Predictive markers in breast cancer--the present

Breast cancer is a heterogeneous disease and there is a continual drive to identify markers that will aid in predicting prognosis and response to therapy. To date, relatively few markers have established prognostic power. Oestrogen receptor (ER) is probably the most powerful predictive marker in breast cancer management, both in determining prognosis and in predicting response to hormone therapies. Progesterone receptor (PR) is also a widely used marker, although its value is less well established. HER-2 status has also become a routine prognostic and predictive factor in breast cancer. Given the importance of these biological markers in patient management, it is essential that assays are robust and quality controlled, and that interpretation is standardized. Furthermore, it is important to be aware of the limitations in their predictive power, and how this may be refined through addition of further biological markers. The aim of this review is to provide an overview of the established role of ER, PR and HER-2 in patient management, the current standards for assessing these markers, as well as highlighting the controversies that still surround their use and methods of assessment.     

Ulipristal acetate does not impact human normal breast tissue

BACKGROUND Antiprogestins are of growing interest for the development of new treatments in the gynecological field. Ulipristal acetate (UPA) is a progesterone receptor (PR) modulator considered for long-term administration in contraception and is currently being registered for the treatment of uterine fibroids. In light of the influences of hormonal dysfunction in breast pathologies, the secondary consequences of chronic UPA therapy need to be established. The aim of this study was to determine UPA actions mediated by PR and glucocorticoid receptor (GR) in normal and transformed breast. METHODS UPA, progesterone (P) and dexamethasone (DEX) effects were observed on PR and GR responsive genes and on proliferation and apoptosis of normal human breast epithelial (HBE) and breast cancer cells. Human normal breast tissue samples were xenografted in athymic mice and treated with estradiol (E2), or E2 + P, or E2 + P + UPA. RESULTS Analysis of PR and GR reporter gene transactivation and their respective endogenous target genes indicated that UPA exerted anti-progestational and anti-glucocorticoid activity in both types of cells with a more pronounced effect in cancer cells. When combined with P or DEX, UPA limits the proliferation of HBE cells but increases growth in breast cancer cell lines. UPA administration had no impact on the mitotic index on xenografted human breast tissue exposed to gonadal hormones at similar concentrations to those present in normal women. CONCLUSIONS Although further clinical trials are required to confirm that the results from our experimental models can be extrapolated to women treated with UPA, they suggest that such treatment would not be deleterious to normal breast tissue at least for a cycle (28 days) of continuous administration.     

Proteins induced by estrogens. Search for new markers of hormone dependence in breast cancers

The hormone dependence and the prognosis of human breast cancers are now based on the assays of the oestrogen receptor (RE) and progesterone receptor (PR) in the tumor. However, such prediction is not fully accurate since RE may be non functional in some tumors and the estrogenic regulation in PR is not directly correlated with the effects of estrogens on cell growth. Here, we review other estrogen induced proteins. A special emphasis is made on a 52,000 dalton glycoprotein released into the medium by human breast cancer cells. Studies on the regulation and biological role of this protein should improve our understanding of the mechanisms by which estrogens stimulate the growth and spreading of breast cancers. Such secreted proteins could later provide convenient circulatory markers of hormone dependency.     

Role of the RANK/RANKL pathway in breast cancer

The discovery of the OPG/RANK/RANKL pathway two decades ago has initiated novel insights into regulation of bone formation. More recently this pathway has been found to be also relevant in osteoclastic-independent mechanisms, mainly in mammary physiology and breast cancer. RANKL/RANK function is essential for epithelial cell proliferation and cellular survival as well as lobulo-alveolar development. The endogenous OPG functions as a soluble decoy receptor, binding the cytokine RANKL to prevent RANKL from activating its receptor RANK. The regulatory function of RANKL is one of the key factors in progesterone-induced proliferation of the breast. Progesterone has a direct action of progesterone on progesterone-receptor (PR) expressing cells but PR-negative cells are affected indirectly through RANKL-induced paracrine actions leading to proliferation of mammary epithelial PR-negative cells. RANK induces epithelial-mesenchymal transition and stemness in human mammary epithelial cells and promotes tumorigenesis and metastasis. Inhibition of the RANK/RANKL pathway using the monoclonal antibody denosumab can neutralize RANKL and inhibiting its interaction with its receptor RANK. Denosumab is currently used to treat osteoporosis and in prevention of skeletal related events in patients suffering from bone metastases due to solid tumors. As preclinical experiments suggest the RANKL/RANK pathway plays an important role in primary breast cancer development. The interference with the RANK/RANKL system could therefore serve as a potential target for prevention and treatment of breast cancer.     

ER,PR and HER2 testing in breast cancer

The application of targeted therapies has played important roles in the improvement of breast cancer survival rate during the past two decades. Estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) are well established biomarkers for breast cancer prognosis and for guiding treatment. Emerging data furthers our understanding of the biomarkers and their validity as predictive and prognostic indicators. Breast cancer biomarker testing guidelines have been recently updated. There are still several key challenges in the evaluations of these markers, including pre-analytic standards, tissue selection for testing and re-testing, result interpretations, and tumour heterogeneity. In addition to ER, PR and HER2, newer markers and multigene testings may provide additional information in guiding targeted therapy for breast cancer.     

Endocrinology of breast cancer

Oestrogen predominance over progesterone may cause hyperproliferation of mammary epithelium and thus promote breast carcinogenesis. In patients with a hormone-dependent tumour, oestrogens may also accelerate cancer growth. Conversely, they may inhibit tumour growth in patients with an oestrogen receptor-negative carcinoma which has grown in an oestrogen-poor environment. Progesterone opposes oestrogen-induced epithelial proliferation and causes cellular differentiation with decreased mitosis, thus reducing the risk of breast cancer. Prolactin brings about mammary epithelial differentiation for secretory function; in the lactation state, epithelial proliferation is minimal. The role of androgens, melatonin, thymosin, metabolic hormones (growth hormone, thyroid hormone(s), insulin, glucocorticosteroids) and prostaglandins in the pathobiology of breast cancer is poorly understood. A breast cancer population consists of individuals in whom more than 20 different tumour subsets may be present, i.e. patients with different individual tumour pathobiology and endocrinology patterns and therefore different prognoses. Progress in the endocrinology of breast cancer seems possible through prospective studies in which hormones are determined in normal breast tissue (ductal fluid, cyst fluid) and then related to the corresponding concentrations in the plasma and urine of patients who develop breast cancer and those who do not. In addition, genetic and nonhormonal risk factors for breast cancer must be taken into consideration to define the endocrinological aspects involved.     

KDM5B基因在乳腺癌中的表达及其临床意义

目的:研究KDM5B基因在乳腺癌组织中的表达情况,并探讨其表达差异与患者临床病理资料和预后的关系。方法:从肿瘤基因组图谱(TCGA)数据库中收集113例正常乳腺组织和1 090例乳腺癌数据集,下载KDM5B mRNA表达谱资料;收集中山大学附属第三医院甲乳外科2015年～2016年乳腺癌切除标本共90例,采用real-time PCR的方法检测乳腺癌及其癌旁组织中KDM5B mRNA的表达量,取中位数分为高表达组与低表达组,分析其与临床资料及病例特征的关系;利用Kaplan-Meier plotter分析KDM5B mRNA表达与乳腺癌患者预后的相关性。结果:KDM5B在乳腺癌中的表达均显著高于正常乳腺组织(P 0. 01)。在TCGA的乳腺癌数据中,KDM5B的表达与人表皮生长因子受体2(HER2)、雌激素受体(ER)、年龄、病理组织类型及淋巴结转移显著相关(P 0. 01),与孕激素受体(PR)、绝经及远处转移无显著相关。在我们收集的乳腺癌样本中,KDM5B的表达与HER2、年龄及淋巴结转移显著相关(P 0. 05),而与ER、PR、绝经、病理组织类型和远处转移无显著相关。KDM5B表达越高,乳腺癌患者总生存时间(HR=1. 39,P=0. 005)和无病生存时间(HR=1. 32,P 0. 001)越短。结论:在乳腺癌组织中KDM5B高表达,且与患者的预后相关; KDM5B的表达与乳腺癌患者HER2表达、年龄和淋巴结转移显著相关。     

ACLY: A biomarker of recurrence in breast cancer

ObjectiveACLY is a cytoplasmic metabolic enzyme involved in lipid synthesis. It also affects proliferation and metastasis of breast cancer. However, the correlation of ACLY expression with breast cancer recurrence is unclear.MethodsThe Oncomine and TCGA databases were used to investigate the mRNA expression of ACLY in breast cancer. Immunohistochemistry (IHC) was used to evaluate ACLY expression level in tumor tissues and normal tissues from 127 breast cancer patients. Next, the prognostic role of ACLY was explored by analyzing the clinicopathological features and prognosis during follow-up. The role of ACLY in breast cancer cells drug resistance was further detected by CCK-8 assays and quantitative real-time polymerase chain reaction (qRT-PCR).ResultsACLY mRNA and protein expression was significantly increased in the breast cancer tissues compared to normal tissues. Clinically, high ACLY levels were associated with ER status, PR status, tumor size, TNM stage, and lymph node invasion. Upregulated ACLY predicted worse tumor relapse-free survival (RFS) of breast cancer patients in univariate analyses and in multivariate models. In subgroup analysis, patients with high ACLY expression showed worse RFS in the TNM III or ER positive subgroups. Moreover, ACLY over-expression induced the resistance of breast cancer cells to docetaxel and promoted the expression of multi-drug resistant protein ABCB1/ABCG2.ConclusionsOur study highlights the possibility of ACLY as a potential and independent biomarker for the recurrence prediction in breast cancer patients. It may be related to ACLY promoting drug resistance in breast cancer cells.     

Clinicopathological significance of maspin expression in breast cancer

Maspin is a unique serine proteinase inhibitor that has tumor suppressor activity. It has been reported that maspin is expressed in normal human mammary epithelial cells and it is down-regulated during the progression of cancer. However, to date, there is very limited data on the clinical significance of maspin expression in human breast cancer. In this study, maspin expression was assessed immunohistochemically from 80 invasive ductal carcinoma (IDC) specimens of the breast. Also, maspin expression was compared with the clinicopathological factors (age, grade, tumor size and lymph node status), the expression of estrogen receptor (ER), progesterone receptor (PR) and p53, DNA ploidy and the overall survival in an attempt to assess its prognostic value. The maspin expression was positive in 25 IDC cases (31.3%). The maspin expression in IDC was significantly correlated with a higher histologic grade, a larger tumor size, a positive p53 status and shorter survival. There was an inverse association with maspin expression and the PR status. These findings suggest that maspin expression is not down-regulated with the progression of cancer and maspin expression may be associated with a poor prognosis. The immunohistochemical detection of maspin in breast cancers may be helpful for predicting an aggressive phenotype.     

Estrogen receptor beta is coexpressed with ERalpha and PR and associated with nodal status, grade, and proliferation rate in breast cancer

The role of estrogen (ER) and progesterone receptors (PR) in breast cancer is well established. Identification of the second human estrogen receptor, the estrogen receptor beta (ERbeta), prompted us to evaluate its role in breast cancer. We studied the expression of ERbeta by immunohistochemistry and mRNA in situ hybridization in 92 primary breast cancers and studied its association with ERalpha, PR, and various other clinicopathological factors. Sixty percent of tumors were defined as ERbeta-positive (nuclear staining in >20% of the cancer cells). Normal ductal epithelium and 5 of 7 intraductal cancers were also found to express ERbeta. Three-fourths of the ERalpha- and PR-positive tumors were positive for ERbeta, whereas ERalpha and PR were positive in 87% and 67% of ERbeta-positive tumors, respectively. ERbeta was associated with negative axillary node status (P < 0.0001), low grade (P = 0.0003), low S-phase fraction (P = 0.0003), and premenopausal status (P = 0.04). In conclusion, the coexpression of ERbeta with ERalpha and PR as well as its association with the other indicators of low biological aggressiveness of breast cancer suggest that ERbeta-positive tumors are likely to respond to hormonal therapy. The independent predictive value of ERbeta remains to be established.     

Keeping abreast of the mammary epithelial hierarchy and breast tumorigenesis

The epithelium of the mammary gland exists in a highly dynamic state, undergoing dramatic morphogenetic changes during puberty, pregnancy, lactation, and regression. The recent identification of stem and progenitor populations in mouse and human mammary tissue has provided evidence that the mammary epithelium is organized in a hierarchical manner. Characterization of these normal epithelial subtypes is an important step toward understanding which cells are predisposed to oncogenesis. This review summarizes progress in the field toward defining constituent cells and key molecular regulators of the mammary epithelial hierarchy. Potential relationships between normal epithelial populations and breast tumor subtypes are discussed, with implications for understanding the cellular etiology underpinning breast tumor heterogeneity.     

人乳腺癌中HLA-DR的异常表达及其与浸润淋巴细胞的关系

目的通过观察乳腺癌细胞HLA-DR的异常表达及其与浸润淋巴细胞的关系,探讨乳腺癌细胞HLA-DR抗原异常表达的免疫生物学意义。方法收集手术切除的人乳腺癌组织和癌旁相对正常乳腺组织,用免疫组织化学方法和图像分析技术对23例乳腺癌标本进行HLA-DR和浸润淋巴细胞的检测。结果 HLA-DR在相对正常乳腺组织中几乎不表达,在乳腺癌组织中的阳性表达率为47.7%,显著高于相对正常乳腺组织(P<0.05)。肿瘤浸润CD4+T和CD8+T的数量均较相对正常乳腺组织明显增多(P<0.05),乳腺癌细胞HLA-DR抗原的表达量与浸润T细胞存在正相关关系(r=0.892)。结论 HLA-DR在乳腺癌细胞过表达与浸润淋巴细胞之间存在正相关关系,HLA-DR在乳腺癌的自身免疫调节过程中可能起重要作用,这为临床开展乳腺癌的生物治疗提供了实验依据。     

孕酮调节乳腺癌耐药蛋白的机制研究

目的: 探讨孕酮调控乳腺癌耐药蛋白(BCRP)表达的机制。方法: 通过米托蒽醌(MX)诱导或基因转染的方法,作用于孕酮受体(PR)阳性的T47D和PR阴性的MDA-MB-231乳腺癌细胞系,建立由 BCRP 启动子或巨细胞病毒(CMV)启动子启动表达BCRP的4种耐药细胞系T47D/MX、T47D/CMV-BCRP、MDA-MB-231/MX和MDA-MB-231/CMV-BCRP,将孕酮加入耐药细胞的培养液中,通过RT-PCR、Western blotting及MX外排实验观察其对不同耐药细胞系BCRP表达的影响。结果: 孕酮可以剂量依赖方式明显上调PR阳性的乳腺癌细胞系T47D/MX中BCRP mRNA和蛋白的表达,细胞中MX的荧光强度明显减弱。而对照组T47D/CMV-BCRP、MDA-MB-231/MX和MDA-MB-231/CMV-BCRP细胞系,各组处理前后相比,BCRP的表达量无明显变化。结论: 孕酮可能通过PR的介导与 BCRP 启动子上游调控序列中的孕激素反应元件(PRE)结合,激活 BCRP 基因的启动子而增强BCRP mRNA的转录,正性调节BCRP蛋白的表达和功能。     

Amplified in breast cancer 1 expression in breast cancer

Aims: The amplified in breast cancer 1 (AIB1), steroid receptor co‐activator family member, acts as an oestrogen receptor (ER) co‐activator. Acting with HER‐2, it is thought to play a role in endocrine resistance by facilitating ER–growth factor crosstalk. The aim was to analyse AIB1 expression by immunohistochemistry and study its correlations with other prognostic variables in breast cancer and its effect on survival. Methods: A tissue microarray comprising tumours from 438 patients with 15.4 years’ median follow‐up was used. Interpretable AIB1 expression obtained in 395 patients was analysed along with other prognostic factors in breast cancer. Results: AIB1 expression scores ranged from 0 to 30; positive AIB1 expression (score > 14) was seen in 146/395 breast cancers; it correlated negatively with ER (P = 0.003) and progesterone receptor (PR) (P = 0.007), and positively with HER‐2 (P = 0.005) and tumour grade (P = 0.014). It did not correlate with nodal status (P = 0.437). Among ER+ patients, AIB1 expression showed a trend towards loss of PR expression (29% versus 20%; P = 0.14). AIB1 did not predict survival on univariate or multivariate analysis. Conclusions: AIB1 expression correlates with HER‐2 expression in breast cancer and shows a trend of association with loss of PR expression in ER+ tumours. Our study supports the postulated role of AIB1 in ER–growth factor interactions.     

Psychosocial factors in the etiology of breast cancer: review of a popular link

Breast cancer is the most frequently occurring type of cancer in women in the western world. The etiology of a large proportion of breast cancers is still unexplained, and the possibility that psychosocial factors could play a role is not ruled out. Already in pre-Christian times, it was assumed that psychological factors might play a significant role in the development of breast cancer. However, studies have failed to produce conclusive results. There is still a lack of knowledge on the relationship between breast cancer development and psychosocial factors such as stressful life events, coping styles, depression, and the ability to express emotions. The results of this review show that there is not enough evidence that psychosocial factors like 'ways of coping' or 'non-expression of negative emotions', play a significant role in the etiology of breast cancer.