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。     

Influence of thyroid hormone receptors on breast cancer cell proliferation.

BACKGROUND: The involvement of thyroid hormones in the development and differentiation of normal breast tissue has been established. However, the association between breast cancer and these hormones is controversial. Therefore, the objective of the present study was to determine the protein expression pattern of thyroid hormone receptors in different human breast pathologies and to evaluate their possible relationship with cellular proliferation. PATIENTS AND METHODS: The presence of thyroid hormone receptors was evaluated by immunohistochemistry and western blot analysis in 84 breast samples that included 12 cases of benign proliferative diseases, 20 carcinomas in situ and 52 infiltrative carcinomas. RESULTS: TR-alpha was detected in the nuclei of epithelial cells from normal breast ducts and acini, while in any pathological type this receptor was located in the cytoplasm. However, TR-beta presented a nuclear location in benign proliferative diseases and carcinomas in situ and a cytoplasmatic location in normal breast and infiltrative carcinomas. The highest proliferation index was observed in carcinomas in situ, although in infiltrative carcinomas an inverse correlation between this index and the TR-alpha expression was encountered. CONCLUSIONS: The results of this study reveal substantial changes in the expression profile of thyroid hormone receptors suggesting a possible deregulation that could trigger breast cancer development.     

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.     

Prevalence of hormone receptors and HER2/neu in breast cancer cases in Jordan

The management and prognosis of breast cancer nowadays require the evaluation of Estrogen (ER), Progesterone Receptors (PR) and HER2/neu. Ethnic variation in the expression of these receptors is well documented. The aim of this study is to determine the prevalence of ER, PR and HER2/neu among Jordanian women with breast cancer of ductal and lobular types. A retrospective analysis was performed on 267 cases of breast cancer referred for treatment at King Hussein Cancer Center, Jordan between the period of June 2003 and June 2004. Standard immune stains were used for evaluation of hormone receptors and HER2/neu. In addition, evaluation of HER2/neu was done by FISH in selected cases. Of these 267 cases, 240 (89.9%) were ductal carcinomas of various histological grades, 122 (50.8%) of which were ER-positive, 138 (57.5%) PRpositive and 42 (17.5%) HER2/neu-positive. Twentytwo (8.2%) of all cases were lobular carcinomas, 15 (68%) of which were ER-positive, 20 (90.9%) PRpositive and 3 (13.6%) HER2/neu-positive. Five (1.9%) of the total cases were of mixed lobular and ductal types, 4 (80%) of which were ER-positive, 3 (60%) PR-positive and none were positive for HER2/neu. The prevalence of hormone receptor positivity in breast cancer of Jordanian women is lower than that of the western populations and close to other populations such as the Chinese and the minor ethnic groups of Northern America (African Americans).     

Reproductive factors and subtypes of breast cancer defined by hormone receptor and histology

Reproductive factors are associated with reduced risk of breast cancer, but less is known about whether there is differential protection against subtypes of breast cancer. Assuming reproductive factors act through hormonal mechanisms they should protect predominantly against cancers expressing oestrogen (ER) and progesterone (PR) receptors. We examined the effect of reproductive factors on subgroups of tumours defined by hormone receptor status as well as histology using data from the NIHCD Women's Contraceptive and Reproductive Experiences (CARE) Study, a multicenter case-control study of breast cancer. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) as measures of relative risk using multivariate unconditional logistic regression methods. Multiparity and early age at first birth were associated with reduced relative risk of ER + PR + tumours (P for trend=0.0001 and 0.01, respectively), but not of ER - PR - tumours (P for trend=0.27 and 0.85), whereas duration of breastfeeding was associated with lower relative risk of both receptor-positive (P for trend=0.0002) and receptor-negative tumours (P=0.0004). Our results were consistent across subgroups of women based on age and ethnicity. We found few significant differences by histologic subtype, although the strongest protective effect of multiparity was seen for mixed ductolobular tumours. Our results indicate that parity and age at first birth are associated with reduced risk of receptor-positive tumours only, while lactation is associated with reduced risk of both receptor-positive and -negative tumours. This suggests that parity and lactation act through different mechanisms. This study also suggests that reproductive factors have similar protective effects on breast tumours of lobular and ductal origin.     

DNA ploidy,S-phase,and steroid receptors in more than 127,000 breast cancer patients

Summary Several potential prognostic factors are available today for patients with breast cancer, and many more are being identified and studied. To evaluate the clinical utility of these factors, it will be necessary to measure them on a large number of patients, and then follow these patients so that multivariate survival analyses can be performed.The Oncology Research Network was established in 1986 by the University of Texas Health Science Center at San Antonio and Nichols Institute Reference Laboratories in order to evaluate the clinical utility of new prognostic factors for patients with primary breast cancer. The first generation of prognostic factors included steroid receptors, along with DNA ploidy and S-phase fraction determined by flow cytometry. Currently, laboratory results have been obtained from more than 127,000 patients, and follow-up information is available on a subset of more than 25,000 of these patients.S-phase fraction was related to the ploidy status of the tumor. An increased incidence of aneuploidy and higher S-phase fractions were found in estrogen and progesterone receptor negative tumors, tumors from patients with positive axillary lymph nodes, tumors greater than 2 cm in diameter, and patients younger than 35 years of age. Preliminary survival analyses suggest that S-phase fraction and DNA ploidy, in combination with other prognostic factors, are powerful predictors of early disease relapse.The Oncology Research Network provides an important resource for examining the clinical significance of new laboratory assays and for expediting improvements in existing laboratory techniques.We regret to report that Dr. William L. McGuire died on March 25, 1992, after this work was largely completed     

Elevated luteinizing hormone in serum,breast cancer tissue,and normal breast tissue from breast cancer patients

Purpose. Hormones are known to be important in breast cancer, but studies have focused on steroid hormones and their cognate receptors. We report here an analysis of luteinizing hormone (LH) concentration in serum and breast tissue samples. Materials and methods. We studied serum and breast tissue samples from 353 women, 231 with breast cancer and 122 controls. Four breast tissue sites were sampled in every case. Tumor samples were also available from 48 patients and serum from 101 subjects. LH was measured by enzyme-linked immunosorbent assay. Results. LH concentration in breast tissue was significantly higher in samples from patients with breast cancer than in samples from control subjects. In breast cancer patients, there was a decreasing gradiant from the cancer to the normal breast tissue, near and far from the tumor. Serum LH levels could not distinguish between breast cancer and control cases in most cases; but tissue LH could. Conclusions. LH concentrations were higher in breast tumors than in normal tissue near to or far from the tumor in women with breast cancer, and these concentrations were higher in women with breast cancer than in control cases. The different LH concentrations in breast tissue might be used to detect small or hidden carcinomas. In addition, the identification of luteinizing hormone in breast tissue offers a different explanation for the mechanism of action of LHRH agonists and might identify patients that respond to this treatment.     

Histologic types and hormone receptors in breast cancer in men: a population-based study in 282 United States men

Histologic slides from 282 incident cases of breast cancer in men, that were identified in 10 population-based cancer registries in the United States, were reviewed by a single pathologist. Breast cancer more often presented in the noninvasive stage in men (10.8 percent of all cases) than would be expected among women. All noninvasive carcinomas were of the ductal type. Of invasive carcinomas, compared with women, men had smaller proportions of lobular and mucinous types and larger proportions of ductal and papillary types and Paget's disease. No case of tubular or medullary carcinoma was seen. The breast in men is composed only of ducts and normally contains no lobules, and the histologic types of breast carcinomas that predominate in men are likely of ductal origin. Estrogen and progesterone receptors were present in 86.7 percent and 76.3 percent of invasive carcinomas, respectively, which are higher proportions than would be expected among women. Also, unlike findings in women, receptor content was not associated with patient age at diagnosis.Dr Stalsberg is with the Institute of Medical Biology, University of Tromsø, Tromsø, Norway, and Drs Thomas, Rosenblatt, Jimenez, and McTiernan are with the Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA, Authors also are affiliated with the University of Illinois, Champaign, IL, USA (Dr Rosenblatt); the Institutio Regional de Investigacion en Salud Publica, Guadalajara, Mexico (Dr Jimenez); the University of Washington School of Medicine, Seattle, WA, USA (Dr McTiernan); the Pharmaceutical Division, CIBAGEIGY Corp., Summit, NJ, USA (Dr Stembagen); the University of Southern Maine, Portland, ME, USA (Dr Thompson); the Connecticut Cancer Epidemiology Unit, New Haven, CT, USA (Dr McCrea Curnen); the School of Public Health, University of California, Berkeley, CA, USA (Dr Satariano); the Resource for Cancer Epidemiology, Department of Health Services, Emeryville, CA, USA (Dr Austin); the School of Public Health, Emory University, Atlanta, GA, USA (Dr Greenberg); the New Mexico Tumor Registry, Albuquerque, NM, USA (Dr Key); the Epidemiology Program, Cancer Research Center of Hawaii, Honolulu, HI, USA (Dr Kolonel); the Northern California Cancer Center, Alameda, CA, USA (Dr West). Address correspondence to Dr Stalsberg, Institute of Medical Biology, University of Tromsø, N-9037 Tromsø, Norway. This study was funded by grant number RO1 CA35653 from the US National Cancer Institute.     

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.     

Pre-morbid body-mass-index in breast cancer: Reversed effect on survival in hormone receptor negative patients

Summary The present study consists of 1,238 women with unilateral breast cancer treated with modified radical mastectomy living in the geographic area of Haukeland Hospital. Their weight and height had been measured years before presentation of the disease. Age-adjusted Quetelet's index (weight/height²) showed that obese women had a 49% higher risk of dying from breast cancer than lean ones. The relative risk decreased slightly when adjusted for tumour diameter, lymph node status, and mean nuclear area of the tumour cells. The prognostic effect of Quetelet's index was examined according to the estrogen and/or progesterone receptor status of the tumour. In patients with a hormone receptor positive tumour, obese women had a risk that was more than three times higher than lean ones. In patients with hormone receptor negative tumour, the effect of obesity was reversed, lean patients having a risk that was more than six times higher than obese ones, even after adjustment for lymph node status, tumour diameter, and mean nuclear area. Quetelet's index, while being a prognostic variable in its own right, thus acts differently in patients with hormone receptor positive and negative tumours.     

Hormone receptors in male breast carcinoma

It is well established that approximately 60% of female breast cancers contain estrogen receptors (ER+). The hormonal receptor status of male breast cancers remains relatively unknown. Tumor tissue from 14 patients has been reviewed at the University of Oregon Health Sciences Center. Specimens of all 14 patients were ER+ with a range of 5.5 to 374 fmol/mg protein. Eight of 12 patients had tumors which also contained progesterone receptors (PR+) with a range of 42 to 1852 fmol/mg protein. Nine patients were treated by modified radical mastectomy, two by radical mastectomy, one by simple mastectomy, and two by biopsies only. Twelve patients remain free of disease with a mean follow-up of less than 2 years. The two patients who developed metastases both responded to endocrine ablation by orchiectomy and subsequent adrenalectomy. These data suggest that male breast cancer is highly endocrine sensitive and that endocrine ablation can play an integral part in those men unfortunate enough to develop disseminated disease.     

Characterization of prolactin receptors in human breast cancer

Summary In order to perform measurement of PRL binding and to improve the knowledge of pathophysiological variations in human mammary cancers, we have investigated in detail the binding characteristics of PRL in membranes prepared from these tumors. The optimization of the assay requires the selection of membranous components of light density (<1.17); the tracer could be either¹²⁵I-PRL after affinity purification on PRL receptors or¹²⁵I-hGH without a purification step. It is favorable to utilize a high amount of protein and 200 000 cpm (2 ng) of tracer. Demonstration of the presence of receptors for PRL with a high affinity (K_d = 3 × 10^–10 M) in breast cancer is presented. The hormonal specificity of these receptors is studied: only lactogenic hormones (hGH, oPRL, hPRL, and hPL) are able to compete for binding of¹²⁵I-hPRL whereas bGH or insulin are without effect. Considering the known effect of PRL on cell multiplication, it is tempting to suggest that this hormone could have a crucial role in the development of breast tumor in humans and that therapies which would suppress secretion of PRL and GH could be beneficial.     

Association between estrogen receptors and weight in women with breast cancer

A significant association between body weight and estrogen receptor protein (ERP) was noted in 83 women with primary and metastatic breast cancer. Thirteen of 34 (54%) women with weight >150 lb had low or absent receptor protein (<10 femtomoles/mg of cytoplasmic protein) compared to 15 of 59 (25%) women with weight <150 lb (P <0.025). The observed association was stronger in the group of 62 postmenopausal women (P <0.01). The findings suggest that the endocrine and metabolic milieu in women with increased weight favors autonomous growth of breast cancer, and adjuvant treatment in this group should be planned accordingly.     

Electrocautery: Effects on steroid receptors in human breast cancer

The determination of steroid receptors in human breast cancers has assumed increasing importance over the past several decades. Improper handling of the specimens could affect results obtained. This study details the effects excessive levels of heat that occur with the use of electrocautery can have on steroid receptor quantities and localization. Twelve resected primary and metastatic human breast cancers were analyzed for cytoplasmic and nuclear receptors by biochemical analysis. In addition, steroid binding was determined by direct fluorescent histochemical techniques. To a portion of each resected specimen a Bovie^c was applied to simulate electrocautery resection. Analysis of the different portions of the same tumor revealed that there was a decrease in measurable cytoplasmic receptor in all cauterized specimens and a concomitant increase in the nuclear receptor. A similar shift in steroid binding was noted in all the specimens analyzed by fluorescent histochemical techniques. The results of this study show that the application of excessive heat to human breast cancers will lead to false negative biochemical steroid receptor determination by shifting the receptors intranuclear.     

Postmenopausal hormone therapy and breast cancer risk: the Multiethnic Cohort

Epidemiological studies indicate that menopausal estrogen-progestin therapy (EPT) use is associated with an increase in breast cancer risk. Further data are needed on whether this association varies by specific prognostic factors and ethnicity. We conducted a cohort study among 55,371 African-American, Native Hawaiian, Japanese-American, Latina and White postmenopausal women aged 45-75 years old in the Multiethnic Cohort Study (MEC). A total of 1,615 incident invasive breast cancer cases were identified over an average of 7.3 years. Adjusted relative risks (RRs) were computed for the various forms of hormone therapy (HT). Assuming current users continued HT use to the end of follow-up, current EPT use was associated with a 29% increased risk of breast cancer per 5 years of use (95% confidence interval (CI) = 23-35%), and current estrogen therapy (ET) use with a 10% increase in risk per 5 years of use (95% CI = 5-16%). These figures increased to only a very small extent when we adjusted for the estimated 3% of such women who stop HT use per year of follow-up. EPT and ET use were associated with greater risk among leaner women, but the increase in risk with EPT use was still very evident in women with BMI > or =30 kg/m(2). Current EPT use was associated with increased risk for ER+/PR+, ER+/PR- and ER-/PR- tumors. There was little difference in risk by stage of disease or histologic subtype. The increase with EPT use was clearly seen in all 5 ethnic groups; and the increase with ET in 4 of the 5 groups.     

Steroid hormone receptors in breast tumours presenting during pregnancy or lactation

Cytosol oestrogen receptor (ER) and progesterone receptor (PR) levels were measured in tumours from three patients with breast cancer during pregnancy and from three patients developing breast cancer while lactating. All lactating patients were ER-positive and two were PR-positive, whereas pregnant patients were uniformly ER-negative and PR-negative. Pregnant patients had a significantly shorter disease-free survival compared with matched nonpregnant women with breast cancer. Of five patients developing metastatic disease, one from the lactating group had a complete remission with chemotherapy and one had static disease with endocrine treatment, whereas all others had progressive disease despite a variety of treatments. Although numbers are too small to permit generalisation, these provisional data suggest that patients presenting with breast cancer during pregnancy may have mainly receptor-negative tumours, a short disease-free interval, and may be relatively resistant to treatment of metastatic disease. By comparison, patients with breast tumours during lactation have receptor-positive disease and metastases may respond to systemic therapy.     

乳腺癌新辅助化疗中肿瘤标志物检测的临床意义

目的检测肿瘤标志物在新辅助化疗乳腺癌中的表达,探讨新辅助化疗患者中ER、PR、c-erbB2和Ki67的表达及临床意义.方法用免疫组织化学法检测ER、PR、c-erbB2和Ki67在89例新辅助化疗乳腺癌组织中的表达状况,分析上述指标与化疗的关系.结果新辅助化疗总有效率89.9%,其中完全缓解CR32.6%,部分缓解PR57.3%,病理完全缓解pCR17.9%,疾病稳定SD10.5%,无恶化病例.ER/PR表达与疗效有关（P〈0.05）,c-erbB2、Ki67表达与化疗疗程无关.结论激素受体阴性者对新辅助化疗的敏感性较高,新辅助化疗肿瘤标志物的检测可以为临床评价疗效判断预后提供依据.     

Leukocyte alkaline phosphatase and carcinoembryonic antigen in breast cancer patients: clinical correlation with the markers

Leukocyte alkaline phosphatase (LAP) scores in peripheral blood and plasma carcinoembryonic antigen (CEA) levels were determined in 208 breast cancer patients with nonmetastatic disease. Patients were followed until clinical manifestations of metastases appeared. Then the LAP score and CEA level were analyzed in relation to the clinical appearance of metastases. Of the 208 patients studied, 58 developed metastases during the follow-up period. The LAP scores and CEA levels of this group of patients were compared to a control group of 60 breast cancer patients who did not develop metastases. Of the two markers, LAP score seems to be considerably more useful in detecting metastatic disease.     

Estrogen receptor negative and progesterone receptor positive primary breast cancer: Pathological characteristics and clinical outcome

The expression of estrogen (ER) and progesterone (PgR) receptors was analyzed in a retrospective series of 3000 patients who had operable primary breast cancer. Patients were stratified according to ER and PgR status and the study was focused on the two groups (ER–PgR+ and ER–PgR–) of patients whose tumors contained low levels of ER (< 15 fmol/mg protein), regarding potential response to endocrine therapy. The comparison of clinical or histological characteristics between ER–PgR+ and ER–PgR– patients was analyzed as well as the disease-related death and survival. The mean follow-up was 86.3 months. Among the 529 ER–patients, 62 were PgR+ (12%), whereas 467 were PgR– (88%). The ER–PgR+ and ER–PgR– populations represented 2% and 15.6% of the overall population, respectively. In ER– tumors, the PgR status was significantly related to: age, menopausal status, tumor size, SBR grade, and histological type, but not to the type of surgical treatment or to lymph node involvement. ER–PgR+ tumors had smaller size (64% T1 vs 43%) (p=0.004) and were more frequently grade I (28% vs 12%) than ER–PgR– ones (p < 0.001). In addition, the patients with ER–PgR+ tumors were significantly younger (49.4 years vs 58.4 years; p < 0.0001), and were more frequently premenopausal (76% vs 36%; p < 0.001). The disease-free interval and the metastasis-free survival tended to be worse for ER–PgR– than for ER–PgR+ patients, but the difference was not statistically significant at 10 years. However, a small but significant difference in overall survival, in favor of the PgR+ group, was observed between the two groups during the first 5 years (p=0.03).We conclude that in combination with ER, PgR status defines a group of patients with clinical and biological specificity, which could be considered for specific endocrine therapy.