Thyroid hormone receptors in human breast cancer: effect of thyroxine administration

The present study was designed to establish the presence and pharmacological properties of the nuclear triiodothyronine receptors (T3R) (binding capacity, affinity and number of sites) in human breast cancer samples as well as the effects on them of thyroid hormone administration (T4). A computerized Scatchard plot analysis was designed to resolve the exponential curves in order to estimate the real number of T3R. T3R was present in 83% of the patients studied. In the thyroxine treated group, the number of nuclear T3R increased in the postmenopausal women, and may decrease in the premenopausal group, compared with the control group. These results suggest that T3R and thyroid hormone may play a role in breast cancer growth regulation; they also suggest that the T3R could open up the possibility of the classification of patients (as for ER and PgR), and consequently of new therapeutic trials.     

Thyroid hormone receptors/THR genes in human cancer

Thyroid hormone (triiodothyronine, T3) is a pleiotropic regulator of growth, differentiation and tissue homeostasis in higher organisms that acts through the control of target gene expression. Most, if not all, major T3 actions are mediated by specific high affinity nuclear receptors (TR) which are encoded by two genes, THRA and THRB. Several TRalpha and TRbeta receptor isoforms are expressed. Abundant and contradictory literature exists on the relationship between circulating thyroid hormone levels, thyroid diseases and human cancer. In 1986, a connection between TR and cancer became evident when the chicken TRalpha1 was characterized as the c-erbA proto-oncogene, the cellular counterpart of the retroviral v-erbA oncogene. V-erbA causes erythroleukemias and sarcomas in birds, and hepatocellular carcinomas in transgenic mice. In recent years, many studies have analyzed the presence of quantitative (abnormal levels) or qualitative (mutations) alterations in the expression of THR genes in different types of human neoplasias. While their role in tumor generation or progression is currently unclear, both gross chromosomal and minor mutations (deletions, aberrant splicing, point mutations) and changes in the level of expression of THRA and THRB genes have been found. Together with other in vitro data indicating connections between TR and p53, Rb, cyclin D and other cell cycle regulators and oncogenes, these results suggest that THRA and THRB may be involved in human cancer.     

甲状腺激素受体与肿瘤

研究表明,甲状腺激素受体(TR)在许多肿瘤的发生过程中伴有染色体杂合子丢失、基因启动子区甲基化及基因突变等,出现TR mRNA或蛋白质表达异常,且TR异常与某些神经系统肿瘤如星形细胞瘤和垂体瘤的分化程度相关.目前,关于TR的作用途径及机制主要包括:垂体瘤转化-1、β-连环蛋白等肿瘤相关因子和细胞外信号调节激酶、磷脂酰肌醇-3激酶信号传导通路等.     

Correlation between steroid hormone receptors and prognostic factors in human breast cancer

Knowledge of the tumor content of estrogen (ER) and progesterone (PgR) receptors has proved to be of significant value in human breast cancer. Relative determinations were performed in 589 specimens in our laboratory. The positivity of ER and PgR is correlated with the patients' age at diagnosis, tumor size and relative grade. In particular, the significance of PgR versus ER status and the possible prognostic role of these receptors are investigated.     

Prognostic value of hormone receptors in breast cancer

The aim of this study was to establish the role of estrogen receptor (ER) and progesterone receptor (PgR) as prognostic indicators for early recurrence and survival. In all, among breast cancer patients, 166 patients who had undergone radical or extended radical mastectomy were studied. These patients were treated with adjuvant chemotherapy alone for 2-3 years after surgery. No patients had adjuvant endocrine therapy. Local recurrence and/or distant metastases were treated by endocrine therapy and/or chemotherapy. The relapse-free interval was not different between the ER-positive and ER-negative patients. The postrelapse survival curve was significantly different between the two groups. There was no significant difference in the relapse-free interval and the postrelapse survival curve between the PgR-positive and PgR-negative patients. These results suggest that ER is a good predictor of the response to endocrine therapy given after relapse, but not of early recurrence.     

Steroid hormone receptors and prognosis in breast cancer

Summary The importance of steroid receptors for the prognosis of mammary carcinoma has been evaluated by investigating the course of disease in 163 patients for a median follow up time of 66 months after mastectomy. Multivariate analysis including estrogen receptor (ER), progesterone receptor (PgR), the presence of 8S and 4S ER together or 4S ER only, and the lymph node status revealed only the latter to have significant (p<0.001) predictive potency. Lymph node positive (N-pos) patients had a 3.3 (1.7–6.2) fold risk of death and 2.8 (1.7–4.7) fold risk of recurrence relative to node negative (N-neg) patients.When we compared overall survival (OAS) and disease-free survival (DFS) in the various receptorpositive groups with the groups that displayed neither ER nor PgR, significant differences in prognosis were only seen in N-neg patients. PgR did not turn out to be a better prognostic factor than ER, nor was the 8S ER a sing of increased OAS and DFS compared to total ER. However, the number of patients in this group was too small to allow a definite statement.     

Steroid hormone receptors and survival in breast cancer patients

Estrogen receptor (ER) levels were measured in 280 breast cancer patients (mean age 54.5 years). Progesterone receptor (PR) levels were assayed in 101 of them. 61.4% of cases were at stages I and IIa. No significant difference in 2-year survival was established between ER-negative and ER-positive patients (96.7 and 96.0%, respectively). Two-year survival rate and recurrence--free survival for PR-positive cases were significantly higher than those for PR-negative ones (p greater than 0.05).     

Multiple steroid receptors in human breast cancer

Summary Histopathologic features (tumor cell density, histological type, and histoprognostic grade) were analyzed in 314 breast cancers investigated for estrogen (E) and progestin (P) receptors (R). The presence of PR is associated with the presence of ER. A relationship was found between the acinoductal differentiation of the lesions and the presence of SR: the more differentiated the carcinoma, the higher the frequency of ER. HPG III carcinomas have the lowest frequency of positive ER and HPG I tumors the opposite: the likelihood of the presence of SRs is inversely correlated with HPG. No statistically significant relationship existed between tumor cell density (TCD) and the presence of ER or ER content. Similar findings were observed for the stromal reaction. The results are discussed with respect to the biological significance of SR and histopathologic features: SR presence could be correlated with (1) a differentiated state of the tumors and (2) a slow rate of cellular replication.     

Nuclear thyroid hormone receptors in human cancer tissues

Saturable, high affinity binding sites for 3,5,3' triiodothyronine (T3) were identified in nuclei isolated from human tumors of various origins (breast cancers, other epitheliomas, sarcomas, tumors of the central nervous system). Nuclear T3 receptors were present in all samples of primary breast cancer (n = 93; average Cmax = 215 fmol/mg DNA) and in metastatic tissues originating from breast tumors. A significantly lower T3 binding capacity was found in non-tumor tissues, obtained from breast sites distal to the tumor (n = 30; average Cmax = 133 fmol/mg DNA; paired t-test: p less than 0.01). Specific nuclear T3 receptors were also present in other epitheliomas (n = 8; average Cmax = 432 fmol/mg DNA), sarcomas (n = 4; average Cmax = 297 fmol/mg DNA) and cerebral tumors (n = 13; average Cmax = 364 fmol/mg DNA. In 93 cases of breast cancer, a negative relationship was found between the nuclear T3 receptor level and the involvement of axillary lymph nodes (Pearson chi square value: p = 0.017). Except a possible relationship between the T3 receptor and the progesterone receptor concentrations, no significant correlation was observed between the nuclear T3 binding capacity in breast cancer samples and other clinical and biochemical parameters: age, tumour stage, histopathological grade, serum concentrations of thyroid hormones, TSH, CEA (carcinoembryonic antigen) and prolactin, cytoplasmic estrogen receptors. The presence of high affinity T3-binding sites in human tumor nuclei indicates that the thyroid hormones may play a role, at the cellular level, on the development of certain human cancers.     

Progesterone receptors and human breast cancer

Estrogen receptor protein is known to be an important prognostic factor for patients with breast cancer. The presence of estrogen receptor correlates with response to endocrine therapy in patients with metastatic disease and is associated with prolonged disease-free and overall survival in patients with primary disease. But the correlation between estrogen receptor positivity and endocrine dependence is not perfect. Approximately 40% of estrogen receptor positive tumors fail to regress with endocrine therapy. It has been hypothesized that another protein, progesterone receptor, may be a more effective marker of endocrine responsiveness since progesterone receptor is the end product of estrogen action. We have examined the relationship between progesterone receptor and response of advanced breast cancer tumors to hormonal manipulations. Promising retrospective results indicate the need for new, prospective clinical trials to further define the prognostic value of progesterone receptor for these tumors. We have also analyzed the disease-free intervals of patients with primary disease and found that progesterone receptor was more important than estrogen receptor for predicting time to recurrence. We suggest that both estrogen receptor and progesterone receptor be routinely measured in all breast cancer tumors, and that the results of these assays will help the physician individualize therapy for breast cancer patients.     

Extranuclear expression of hormone receptors in primary breast cancer.

BACKGROUND: Hormone receptor (HR)-positive breast cancer cells grow through estrogen receptor (ER)-signaling pathways that mediate both genomic and nongenomic actions, which cross-talk with growth factors associated with resistance to tamoxifen. The aim of this study was to explore the cross-talk between extranuclear expression of ER and progesterone receptor (PR) and growth factor signaling pathways in primary breast cancer. PATIENTS AND METHODS: The extranuclear expression of ER and PR was examined in 219 primary breast cancers by immunohistochemical staining. Specimens showing such expression were further examined for the expression of pAkt and aromatase. Staining reactions were scored on the basis of intensity and distribution in the tumors. RESULTS: Extranuclear expression of ER or PR was observed in 21 cases (9.5%), which included four cases for ER and 20 cases for PR. Among these patients, HER-2, pAkt, and aromatase-positivity were observed in 14 cases (66.6%), 13 cases (61.9%), and 14 cases (66.6%), respectively. On the basis of nuclear HR expression, 11 of these cases were categorized as ER-positive/PR-negative, while two were ER-negative/PR-positive. Of these 13 cases, increased pAkt staining was found in 11 cases (84.6%). In particular, among the 11 ER-positive/PR-negative cases, elevated pAkt and aromatase were found in 10 (90.9%; P<0.01) and nine cases (81.8%), respectively. CONCLUSIONS: PR is expressed extranuclearly more frequently than ER in primary breast cancer, and extranuclear HRs cross-talk with the Akt/HER-2-signaling pathways and activation of aromatase. These observations may explain the more beneficial effects of aromatase inhibitors than tamoxifen for ER-positive/PR-negative patients.     

The significance of hormone receptors to predict the endocrine responsiveness of human breast cancer

The paper reviews clinical data on the correlation between the response of human breast cancer to endocrine therapy and the tumour cell content of receptors of e.g. oestrogen (OeR), progesterone (PgR), androgens (AR) and the epidermal growth factor (EGFR). In advanced disease there is a well established correlation between OeR content and the rate of objective response to all types of endocrine therapy. However, if selection of first-line salvage therapy based on OeR status will result in prolonged survival or improved quality of life remains controversial. Assays of PgR, AR, and EGFR--in addition to OeR--increase the predictive ability but no study has been able to define an entirely unresponsive subgroup of patients on the basis of receptor status. In the adjuvant setting conflicting relationships have been reported. Some authors have found a benefit with tamoxifen also among OeR negative patients whereas others have concluded that adjuvant tamoxifen is ineffective in such patients. Prospective randomized trials are warranted to further assess the predictive value of hormone receptors, particularly in view of the increased frequency of thrombotic events and endometrial cancer associated with long-term adjuvant tamoxifen.     

甲状腺激素及其受体与乳腺癌的关系

乳腺是激素依赖性器官,多种激素对其均有影响。许多研究表明,甲状腺激素与乳腺癌具有密切关系,它可以直接调控乳腺细胞的生长分化,也能通过类雌激素样作用影响乳腺癌的发生发展。而甲状腺激素受体的异常表达亦与乳腺癌发病相关。