乳腺癌内分泌治疗耐药机制的研究进展

内分泌治疗是雌激素受体阳性乳腺癌的重要系统治疗手段,但原发性与继发性耐药是当前内分泌治疗面临的难题。耐药机制主要包括:ER表达缺失或表观遗传修饰;共调因子表达失衡;雌激素受体通路与生长因子受体（growth factor receptor,GFR）通路的交叉效应;特异性miRNA表达改变;乳腺癌上皮间质转化（EMT）等。根据PubMed检索获取相关资料,就近年来雌激素受体阳性乳腺癌内分泌耐药机制及治疗策略研究进展进行综述。     

SERPINA1 is a direct estrogen receptor target gene and a predictor of survival in breast cancer patients

Of all breast cancer patients, about 70% are ER+ and 10% are ER+/HER2+. The ER+/HER2+ patients have a worse outcome compared to ER+/HER2- patients. Currently there is a lack of effective prognosis biomarkers for the prediction of outcome in ER+/HER2+ patients. Genome-wide differences in ER binding between the endocrine-responsive and endocrine-resistant cells were discovered using ChIP-seq, and combined with gene expression microarray data to identify direct ER target genes. These genes were correlated to survival outcome using publicly available breast cancer patient cohorts. We found the expression of the gene SERPINA1 to have a significant predictive value for the overall survival (OS) of ER+ patients in the TCGA cohort, and validated this finding in the Curtis cohort. SERPINA1 also has a significant predictive value for the OS of ER+/HER2+ patients in the TCGA cohort, with validation in the Bild cohort. The expression of SERPINA1 can be suppressed by fulvestrant and HER2 siRNA. Our results indicate that ER is constitutively activated, resulting in an E2-independent ER binding to the SERPINA1 gene and upregulation of SERPINA1 expression. Importantly, results of survival correlation suggests that high expression of SERPINA1 could be predictive for a better clinical outcome of ER+ and ER+/HER2+ patients.     

Steroid hormone receptor levels and adjuvant tamoxifen in early breast cancer

Summary Ten year disease-free survival (DFS) results of the Naples randomized trial of adjuvant tamoxifen (TM), 30 mg per day for 2 years versus no therapy according to receptor levels, are reported. From Feb. 1, 1978, through Dec. 31, 1983, 308 pre- and postmenopausal patients with early breast cancer entered the trial. Estrogen receptor (ER) data were available on 239 (77.6%) patients, progesterone receptor (PgR) data on 194 (63.0%), and both receptor data on 181 (58.8%).ER and PgR were assayed by dextran-coated charcoal technique in a single laboratory. The effect of adjuvant TM was significantly related to ER and PgR concentration of the primary tumor. The greatest TM benefit on DFS was evident in patients with the highest levels of receptors. The interaction between the treatment effect and receptor concentration was found whether ER and PgR were considered separately or together. Address for reprints: A. Raffaele Bianco, Division of Medical Oncology, University of Naples Medical School II, via S. Pansini, 5-80131 Naples, Italy     

Basic research for hormone-sensitivity of breast cancer

Hormonal therapy is a rapidly progressing molecular-targeted therapy for breast cancer, using drugs such as LH-RH agonists, SERMs and aromatase inhibitors. Basic research for estrogen signaling and hormone sensitivity in breast cancer cells strongly contributes to the progression of clinical treatment of breast cancer. However, further problems remain unresolved, for example the accurate prediction of individual response to each hormonal therapy. Moreover, novel combinations with other molecular-targeted therapies might be advance the effectiveness of hormonal therapies. To address these issues, we are developing several new tools such as focused microarray and a GFP-reporter cell system. We first identified estrogen-responsive genes by comprehensive expression profiling of estrogen receptor (ER)-positive breast cancer cells, and produced a custom-made estrogen-responsive microarray of a narrowed-down subset. Using this microarray, we studied several basic issues regarding estrogen signaling and expression analysis of estrogen-responsive genes in breast cancer tissues. Furthermore, expression of several candidate genes selected from the contents of the customarray was also analyzed by real-time RT-PCR and by immunohistochemical techniques, to find new predictive factors for responsiveness to hormone therapy for primary breast cancer patients. We found that the expression of several genes such as HDAC6 significantly correlated with disease-free and overall survival of ER-positive patients. Furthermore, we are developing a new tool for analyzing the estrogen-related microenvironment on individual breast cancer patients using ERE-GFP-indicator cells. This system enables visualization of tumor-stroma interactions and the effects of aromatase inhibitors in an individual breast cancer sample. We believe that these approaches could provide not only new clues to elucidate the estrogen-dependent mechanisms of cancer, but also clinical benefits to patients by predicting individual response to hormonal therapy.     

乳腺癌内分泌耐药机制及治疗对策的研究进展

内分泌治疗在激素受体阳性乳腺癌患者的治疗中占重要地位,但耐药的产生为内分泌治疗增加了难度。近年来,内分泌耐药发生的机制是研究的热点问题,已有研究证实内分泌耐药的发生与生长因子受体、磷脂酰肌醇3-激酶/蛋白激酶 B/哺乳动物雷帕霉素靶蛋白信号通路、细胞周期蛋白依赖性激酶及组蛋白去乙酰化酶有关。目前,针对耐药相关信号通路中的各个分子靶点已经研发了众多的靶向药物。本文将针对内分泌耐药的不同机制以及逆转耐药的治疗进行综述。     

Racial Differences in Depressive Symptoms and Self-Rated Health Among Breast Cancer Survivors on Aromatase Inhibitor Therapy

The goal of this survey-based study was to examine whether aromatase inhibitor (AI) therapy was associated with depressive symptoms and self-rated health among Black and White breast cancer survivors (N = 761). Results showed that among Black, but not White, breast cancer survivors current AI therapy was associated with a significant increase in the odds of both depressive symptoms (OR 3.59; 95% CI 1.01, 13.00) and poorer self-rated health (OR 3.16; 95% CI 1.06, 9.46). Presence of pain was significantly associated with increased odds of both outcomes among both groups. The findings underscore the importance of addressing not only physical but mental health among breast cancer survivors on AIs, especially those of Black race.     

CDK4/6抑制剂在激素受体阳性进展期乳腺癌治疗中的研究进展

内分泌治疗因其兼具良好的疗效及安全性,是激素受体阳性进展期乳腺癌患者的重要治疗手段。近年来内分泌领域进展迅速,很多新型药物相继出现,其中包括多种可以逆转或延迟内分泌耐药的周期蛋白依赖性激酶(cyclin-dependent kinase,CDK)4/6抑制剂。CDK4/6抑制剂联合内分泌治疗可为激素受体阳性进展期乳腺癌患者带来生存获益、延迟至化疗时间,正逐渐改变国内外激素受体阳性进展期乳腺癌的治疗模式。本文将就CDK4/6抑制剂在激素受体阳性进展期乳腺癌中的治疗进展进行综述。     

ER、PR在乳腺癌中的表达及临床意义

目的：检测并分析ER和PR在乳腺癌中的表达,探讨ER、PR在内分泌治疗中的作用。方法：选取137例有完整临床和病理资料的乳腺癌患者,采用免疫组化法检测其乳腺癌组织中的ER、PR表达。结果：ER,PR阳性率分别为55．47％,51．09％,PR（＋）患者,其ER大多数表达阳性;绝经后ER阳性患者较绝经前患者多;ER、PR阳性率表达与淋巴结是否转移无明显相关性。结论：ER和PR在乳腺癌组织中的存在可以预测肿瘤对激素治疗是否敏感,为临床指导辅助内分泌治疗提供有力的证据。     

Cyclical use of tamoxifen and high-dose medroxyprogesterone acetate in advanced estrogen receptor positive breast cancer

Summary One-hundred and seventy patients with estrogen receptor positive (10 pmol/g protein) advanced breast cancer have been treated in a prospective randomized study either with continuous tamoxifen 30 mg × 1 daily (TAM), or with TAM 30 mg × 1 daily for 8 weeks alternating with medroxyprogesterone acetate 500 mg × 2 daily for 8 weeks (TAM/HD-MPA). The response rate was 62% in the group treated with cyclic TAM/HD-MPA versus 41% in the TAM alone group (p = 0.02). There was no significant difference in duration of remissions or survival.     

Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer: A review

Deregulation of the cyclin D-CDK4/6-INK4-RB pathway leading to uncontrolled cell proliferation, is frequently observed in breast cancer. Currently, three selective CDK4/6 inhibitors have been FDA approved: palbociclib, ribociclib and abemaciclib. Despite promising clinical outcomes, intrinsic or acquired resistance to CDK4/6 inhibitors has limited the success of these treatments; therefore, the development of various strategies to overcome this resistance is of great importance. We highlight the various mechanisms that are directly or indirectly responsible for resistance to CDK4/6 inhibitors, categorizing them into two broad groups; cell cycle-specific mechanisms and cell cycle-nonspecific mechanisms. Elucidation of the diverse mechanisms through which resistance to CDK4/6 inhibitors occurs, may aid in the design of novel therapeutic strategies to improve patient outcomes. This review summarizes the currently available knowledge regarding mechanisms of resistance to CDK4/6 inhibitors, and possible therapeutic strategies that may overcome this resistance as well.     

Estrogen Receptor Beta (ESR2) Polymorphisms in Familial and Sporadic Breast Cancer

Summary Estrogen is involved in both normal mammary development and in breast carcinogenesis. A family history of disease and exposure to estrogen are major risk factors for developing breast cancer. Estrogen exerts its biological effects through binding to the estrogen receptors, estrogen receptor alpha (ESR1) and the more recently discovered estrogen receptor beta (ESR2). Genetic variation in genes involved in estrogen biosynthesis, metabolism and signal transduction have been suggested to play a role in breast cancer risk. We therefore tested the hypothesis that common genetic variants of the ESR2 gene may be associated with increased risk for breast cancer and this risk may vary between breast cancer groups. We investigated three common ESR2 polymorphisms, rs1256049 (G1082A), rs4986938 (G1730A) and rs928554 (Cx+56 A→G) for association to breast cancer risk. A total of 723 breast cancer cases and 480 controls were included in the study. Of the breast cancer cases, 323 were sporadic and 400 were familial, the familial cases were further divided into familial high-risk and familial low-risk breast cancer cases. We found no overall statistically significant association for any of the single polymorphisms studied. Haplotype analysis suggested one haplotype associated with increased risk in sporadic breast cancer patients (OR = 3.0, p = 0.03). Further analysis is needed to elucidate the role of estrogen receptor beta in breast cancer susceptibility.