer registries have been collecting data regarding estrogen receptor (ER) and progesterone receptor (PR) status in breast cancer since 1990. The current study reports on some of these data for eight racial/ethnic groups. METHODS: Stratified by ER and PR status, the frequency distributions of 112,588 breast cancer cases diagnosed between 1992--1997 in 11 SEER cancer registries were examined by age at diagnosis, stage at diagnosis, histologic grade, and tumor type for white, black, Hispanic, Japanese, Chinese, Filipino, Native Hawaiian, and American Indian and Alaska Native (AI/AN) females. RESULTS: For each racial/ethnic group, the percentage of ER positive (+)/PR+ was > ER-PR- > ER+PR- > ER-PR+ tumors. For the two major ER/PR groups, the ER+PR+ tumors were different from the ER-PR- tumors in several ways. For white females, there were differences in the age distributions, stage at diagnosis, and histologic grade. For black females, the differences involved the age distributions and tumor grades. For Hispanic and Japanese females, there were differences with regard to the age distributions and tumor grades. For Filipino, Chinese, and AI/AN females, the tumor stages and grades differed. For Native Hawaiians, the histologic tumor grades were different. CONCLUSIONS: For each racial/ethnic group, the ER/PR status appeared to divide breast cancer patients into two or more subgroups with unique tumor characteristics. In general, ER status appeared to have the greatest impact on delineating these subgroups, whereas in some cases, PR status was able to modify the subgroups further. It is hoped that reporting these tumor characteristics by ER/PR status for each racial/ethnic group will spur more investigation into the significance of ER/PR status in each racial/ethnic group.     

Risk factors for hormone receptor-defined breast cancer in postmenopausal women.

The effect of classic breast cancer risk factors on hormone receptor-defined breast cancer is not fully clarified. We explored these associations in a Swedish population-based study. Postmenopausal women ages 50 to 74 years, diagnosed with invasive breast cancer during 1993 to 1995, were compared with 3,065 age frequency-matched controls. We identified 332 estrogen receptor (ER-) and progesterone receptor (PR-) negative, 286 ER+PR-, 71 ER-PR+, 1,165 ER+PR+, and 789 tumors with unknown receptor status. Unconditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (95% CI). Women ages >or=30 years, compared with those ages 20 to 24 years at first birth, were at an increased risk of ER+PR+ tumors (OR, 1.5; 95% CI, 1.2-1.8) but not ER-PR- tumors (OR, 1.1; 95% CI, 0.8-1.6). Women who gained >or=30 kg in weight during adulthood had an approximately 3-fold increased relative risk of ER+PR+ tumors (OR, 2.7; 95% CI, 1.9-3.8), but no risk increase of ER-PR- tumors (OR, 1.0; 95% CI, 0.5-2.1), compared with women who gained <10 kg. Compared with never users, women who used menopausal estrogen-progestin therapy for at least 5 years were at increased risk of ER+PR+ tumors (OR, 3.0; 95% CI, 2.1-4.1) but not ER-PR- tumors (OR, 1.3; 95% CI, 0.7-2.5). In conclusion, other risk factors were similarly related to breast cancer regardless of receptor status, but high age at first birth, substantial weight gain in adult age, and use of menopausal estrogen-progestin therapy were more strongly related to receptor-positive breast cancer than receptor-negative breast cancer.     

Hormonal factors and the risk of breast cancer according to estrogen- and progesterone-receptor subgroup.

Evidence suggests hormonal factors may be more strongly associated with estrogen receptor+progesterone receptor+ (ER+PR+) than ER-PR- breast cancer risk. This study evaluated risk factors according to ERPR tumor status among pre- and postmenopausal women participating in two recent population-based case-control studies. Breast cancer cases, ages 25-74 years, and diagnosed 1995-1998 were sampled from the Ontario Cancer Registry. Controls were a random sample of women identified using the Ontario Ministry of Finance rolls and were frequency-matched to cases within 5-year age groups. Epidemiological data were collected from breast cancer cases and controls using two self-administered questionnaires. ERPR data were obtained for 87% of the breast cancer cases (3,276 of 3,748). Multivariate polytomous logistic regression was used to obtain odds ratios estimates and 95% confidence intervals. The following significant differences were observed in the risk factor profiles for ER+PR+ and ER-PR- breast cancer: among premenopausal women, late age at menarche was only associated with a reduction in ER+PR+ breast cancer risk; obesity was associated with an increased ER-PR- and decreased ER+PR+ cancer risk; and the association between alcohol intake and breast cancer risk was heterogeneous across ERPR subgroups, although the direction varied across the levels of alcohol intake. Among postmenopausal women, there were no statistically significant differences observed in the risk factor profiles for ER+PR+ and ER-PR- breast cancer. Some heterogeneity exists in the risk factor profiles of ER+PR+ and ER-PR- premenopausal breast cancer; however, risk factor profiles did not differ markedly for postmenopausal breast cancer.     

Body weight and incidence of breast cancer defined by estrogen and progesterone receptor status--a meta-analysis

Epidemiological evidence indicates that the association between body weight and breast cancer risk may differ across menopausal status as well as the estrogen receptor (ER) and progesterone receptor (PR) tumor status. To date, no meta-analysis has been conducted to assess the association between body weight and ER/PR defined breast cancer risk, taking into account menopausal status and study design. We searched MEDLINE for relevant studies published from January 1, 1970 through December 31, 2007. Summarized risk estimates with 95% confidence intervals (CIs) were calculated using a random-effects model. The summarized results of 9 cohorts and 22 case-control studies comparing the highest versus the reference categories of relative body weight showed that the risk for ER+PR+ tumors was 20% lower (95% CI=-30% to -8%) among premenopausal (2,643 cases) and 82% higher (95% CI=55-114%) among postmenopausal (5,469 cases) women. The dose-response meta-analysis of ER+PR+ tumors showed that each 5-unit increase in body mass index (BMI, kg/m2) was associated with a 33% increased risk among postmenopausal women (95% CI=20-48%) and 10% decreased risk among premenopausal women (95% CI=-18% to -1%). No associations were observed for ER-PR- or ER+PR- tumors. For discordant tumors ER+PR- (pre) and ER-PR+ (pre/post) the number of cases were too small (<200) to interpret results. The relation between body weight and breast cancer risk is critically dependent on the tumor's ER/PR status and the woman's menopausal status. Body weight control is the effective strategy for preventing ER+PR+ tumors after menopause.     

Steroid hormone receptors and long term survival in invasive ovarian cancer

BACKGROUND: Steroid hormone receptors are important determinants of prognosis and predictive behavior in tumor tissues of several origins. Since their role in ovarian cancer is still controversial, we investigated the prevalence and prognostic impact of the estrogen (ER) and progesterone (PR) receptors and combinations (ER+PR+, ER+PR-, ER-PR+, and ER-PR-) in a comparably large number of patients with a long clinical follow-up. METHODS: The present analysis included 186 patients with invasive ovarian carcinomas treated at the Department of Obstetrics and Gynecology of the Justus-Liebig-University Giessen between 1982 and 1996, the follow-up lasting up to 15.8 years (median 2.4 yrs). The expression of ER and PR was assessed by immunohistochemistry using alkaline phosphatase antialkaline phosphatase in microwave pretreated, formalin fixed, and paraffin embedded specimens of the primary tumors and was evaluated semiquantitatively using a standardized immunoreactive scoring system. Receptor expression and combinations were compared to clinical, histologic and prognostic factors, the tumor proliferation, and the clinical outcome. RESULTS: Kaplan-Meier survival analyses supported the favorable prognostic value of PR and its level of expression in ovarian carcinomas. Especially the ER-PR+ combination, which accounted for 10.2% of all tumors, showed a significantly superior prognosis when compared with all other combinations (survivors 15 of 19 vs. 67 of 167, log rank P = 0.009) and was associated with early stage, low ascites quantity, and higher tumor differentiation. Five-year survival rates were 13/16 (81.3%) for ER-PR+ tumors versus 58/128 (45.3%) for all other steroid hormone receptor combinations. Residual analysis proved the results. CONCLUSIONS: The determination of steroid hormone receptor status offers additional prognostic information in ovarian carcinomas. Especially the ER-PR+ phenotype predicts a favorable tumor biology and long term survival, probably reflecting functional effects on tumor proliferation, differentiation, and cellular apoptosis.     

Alcohol intake and risk of breast cancer defined by estrogen and progesterone receptor status--a meta-analysis of epidemiological studies

The association between alcohol consumption and an increased risk of breast cancer has been established. It is still unclear however, whether this relationship differs across the estrogen receptor (ER) and progesterone receptor (PR) tumors subtypes. To provide a quantitative assessment of the association between alcohol intake and the risk of ER-/PR-defined breast cancer, we conducted a meta-analysis of cohort and case-control studies. Studies were identified by a literature search of PubMed through April 20, 2007 and by searching the reference lists of relevant articles. Summarized risk estimates (REs) with 95% confidence intervals (CIs) were calculated using random-effects models. The summarized results of the meta-analysis comparing the highest versus the lowest consumption categories showed statistically significant higher risks of developing all ER+ (27%), all ER- (14%), ER+PR+ (22%) and ER+PR- (28%), but not ER-PR- tumors. The dose-response meta-analysis showed that an increase in alcohol consumption of 10 g of ethanol per day was associated with statistically significant increased risks for all ER+ (12%), all ER- (7%), ER+PR+ (11%) and ER+PR- (15%), but not ER-PR-. A statistically significant heterogeneity of the REs across all ER+ versus ER-PR- was observed (p(heterogeneity) = 0.02). The summarized results from studies with adjustment for postmenopausal hormone use, body mass index and family history of breast cancer were higher and statistically significantly different from those without. The observed positive associations with alcohol for ER+PR+ and ER+PR- tumors cannot be explained by estrogen-dependent pathway only. Further studies need to clarify the biological mechanisms.     

Pathologic findings from the national surgical adjuvant breast project. Correlations with concordant and discordant estrogen and progesterone receptors

Pathologic materials were available for review from 1597 women with Stage II (positive regional node metastases) invasive breast cancer in whom estrogen receptor (ER) and progesterone receptor (PR) assays of the primary tumor were performed. These women were enrolled in a clinical trial comparing the effect of postmastectomy adjuvant L-phenylalanine mustard (L-PAM) and 5-fluorouracil (5-FU) with and without tamoxifen (NSABP Protocol No. 9). Significant pathologic and clinical associations with receptor status were similar for both ER and PR except that the latter, unlike ER, was not related to patient age. Regression analyses revealed that the most significant pathologic features related to a concordant positive ERPR receptor status was low (well differentiated) nuclear and histologic grades, slight or absent tumor lymphoid infiltrate, slight or absent necrosis and moderate or marked elastica in decreasing order of importance. All of the factors enumerated are directly or indirectly related to tumor differentiation. Recognition of four or five conforming pathologic features allows for the prediction of either ER or PR status in 70% to 80% of instances respectively, and the presence of three features in 69%. This latter figure is similar to that of estimation of nuclear grade alone. Thirty percent of ERPR estimates were discordant i.e., either ER-PR+ or ER+PR-. Pathologic features associated with discordant assays were not similar to those found when the ERPR estimates were concordant. Life table analyses revealed patients with discordant receptors to exhibit disease-free survival intermediate to that of those with ER+PR+ and ER-PR- values. This information suggests that a discordant receptor status is more reflective of an aberration of ER metabolism than a methodologic error. Histograms correlating frequency of nuclear grades with levels of ER and PR were comparable and revealed patterns indicating the propriety of relating values less than 10 fm/mg as being receptor negative. The frequency of well-differentiated nuclei increased with ascending levels of ER and PR.     

Estrogen and progesterone receptors in breast cancer patients. Epidemiologic characteristics and survival differences

Risk factors commonly associated with breast cancer were studied in relation to: (1) tumor estrogen receptor (ER) or progesterone receptor (PR) status and (2) the presence of tumor hormone receptors in relation to subsequent survival. For 171 Israeli women diagnosed with breast cancer in 1976 to 1979, tumor hormone receptor status (positive if greater than 20 fmol receptors/mg protein; negative if less than or equal to 20 fmol/mg) and survival as of April 1984 were ascertained. There were 77 ER- versus 94 ER+ and (for 134 PR analyses) 69 PR- versus 65 PR+. Although ER status and PR status were found to be highly positively related, the epidemiologic features of women with an ER+ tumor were different from those with a PR+ tumor. Age tended to be associated positively with both ER+ and PR+. Being postmenopausal, older at menopause or at first birth, nulliparous, having more years of schooling, and a higher body mass index for older women or a lower body mass index for younger women were correlated positively with ER and negatively with PR. Among women with Stage III or IV tumors at diagnosis significant differences existed: restricted mean survival for follow-up time was 47.2 months for ER-, 73.8 months for ER+, 45.8 months for PR-, and 61.9 months for PR+. The combined hormone effects on survival at Stages III to IV showed a similar trend: restricted mean survival of 38.4 months for ER-PR-, intermediate survival with one positive hormone receptor status, and 74.6 months for ER+PR+.     

Immunohistochemical investigation of estrogen and progesterone receptors in breast tumors

Estrogen (ER) and progesterone (PR) receptor levels were assayed in 344 breast tumors. The following 4 patterns were identified: ER+ PR(+)--61%; ER+ PR- 24%; ER- PR(+)--15% and ER- PR(-)--35%. While no correlation was found between histological pattern, on the one hand, and the ER/PR ratio and age, on the other, there was one between estrogen and progesterone receptor content, on the one hand, and age, tumor size and metastatic spread to regional lymph nodes, on the other (p > 0.001).     

Serum enterolactone and postmenopausal breast cancer risk by estrogen, progesterone and herceptin 2 receptor status

Lignans are a group of estrogenic compounds present in plants. Several epidemiological studies proposed that lignans may protect against breast cancer by exerting anticarcinogenic activity. Levels of enterolactone were determined in serum samples of 1,250 cases and 2,164 controls from a large population-based case-control study. We assessed the association between serum enterolactone and postmenopausal breast cancer risk using conditional logistic regression accounting for potential risk and confounding factors. Fractional polynomials were used to determine the function that best fitted the data. Moreover, we assessed heterogeneity by estrogen/progesterone/herceptin (ER/PR/HER2) status of the tumor. Additionally, a meta-analysis with seven further studies addressing enterolactone concentrations and breast cancer risk was performed. Postmenopausal breast cancer risk decreased with increasing serum enterolactone levels [highest compared to lowest quintile: [odds ratio = 0.65; 95% confidence interval (CI) 0.52-0.83, p(trend) = < 0.0001]. A significant inverse association for ER+/PR+ as well as ER-/PR- tumors was observed, with a significantly stronger association for ER-/PR- tumors (p(heterogeneity) = 0.03). The association for ER-/PR- tumors did not differ by expression of HER2 (p(heterogeneity) = 0.3). The meta-analysis yielded a significant reduced pooled risk estimate of: 0.66; 95% CI: 0.55-0.77) comparing the highest to the lowest quantiles of enterolactone levels. We found strong evidence for a significant inverse association between serum enterolactone and postmenopausal breast cancer risk, which was stronger for ER-PR- than for ER+PR+ tumors but not differential by further expression of HER2. The overall evidence together with other studies supports an inverse association between higher serum enterolactone levels and postmenopausal breast cancer risk.     

Oestrogen and progesterone receptor status in bone biopsy specimens from patients with breast cancer

Of 16 breast cancer patients with histologically proven, tumour-infiltrating biopsy specimens most had low ER and PR values; the ER and PR contents varied between 0 and 135 and 0 and 44 fmol/mg protein, respectively. With the conventional clinical threshold of 10 fmol/mg protein, 8 specimens (50%) were ER-PR-, 4 (25%) ER-PR+, 3 (19%) ER+PR+ and 1 (6%) ER+PR-. ER levels were significantly lower in the tumoral bone lesion compared with the primary tumour. For 15 patients with negative biopsies and without endocrine treatment, ER and PR concentrations were quantifiable (2 fmol/mg protein or more) in 9 (60%) and 11 cases (73%), respectively. 8 of 9 patients over 55 (89%) were ER+ (2 fmol/mg protein or more). Conversely, for patients under 55, 1 of 6 (17%) was ER+ (P < 0.001). Results for PR were similar. These data strongly suggest that steroid receptors are present in healthy bone tissue.     

Steroid receptors in breast cancer patients. Influence of obesity and age at diagnosis.

The influence of host age on estrogen (ER) and progesterone (PR) receptor status was studied in 603 tumors obtained from women with confirmed diagnosis of breast carcinoma. Both ER and PR analysis were performed in our own laboratory using standard techniques. Tumors were classified as positive if minimum receptor contents were greater than 10 fmol/mg cytosol protein and if dissociation constants were 1-9 x 10(-10) M or lower. Data from our study indicate that the incidence of receptor negative (ER-PR-) tumors was higher in women from 21 to 40 years of age than in women from 41 to 60 years of age. In women over 60 years of age, the incidence of ER+PR+ tumors was higher than in women under 40 years of age. Interestingly, women from 51 to 60 years of age had a significantly lower incidence (P less than 0.06, 0.0001) of ER+PR+ but higher incidence (P less than 0.01) of ER-PR- tumors than women 41-50 or greater than 60 years of age. Analysis of steroid receptor distribution in relation to host age and obesity showed a definite tendency: in obese women over 60 years of age, frequency of ER+PR+ was significantly greater than in non-obese women of similar age groups. This altered ER and PR distribution in tumors is probably a result of difference in the hormonal milieu associated with host menopausal status and obesity.     

Association of Poor Prognosis Subtypes of Breast Cancer with Estrogen Receptor Alpha Methylation in Iranian Women

Breast cancer is a prevalent heterogeneous malignant disease. Gene expression profiling by DNA microarraycan classify breast tumors into five different molecular subtypes: luminal A, luminal B, HER-2, basal and normallikewhich have differing prognosis. Recently it has been shown that immunohistochemistry (IHC) markersincluding estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2(Her2), can divide tumors to main subtypes: luminal A (ER+; PR+/-; HER-2-), luminal B (ER+;PR+/-; HER-2+),basal-like (ER-;PR-;HER2-) and Her2+ (ER-; PR-; HER-2+). Some subtypes such as basal-like subtype have beencharacterized by poor prognosis and reduced overall survival. Due to the importance of the ER signaling pathwayin mammary cell proliferation; it appears that epigenetic changes in the ERα gene as a central component of thispathway, may contribute to prognostic prediction. Thus this study aimed to clarify the correlation of differentIHC-based subtypes of breast tumors with ERα methylation in Iranian breast cancer patients. For this purposeone hundred fresh breast tumors obtained by surgical resection underwent DNA extraction for assessedment oftheir ER methylation status by methylation specific PCR (MSP). These tumors were classified into main subtypesaccording to IHC markers and data were collected on pathological features of the patients. ERα methylation wasfound in 25 of 28 (89.3%) basal tumors, 21 of 24 (87.5%) Her2+ tumors, 18 of 34 (52.9%) luminal A tumors and7 of 14 (50%) luminal B tumors. A strong correlation was found between ERα methylation and poor prognosistumor subtypes (basal and Her2+) in patients (P<0.001). Our findings show that ERα methylation is correlatedwith poor prognosis subtypes of breast tumors in Iranian patients and may play an important role in pathogenesisof the more aggressive breast tumors.     

Elevated levels of circulating insulin-like growth factor-I, IGF-binding globulin-3 and testosterone predict hormone-dependent breast cancer in postmenopausal women: a case-control study

There is increasing evidence that different types of breast cancers are related to distinct risk factors. We analyzed the risk of breast cancer with respect to circulating insulin-like growth factor (IGF)-I, IGF-binding protein (IGFBP)-3, 17beta-estradiol, estrone, testosterone, androstenedione and sex hormone-binding globulin (SHBG), taking into consideration the characteristics of the tumors. Plasma hormone levels of 102 postmenopausal patients with breast cancer detected by mammography screening, and 102 matched controls were analyzed in relation to the histological type, the status of the estrogen receptor (ER), the progesterone receptor (PR) and the HER2 in the tumors. Significant positive associations were revealed between the IGF-I concentration and the overall risk of breast cancer (OR=3.1, 95% CI: 1.5-6.2), ER+PR+ breast cancer (OR=2.4, 95% CI: 1.1-5.4) and ER+PR- breast cancer (OR=4.3, 95% CI: 1.2-14.3) when the highest and the lowest ranges of IGF-I were compared. Significant associations were also found between the highest and the lowest quartiles of testosterone, resulting in OR=4.1 (95% CI: 1.8-9.4) for the risks of breast cancer and OR=5.8 (96% CI: 2.1-16.2) of ER+PR+ breast cancer. A synergy was seen between IGF-I and testosterone levels. When both plasma IGF-I and testosterone were in the highest quartile ranges, an OR=26.4 (95% CI: 1.6-426.5, p=0.021) was computed for breast cancer overall. No significant synergistic effects could be demonstrated with other parameters. There were significant, 2.5-fold (95% CI: 1.2-5.6), and 16-fold (95% CI: 2.0-133.5) increases in the overall risks of breast cancer and of ER+PR- breast cancer, respectively, when the highest and the lowest quartiles of IGFBP-3 were compared. No associations were found between any of the hormones and the risk of ER-PR- tumors. The increased prevalence of ER+ breast cancers in patients with higher levels of IGF-I, IGFBP-3 or testosterone implicate these hormones in the etiology of hormone-dependent breast cancer. Additional analyses specific for breast cancer subtypes may shed light on the value of hormone determinations for tailored chemoprevention.     

Progesterone Stimulates Proliferation and Promotes Cytoplasmic Localization of the Cell Cycle Inhibitor p27 in Steroid Receptor Positive Breast Cancers

Progestins are reported to increase the risk of more aggressive estrogen receptor positive, progesterone receptor positive (ER+ PR+) breast cancers in postmenopausal women. Using an in vivo rat model of ER+ PR + mammary cancer, we show that tumors arising in the presence of estrogen and progesterone exhibit increased proliferation and decreased nuclear expression of the cell cycle inhibitor p27 compared with tumors growing in the presence of estrogen alone. In human T47D breast cancer cells, progestin increased proliferation and decreased nuclear p27 expression. The decrease of nuclear p27 protein was dependent on activation of Src and PI3K by progesterone receptor isoforms PRA or PRB. Importantly, increased proliferation and decreased nuclear p27 expression were observed in invasive breast carcinoma compared with carcinoma in situ. These results suggest that progesterone specifically regulates intracellular localization of p27 protein and proliferation. Therefore, progesterone-activated pathways can provide useful therapeutic targets for treatment of more aggressive ER+ PR+ breast cancers.