Steroid sulfatase and estrogen sulfotransferase in human prostate cancer

BACKGROUND: Estrogen sulfotransferase (EST) and steroid sulfatase (STS) are known to be involved in in situ estrogen production in estrogen dependent human cancer such as breast cancer, but unknown in prostate cancer. MATERIALS AND METHODS: We first examined whether these enzymes above were expressed and actually involved in estrogen production and metabolism in prostate cancer cell lines (LNCaP, DU-145, and PC-3). We than examined the expression of EST and STS in human prostate cancer tissues obtained from surgery (n = 52) using immunohistochemistry. RESULTS: mRNAs of both enzymes were detected in all prostate cancer cell lines examined, and the synthesis of estrone (E(1)) and estradiol (E(2)) was also confirmed in these cell lines. In addition, STS immunoreactivity was detected in 44 cases (85%) and EST in 39 cases (75%), respectively. CONCLUSIONS: STS and EST are expressed and may be involved in local production and metabolism of estrogens in human prostate cancers.     

芳香化酶与乳腺癌的相关研究

雌激素在乳腺癌的发生发展中起着重要作用。绝经后妇女的雌激素主要由肾上腺分泌的雄激素前体转化而来,芳香化酶是这一转变过程的关键酶、限速酶。因此,深入研究芳香化酶和乳腺癌的关系具有重要的临床意义。现就芳香化酶在乳腺癌组织中的表达、调控及芳香化酶抑制剂在乳腺癌内分泌治疗中的临床进展作一综述。     

Serum estrone sulfate levels in patients with breast cancer

Estrone and estradiol-17 beta concentration in breast cancer tissue are reported to be an order of magnitude higher than those of circulating plasma in breast cancer patients. This high level of estrogen is provided by local production from estrone sulfate (E1-S) through the sulfatase pathway. Then serum E1-S level was determined using direct radioimmunoassay method in order to monitor the estrogen kinetics of post-operative breast cancer patients. Peri-operative sequential E1-S determination was carried out in 10 patients. Among them, extremely higher level, as compared with normal menstruating level of 625-2670pg/ml, was observed just after an administration of tamoxifen (three weeks after operation) in two of 5 pre-menopausal patients. In order to evaluate the effect of tamoxifen on serum level of E1-S in post-operative pre-menopausal patients, serum E1-S level in 42 post-operative outpatients was examined. Although there was no difference in the average level of E1-S in post-menopausal patients treated with or without tamoxifen, average E1-S level in pre-menopausal patients treated with tamoxifen as adjuvant therapy was significantly higher than that in patients without tamoxifen. These results suggests that the administration of tamoxifen to premenopausal patients should be reconsidered from a view point of the estrogen kinetics.     

芳香化酶抑制剂在乳腺癌治疗中的应用

芳香化酶抑制剂通过抑制肾上腺、脂肪及乳腺癌等组织中的芳香化酶,阻止雄烯二酮及睾酮转化为雌激素,使血液中雌激素水平下降,抑制雌激素依赖性癌细胞生长。内分泌治疗是乳腺癌的一种重要治疗手段[1]。绝经后妇女的雌激素主要来源于雄激素前体物质在外周组织的芳香化,因此芳香化酶抑制剂特别适用于绝经后雌激素受体(ER)和(或)孕激素受体(PR)阳性的乳腺癌患者,使复发、转移的危险性减少,5年、10年生存率明显提高。1非特异性芳香化酶抑制剂代表药物如氨鲁米特(Aminoglutethi mide,AG)为第1代芳香化酶抑制剂,对绝经后晚期乳腺癌有效率为30%,…     

Cytohistochemical studies on estrogen receptors of breast cancer tissue using an immunoperoxidase technique

The estrogen receptors (ER) in breast cancer tissues were investigated in 122 patients using an immunoperoxidase method. ER (+) were evident in 77 of 122 patients (63.1 per cent). If classified according to pre- and postmenopausal subjects. ER (+) was seen in 61.4 per cent and ER (-) in 32.9 per cent before menopause, and ER (+) in 65.4 per cent and ER (-) in 30.8 per cent after menopause with no marked difference between the two. If classified according to histological type, ER (+) was seen in 72.3 per cent of those with papillotubular carcinoma and in 62.0 per cent of those with scirrhous carcinoma, whereas ER (-) was seen in 44.9 per cent of those with medullary tubular carcinoma. ER (+) was seen in carcinoma with apocrine metaplasia, lobular carcinoma and Paget's carcinoma. Concerning the relationship between primary tumors and metastatic lymph nodes, ER (+) for both was seen in 20 of 41 patients (48.8 per cent) whereas ER (-) for both was found in 9 of 41 patients (22.0 per cent). Four patients with local recurrences had a positive ER (+) at the beginning of treatment, but the ER became negative after hormonal treatment and chemotherapy.     

Cytohistochemical studies on estrogen receptors of breast cancer tissue using an immunoperoxidase technique

The estrogen receptors (ER) in breast cancer tissues were investigated in 122 patients using an immunoperoxidase method. ER (+) were evident in 77 of 122 patients (63.1 per cent). If classified according to pre-and postmenopausal subjects. ER (+) was seen in 61.4 per cent and ER (−) in 32.9 per cent before menopause, and ER (+) in 65.4 per cent and ER (−) in 30.8 per cent after menopause with no marked difference between the two. If classified according to histological type, ER (+) was seen in 73.2 per cent of those with papillotubular carcinoma and in 62.0 per cent of those with scirrhous carcinoma, whereas ER (−) was seen in 44.9 per cent of those with medullary tubular carcinoma. ER (+) was seen in carcinoma with apocrine metaplasia, lobular carcinoma and Paget's carcinoma. Concerning the relationship between primary tumors and metastatic lymph nodes, ER (+) for both was seen in 20 of 41 patients (48.8 per cent) whereas ER (−) for both was found in 9 of 41 patients (22.0 per cent). Four patients with local recurrences had a positive ER (+) at the beginning of treatment, but the ER became negative after hormonal treatment and chemotherapy. These data were presented at the 3rd EORTC, Amsterdam, April 27–29, 1983.     

Hidden estrogen production from ovarian remnants leading to progression of disease in metastatic breast cancer

In premenopausal women with hormone dependent breast cancers, ovarian suppression is an important part of treatment, and is often achieved with a bilateral salpingo‐oophorectomy (BSO). However, this procedure can lead to ovarian remnant syndrome (ORS), a rare condition where the adnexal tissue is not completely removed and can produce estrogen. We describe a case of ORS in a patient with estrogen receptor positive (ER+) breast cancer who had progression of disease after undergoing a BSO, despite optimal therapy. ORS therefore poses a significant treatment challenge in premenopausal ER+ breast cancer patients thought to be rendered menopausal with a BSO.     

乳腺癌芳香化酶表达与临床病理因素的关系

目的研究乳腺癌组织中芳香化酶基因表达与乳腺癌临床病理因素的关系。方法（1）应用实时定量PCR检测50例乳腺癌及正常乳腺组织中芳香化酶基因表达;计算肿瘤组织（T）及正常组织（N）的比值（T／N）;（2）以所有肿瘤组织芳香化酶mRNA表达量的中位值,定义各例芳香化酶表达水平的高低。结果（1）激素受体阳性组芳香化酶基因的T／N比值高于激素受体阴性组（P=0．031）;（2）年龄大于50岁组表达高于50岁以下组（P=0．008）;（3）浸润性导管癌组低于其它类型组（P=0．000）;（4）P53阳性组与阴性组表达无差异（P=0．790）;（5）肿瘤小于2cm组与大于2cm组表达无差异（P=0．429）;（6）淋巴结阳性组与淋巴结阴性组表达无差异（P=0．142）。结论（1）乳腺癌芳香化酶基因表达与激素受体、年龄、组织学类型相关,与肿瘤大小、淋巴结状况、P53表达无关。（2）在激素受体阳性、年龄大于50岁的患者中部分为芳香化酶低表达。     

芳香化酶抑制剂在乳腺癌新辅助治疗中的研究进展

近年来,新辅助内分泌治疗已成为乳腺癌的重要治疗手段,芳香化酶抑制剂为乳腺癌内分泌治疗的主要药物,目前共有3代产品,其作用机理已基本明了。现今,第1、2代芳香化酶抑制剂已逐渐被第3代产品所替代,本文重点对第3代芳香化酶抑制剂在乳腺癌术前治疗中的应用进行综述。     

High dehydroepiandrosterone-sulfate predicts breast cancer progression during new aromatase inhibitor therapy and stimulates breast cancer cell growth in tissue culture: a renewed role for adrenalectomy.

BACKGROUND: Stage IV hormone-sensitive breast cancer is often treated with aromatase inhibitors (anastrozole, letrozole, exemestane), which block the conversion of dehydroepiandrosterone (DHEA) to estrone and estradiol. This is intended to obviate the need for steroid replacement and antiquate adrenalectomy. METHODS: Patients who underwent oophorectomy and were being treated with new aromatase inhibitor therapy received serial measurements of serum estrone, estradiol, and DHEA-sulfate (DHEA-S). Steroid values during responsive and progressive phases of disease were compared. In vitro, human breast cancer cell lines T-47D (estrogen-receptor and progesterone-receptor positive) and HCC 1937 (estrogen-receptor and progesterone-receptor negative) were treated with DHEA-S. Proliferation rates were measured by colorimetric assay. RESULTS: Disease in 12 of the 19 patients progressed. DHEA-S was less than 89 microg/dL in patients during the responsive phase and more than or equal to 89 microg/dL during disease progression, with 1 exception (P < .0005). Estrone and estradiol remained suppressed. After disease progression, the condition of 9 patients stabilized with aminoglutethimide therapy (n = 8) or adrenalectomy (n = 1), and their DHEA-S levels were reduced to less than 89 microg/dL. In vitro, elevated DHEA-S induced cell proliferation in T-47D cells. CONCLUSIONS: DHEA-S levels more than or equal to 89 microg/dL predicted disease progression in states of low estrogen. Tissue culture results supported the role of DHEA-S as an estrogenic agent. Oophorectomies with either aminoglutethimide therapy or adrenalectomy were effective remedies for breast cancer progression due to high DHEA-S.     

The role of estrogen receptors in breast cancer metastasis

It has long been appreciated that the estrogen receptor (ER) plays an important role in the biology of breast cancer. It is an accepted factor predicting favorable disease outcome and treatment response, and as such is generally considered to represent a good prognostic marker in breast cancer. In this review we present data suggesting that the ER may also play a pivotal role in the metastatic behavior of breast cancer, and present an argument that the up-regulation of ER and/or the selection of specific ER mutations are early events important for facilitating tumor progression. Thus, ER could serve dual roles in breast cancer, acting as a bad prognostic marker later in the disease process.     

Risk factors for estrogen receptor-positive breast cancer

HYPOTHESIS: Some risk factors associated with breast cancer may be more predictive of estrogen receptor (ER)- positive than ER-negative tumors. DESIGN: Survey of patients enrolled in a study of breast cancer risk factors. SETTING: Community population in a northern California county. PATIENTS: A total of 234 individuals diagnosed as having breast cancer between July 1, 1997, and June 30, 1999, reporting Marin County, California, residence and participating in a questionnaire regarding exposure to breast cancer risk factors. MAIN OUTCOME MEASURE: Diagnosis of ER-positive vs ER-negative breast cancer. RESULTS: Comparison between ER-positive and ER-negative cases showed several factors predictive of ER-positive tumors. In a multivariate model, years of hormone therapy use remained the most significant predictor of ER-positive disease. CONCLUSIONS: Patients diagnosed as having ER-positive breast cancer were more likely to have undergone hormone therapy. The excess of ER-positive breast cancers reported in Marin County could, therefore, in part, be related to hormone therapy.     

Co-targeting estrogen receptor and HER2 pathways in breast cancer

The estrogen steroid hormone receptor (ER) and human epithelial growth factor receptor 2 membrane tyrosine kinase growth factor receptor (HER2) are the mediators of two key pathways involved in breast carcinogenesis, invasive behavior and cell growth. Co-expression of these receptors results in specific biological features that are not fully understood, but include relative resistance to hormonal therapy and chemotherapy as well as better long-term outcome imparted by ER and worse outcome by HER2 expression. The ER and HER2 signaling pathways interact with each other as do many biological networks, and this creates opportunities for therapeutic co-targeting with agents that modulate these respective pathways. However, relatively few studies have been conducted to test concurrent manipulation of ER and HER2. The avoidance of chemotherapy side effects is an attractive feature that has further spurred explorations in this strategy. Still, the only dually targeted strategy approved by some regulatory agencies is the combination of hormonal therapy using aromatase inhibition and the HER2 kinase inhibitor lapatinib. Other dual combinations have also demonstrated a benefit, although most of the testing has compared hormonal therapy with or without HER2-directed agents and not the other way around, limiting the applicability of this concept in routine clinical practice, especially when chemotherapy is also used. Newer generation signal transduction inhibitors can augment the efficacy of hormonal therapy, with one such example of mTOR blockade using everolimus now in the clinic. The logical extension of ER and HER2 co-targeting is the discovery and clinical testing of “synthetic lethal” combinations attacking diverse pathways that produce quantum improvements over either therapy alone. Molecular annotation of human cancers can further inform personalized combinatorial regimens based on the unique circuitry of an individual patient's tumor, with the potential to yield much more than incremental gains in survival.     

Local recurrence of breast cancer.

Pathologic and surgical aspects of 1,027 breast cancer cases treated between 1961 and 1972 were reviewed. Sixty-eight (7%) of the cases recurred locally. This low rate of recurrence is associated with the small average diameter of 2.7 cm of all carcinomas and the correspondingly low rate of axillary lymph node metastasis of 40%. Subsequently recurring tumors had a higher incidence of axillary lymph node metastasis (68%). Eight hundred eighty-eight infiltrating duct carcinomas represented the largest group of cases and had a recurrence rate of 5.7%. Comedo, infiltrating papillary, and infiltrating lobular carcinomas recurred locally more frequently, but none of 26 mucinous carcinomas recurred. In eight cases, the recurrent tumor was of a more malignant histologic type than the primary lesion. The average width of the excised segments of skin decreased from 9.8 cm during the first three-year period (1961 to 1963) to 8.4 cm during the last period (1970 to 1972). The average width for the entire period was 9.1 cm, identical for locally recurring and nonrecurring tumors.     

The current status of aromatase inhibitors in the management of breast cancer

The third generation of specific AIs have made a very exciting contribution to the management of hormone responsive breast cancer. We can now state with confidence that their role in advanced breast cancer has overtaken that of tamoxifen, which should be relegated to a second-line treatment. Indeed, as a recent publication confirmed that first-line anastrozole followed by tamoxifen is an effective treatment sequence, this sequence may be considered the best choice for treating patients with hormone receptor-positive ABC. As far as the primary disease is concerned, the ATAC data certainly suggest that there is an alternative to tamoxifen in selected postmenopausal women with hormone receptor-positive disease. With more mature follow-up the study might even show that after a passage of nearly 20 years tamoxifen has lost its lead position in the adjuvant stakes as well.     

Importance of local aromatase activity in hormone-dependent breast cancer: a review

The cytochrome P-450 enzyme complex aromatase is the rate-limiting step in the production of oestrogens. It catalyses the conversion of androgens to oestrogens. In the treatment of hormone-dependent breast cancer in postmenopausal women, aromatase is the target for treatment with aromatase inhibitors. Recently registered aromatase inhibitors like anastrozole, letrozole and exemestane have proven to be effective therapy for advanced breast cancer in postmenopausal patients failing to respond to treatment with tamoxifen. Intratumoural aromatase activity has predictive value for response to treatment with aromatase inhibitors. Attempts are being made to find an immunohistochemical technique to determine aromatase in tumour tissue, which may serve as a predictive factor. In situ oestrogen synthesis through local aromatase activity in the tumour and adjacent tissue is probably a very important growth-stimulating system in hormone-dependent breast cancer. This synthesis can be blocked with aromatase inhibitors. The regulation of aromatase activity and the cell types that contribute to this process are the subject of extensive research. There seems to be a complex interaction between malignant cells and adjacent cells in which factors such as IL-6 and its soluble receptor, TNF-alpha and prostaglandin E2 play an important role in stimulating aromatase activity.