In situ production of estrogens in human breast carcinoma

Recent studies have demonstrated that biologically active estrogens are locally produced from circulating inactive steroids in the estrogen-dependent breast carcinoma. The in situ production of estrogens in the breast carcinoma is considered to play an important role in the proliferation of breast cancer cells, especially in the postmenopausal women. Therefore, the total blockade of this pathway may inhibit estrogenic actions in breast cancer tissues and lead to an improvement in the prognosis in these patients. In this review, we describe the recent studies concerning the expression of enzymes related to intratumoral estrogen production, including aromatase, 17beta-hydroxysteroid dehydrogenase, steroid sulfatase, and estrogen sulfotransferase in human breast carcinoma tissues, and discuss the biological significance of local production of estrogens in human breast cancer.     

Microenvironmental regulation of estrogen signals in breast cancer

In breast cancers, estrogen activates estrogen receptor (ER) through genomic and nongenomic pathways, which leads to nuclear and extranuclear processes that promote the proliferation of breast cancer cells. Growth factor receptor signaling pathways also activate ER via phosphorylation through the signal crosstalks between estrogen and growth factors. The intratumoral levels of estrogen and growth factors, therefore, profoundly influence ER activity, which are regulated by the tumor-stromal interactions in the microenvironment. In postmenopausal breast cancers, tumor cells activate stromal fibroblasts to express aromatase, a key enzyme in estrogen biosynthesis, resulting in intratumoral estrogen production. At present, aromatase inhibitors are used as a first-line endocrine therapy for breast cancers. We developed a comprehensive system to evaluate the ER-activating ability of stromal fibroblasts for individual patients, and found that it varied among individual cases. This system might be useful for predicting the individual response to endocrine therapy and analyzing the tumor microenvironment. In addition to estrogen production, tumor-associated fibroblasts lead to the progression of breast cancer via different pathways. A study to differentiate the microenvironmental regulation of estrogen-dependent and -independent breast cancer growth would also be useful to improve hormone therapy for breast cancer.     

Imprint immunocytochemistry of estrogen receptors in breast carcinoma

To clarify the accuracy of immunocytochemical detection of estrogen receptors (ER) in breast carcinomas using cytological materials, imprint specimens from tumor tissue were compared with frozen tissue sections and tumors analyzed by the dextran coated charcoal (DCC) method and enzyme immunoassay (EIA). Out of 50 cases examined by imprint immunocytochemistry, there were 39 ER positive cases (78.0% positivity). The positivity in the imprint materials agreed with that of the DCC in 36 out of 40 cases (85.0%), with 100% sensitivity and 60.0% specificity. The two methods statistically correlated with each other in their positivity and grade (p less than 0.001). The positivity and grades of imprint and frozen immunocytochemistry as well as those of imprint immunocytochemistry and the EIA agreed almost perfectly with each other. As a result of the present study, we concluded that immunocytochemical detection of ER is indeed reliable, as accurate as other procedures. We recommend that aspiration biopsy cytology (ABC) be used for morphological examination and ER immunocytochemistry when adequate materials are available and that imprint materials be used when ABC materials are inadequate and fresh tissue is available at the time of surgery.     

Intratumoral androgen metabolism and actions in invasive lobular carcinoma of the breast

Invasive lobular carcinoma (ILC) accounts for approximately 10% of all breast carcinomas and is characterized by higher levels of androgen receptor (AR) compared to invasive ductal carcinoma (IDC). Despite this potentially androgen‐responsive environment, the combined importance of AR and androgen metabolism in non‐neoplastic lobules and lobular carcinoma remains unknown. Therefore, in this study, we evaluated the status of pivotal androgen‐producing enzymes 17β‐hydroxysteroid dehydrogenase type 5 (17βHSD5) and 5α‐reductase type 1 (5αRed1) in 178 cases of ILC and surrounding histologically non‐neoplastic lobular tissue using immunohistochemistry. Androgen receptor prevalence was higher but androgenic enzymes lower in ILC than non‐neoplastic lobules. In ILC cases the status of 5αRed1 and 17βHSD5 was inversely correlated with tumor size (P = 0.0053) and nuclear grade (P = 0.0290), and significantly associated with better overall survival of the patients (P = 0.0059). Based on these findings, we hypothesized that androgen signaling could act as a tumor suppressor. As previous studies suggested that androgens might partially act by increasing levels of the estrogen inactivating enzyme 17β‐hydroxysteroid dehydrogenase type 2 (17βHSD2) in IDC tissues, this was reasonably considered a potential mechanism of androgen actions. Significantly positive correlation was detected between the status of androgenic enzymes and 17βHSD2 (P < 0.0001) and intratumoral 17βHSD2 was inversely correlated with tumor size in ILC (P = 0.0075). These correlations suggest one protective mode of androgen action could be through modulation of estrogen metabolism. Results of our present study indicated that androgen‐producing enzymes could play pivotal protective roles in AR‐enriched ILC cases.     

雌激素受体β蛋白在乳腺癌中表达的意义

目的:检测乳腺癌组织中雌激素受体β(ERβ)蛋白的表达情况,并分析其与乳腺癌临床病理特性的关系。方法:采用免疫组化法检测96例乳腺癌组织中ERβ蛋白的表达情况。结果:ERβ蛋白在96例乳腺癌组织标本中的阳性表达率为75·0%(72/96),癌旁组织中的阳性表达率为90·5%(57/63),二者差别具有显著性(P<0·05);ERβ蛋白表达水平与患者乳癌组织中的ERα蛋白水平、PR蛋白水平及组织学分级相关(P<0·05),与年龄、肿瘤大小、腋淋巴结转移、病理分型、绝经状态无关(P>0·05)。结论:ERβ在乳腺癌癌旁组织内广泛表达,在癌组织内亦有表达,但阳性表达率低于癌旁组织;ERβ蛋白的阳性表达可能是乳腺癌预后良好的一项参考指标。     

Detection of mRNA levels for the estrogen alpha, estrogen beta and androgen nuclear receptor genes in archival breast cancer tissue

Previous studies in our laboratory have shown association of nuclear receptor expression and histological breast cancer grade. To further investigate these findings, it was the objective of this study to determine if expression levels of the estrogen alpha, estrogen beta and androgen nuclear receptor genes varied in different breast cancer grades. RNA extracted from paraffin embedded archival breast tumour tissue was converted into cDNA and cDNA underwent PCR to enable quantitation of mRNA expression. Expression data was normalised against the 18S ribosomal gene multiplex and analysed using ANOVA. Analysis indicated a significant alteration of expression for the androgen receptor in different cancer grades (P=0.014), as well as in tissues that no longer possess estrogen receptor alpha proteins (P=0.025). However, expression of estrogen receptors alpha and beta did not vary significantly with cancer grade (P=0.057 and 0.622, respectively). Also, the expression of estrogen receptor alpha or beta did not change, regardless of the presence of estrogen receptor alpha protein in the tissue (P=0.794 and 0.716, respectively). Post-hoc tests indicate that the expression of the androgen receptor is increased in estrogen receptor negative tissue as well as in grade 2 and grade 3 tumours, compared to control tissue. This increased expression in late stage breast tumours may have implications to the treatment of breast tumours, particularly those lacking expression of other nuclear receptor genes.     

Pre-menopausal breast cancer and aromatase inhibitors: treating a new generation of women

Aromatase inhibitors have revolutionized the treatment of post-menopausal women with hormone receptor positive breast cancer. However, approximately 22% of all cases of breast cancer in North America are diagnosed in women below the age of 50 and a substantial proportion of these women are pre-menopausal. In the pre-menopausal population with hormone receptor positive disease, research on the use of aromatase inhibitors is only beginning to emerge. In this review, the mechanism of action of aromatase inhibitors and the history of endocrine treatment for pre-menopausal breast cancer is briefly presented. Available research to date regarding efficacy and toxicity of aromatase inhibitors in the treatment of pre-menopausal breast cancer and future research directions are also discussed.     

乳腺癌治疗相关的骨成分丢失及其防治

全身辅助治疗在一定程度上降低了乳腺癌死亡率,但也对骨代谢带来不良影响,导致骨成分丢失增加,并可引起骨质疏松症及骨折。这些不良反应主要由内分泌改变介导,如化疗和卵巢切除导致的早期停经、芳香化酶抑制剂对绝经后循环雌激素的抑制,此外化疗也可能对骨细胞功能产生直接影响。随着支持芳香化酶抑制剂治疗的临床资料的出现,乳腺癌患者的骨健康正成为颇受关注的热点问题。本文综述了乳腺癌相关治疗与骨质疏松症的关系以及其防治。     

Shu-Gan-Liang-Xue decoction simultaneously down-regulates expressions of aromatase and steroid sulfatase in estrogen receptor positive breast cancer cells

Objective  

Estradiol (E2) plays an important role in the development of breast cancer. In postmenopausal women, the estrogen can be synthesized via aromatase (CYP19) pathway and steroid-sulfatase (STS) pathway in peripheral tissues, when the production in ovary has ceased. The objective of our study was to explore the effects of Shu-Gan-Liang-Xue Decoction (SGLXD) on the expressions of CYP19 and STS in estrogen receptor positive breast cancer MCF-7 and T47D cells.     

The evolving role of aromatase inhibitors in breast cancer

 Anti-aromatase agents inhibit the cytochrome P-450 component of the aromatase enzyme complex responsible for the final step of estrogen biosynthesis in peripheral tissues. These drugs can be classified into first-generation (e.g., aminoglutethimide), second-generation (e.g., formestane and fadrazole), and third-generation (e.g., anastrozole, letrozole, and exemestane) agents. Anti-aromatase agents can also be divided into type I and type II inhibitors. Type I inhibitors have a steroidal structure similar to androgens and inactivate the enzyme irreversibly by blocking the substrate-binding site, and are therefore known as aromatase inactivators. Type II inhibitors are nonsteroidal and their action is reversible. This article reviews the recent evidence regarding the role of third-generation aromatase inhibitors in the management of breast cancer. Relevant PubMed listed articles and presentations at recent international symposia were reviewed. There is a growing body of evidence supporting the role of third-generation aromatase inhibitors (anastrozole, letrozole, and exemestane) as first-line and second-line therapy for estrogen receptor (ER)- and/or progesterone receptor (PgR)-positive advanced breast cancer in postmenopausal women, and as a neoadjuvant therapy in postmenopausal women with hormone receptor-positive invasive breast cancer unsuitable for breast-conserving surgery. Furthermore, the preliminary results of the ATAC (Arimidex, Tamoxifen, Alone and in Combination) study have shown that adjuvant anastrozole is superior to tamoxifen in terms of disease-free survival (DFS), adverse effects, and prevention of contralateral breast cancer in postmenopausal women with early, ER-positive breast cancer. However, longer follow-up is required to assess the long-term effects of these agents on bone mineral density, cognitive function, and overall survival prior to considering their routine use in the adjuvant setting instead of tamoxifen. The potential role of these drugs in the management of ductal carcinoma in situ (DCIS), premenopausal breast cancer, and breast cancer prevention is worth investigating. Received: January 21, 2002 / Accepted: May 7, 2002 Correspondence to:K. Mokbel     

Intratumoral aromatase as a prognostic factor in human breast carcinoma

Intratumoral aromatase activity (AA) was measured in 145 samples of human primary breast carcinoma using the tritiated water release assay which quantifies the tritium lost to water during the aromatization of 1 beta-[3H]androstenedione to estrone. Significant AA was detected in 91/145 (63%) tumors. The possibility of a relationship between AA and a variety of clinical prognostic factors such as estrogen receptors, menopausal status, site, size, and histological grade of tumor was investigated. Possible relationship with time to relapse, overall survival, and survival of patients after relapse were also studied to determine whether intratumoral AA itself was of any prognostic value. There was no relationship between AA and tumor size, site, nodal status, menopausal status or estrogen receptors. However there was a significant correlation between AA and histological grade with an excess of AA-positive tumors having high grade (P = 0.03). There was no significant relationship between AA and overall survival (P greater than 0.1), but there was a marginal inverse correlation between AA and time to relapse (P less than 0.1). A statistically significant correlation was found between AA and survival of patients after relapse (P less than 0.05).     

乳腺癌肿瘤组织不同部位雌孕激素受体的表达

目的 探讨乳腺浸润性导管癌肿瘤组织中不同部位雌、孕激素受体表达情况.方法 收集32例手术切除乳腺浸润性导管癌肿瘤标本,于每例肿瘤标本4个不同部位取材,用免疫组化方法检测各部位雌、孕激素受体表达情况.结果 肿瘤组织不同部位雌、孕激素受体检测结果一致性好,最好Kappa值分别为0.789和0.810,最差Kappa值分别为...     

乳腺癌芳香化酶抑制剂耐药的研究进展

乳腺癌是女性常见的恶性肿瘤,约70％的患者为雌激素受体(estrogen receptor,ER)和(或)孕激素受体(progesterone receptor,PR)阳性,内分泌治疗是激素受体(hormone receptor,HR)阳性乳腺癌的主要治疗方式之一.近几十年来,内分泌治疗药物不断发展并应用于临床,乳腺癌...     

Clinical significance of P-glycoprotein expression in metastatic breast carcinoma

Multidrug resistance(MDR)is one of the importantfactors,limiting the chemotherapeutic efficacy[l].Thereare various resistance related-proteins overexpression inthe tissue of breast carcinoma[2].MDR phenotype isassociated with overexpression of mdr-1gene andP-glycoprotein,encoding product of mdr-1,which is oneof the major mechanisms of MDR in breast carcinoma[3].We have had partly understanding about the mechanismof breast carcinoma associated with P-gp expression bystudying the mdr-1gene,t…     

Androgen receptor in estrogen receptor positive breast cancer: Beyond expression

In recent years, new therapeutic approaches have reshaped the overall strategy of breast cancer (BC) treatment and have markedly improved patient survival. This is, in part, due to novel therapies for estrogen receptor (ER)-positive BC. Unfortunately, many patients present de novo resistance to these therapies or develop an acquired resistance over time. Therefore, research is now focused on discovering new molecular targets to overcome these resistances. Interestingly, preclinical and clinical studies have shown a critical role for the cross-talk between androgen receptor (AR) and ER in luminal-like BC. AR is expressed in >60% of BC and in up to 90% of ERα-positive tumors. Multiple studies suggest that AR is associated with a favorable prognosis. However, AR overexpression and, in particular, the high AR:ER ratio, seem to be involved in resistance to hormonal treatment. In this setting, a group of BCs could benefit from AR-inhibitors; nevertheless, some ER-positive BC patients do not seem to benefit from this strategy. Therefore, it is crucial to identify biomarkers that would enable the selection of patients who might benefit from combination treatment with ER and AR inhibitors.     

Aromatase and aromatase inhibitors

Aromatase inhibition provides both paracrine/intracrine and endocrine treatment. Recent accumulated data clarified that 3rd generation aromatase inhibitors potently suppress intratumoral estrogen synthesis particularly in postmenopausal patients. In the 2nd-line treatment for metastatic breast cancer patients, aromatase inhibitors achieved results antitumor activity at least equal to and sometimes better than that of tamoxifen. In the first-line treatment for metastatic breast cancer patients, a recent pivotal study clearly demonstrated that aromatase inhibitor was superior to tamoxifen. Based upon these results, various adjuvant trials which compare aromatase inhibitors with tamoxifen and attempt to determine optimal combination therapies and treatment periods with aromatase inhibitors are currently being conducted. In addition, preliminary studies conducted in neoadjuvant setting indicated that aromatase inhibitors showed an extremely high response rate, which predicts a future paradigm, that neoadjuvant therapy using aromatase inhibitors singly or in combination may become standard for hormone-responsive and post-menopausal breast cancer patients.