Nuclear CSPP1 expression defined subtypes of basal-like breast cancer

Background:

The multi-exon CSPP1 gene, encoding for centrosome and microtubule-associated proteins involved in ciliogenesis and cell division, is a candidate oncogene in luminal breast cancer but expression of CSPP1 proteins remained unexplored.

Methods:

CSPP1 gene and protein expression was examined in normal mammary tissue, human breast cancer cell lines, and primary breast cancer biopsies from two patient cohorts. Cell type and epitope-dependent subcellular-specific CSPP1 staining pattern in normal mammary gland epithelium and cancer biopsies were correlated to molecular and clinical parameters.

Results:

A novel, nuclear localised CSPP1 isoform was exclusively detected in luminal epithelial cells, whereas cytoplasmic CSPP-L was generally expressed in normal mammary epithelium. Luminal cell-related nuclear CSPP1 expression was preserved in type-matched cell lines and carcinomas, and correlated to gene copy number and mRNA expression. In contrast, basal-like carcinomas displayed generally lower CSPP1 mRNA expression. Yet, a subgroup of basal-like breast carcinomas depicted nuclear CSPP1 expression, displayed luminal traits, and differed from nuclear CSPP1 devoid counterparts in expression of eight genes. Eight-gene signature defined groups of basal-like tumours from an independent cohort showed significant differences in survival.

Conclusions:

Differential expression of a nuclear CSPP1 isoform identified biologically and clinically distinct subgroups of basal-like breast carcinoma.     

乳腺癌中DEC1与claudin-1的表达及其临床意义

目的：分析DEC1（differentiated embryonic chondrocyte expressed gene 1）和claudin-1在乳腺癌组织中的表达和相关性及其与临床病理因素间的关系。方法：采用免疫组化方法检测DEC1和claudin-1在154例乳腺癌中的表达情况。结果：在154例乳腺癌中 DEC1的表达升高与乳腺癌的高分级（P＝0．002）和淋巴结转移（P＝0．048）相关,而与患者年龄（P＝0．769）、肿瘤大小（P＝0．216）、患者的雌激素水平（P＝0．303）及孕激素水平（P＝0．127）无相关性。而claudin-1的表达缺失与患者的雌激素水平（P＝0．006）和淋巴结转移（P＝0．025）相关,而与患者年龄（P＝0．538）、肿瘤大小（P＝0．801）、肿瘤的分级（P＝0．083）及患者的孕激素水平（P＝0．195）无相关性。并且DEC1在乳腺癌中的表达与claudin-1的表达显著负相关（P＜0．001）。结论：乳腺癌中DEC1的表达与claudin-1的表达负相关,并与肿瘤的高分级相关。     

Predictors of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers

Purpose:

The objective of this study was to estimate the risk of contralateral breast cancer in BRCA1 and BRCA2 carriers; and measure the extent to which host, family history, and cancer treatment-related factors modify the risk.

Patients and methods:

Patients were 810 women, with stage I or II breast cancer, for whom a BRCA1 or BRCA2 mutation had been identified in the family. Patients were followed from the initial diagnosis of cancer until contralateral mastectomy, contralateral breast cancer, death, or last follow-up.

Results:

Overall, 149 subjects (18.4%) developed a contralateral breast cancer. The 15-year actuarial risk of contralateral breast cancer was 36.1% for women with a BRCA1 mutation and was 28.5% for women with a BRCA2 mutation. Women younger than 50 years of age at the time of breast cancer diagnosis were significantly more likely to develop a contralateral breast cancer at 15 years, compared with those older than 50 years (37.6 vs 16.8% P=0.003). Women aged <50 years with two or more first-degree relatives with early-onset breast cancer were at high risk of contralateral breast cancer, compared with women with fewer, or no first-degree relatives with breast cancer (50 vs 36% P=0.005). The risk of contralateral breast cancer was reduced with oophorectomy (RR 0.47; 95% CI 0.30–0.76; P=0.002).

Conclusion:

The risk of contralateral breast cancer risk in BRCA mutation carriers declines with the age of diagnosis and increases with the number of first-degree relatives affected with breast cancer. Oophorectomy reduces the risk of contralateral breast cancer in young women with a BRCA mutation.     

S-1 (TS-1) maintained complete response for approximately 10 years in a case of metastatic breast cancer

We present a patient with pulmonary metastasis from breast cancer who received S-1 (TS-1) and maintained complete response for approximately 10 years after recurrence. A 51-year-old woman underwent modified radical mastectomy for left breast cancer in November 1991. Her cancer was postoperatively classified as pT2 pN0 M0 Stage IIA. As postoperative adjunctive treatment, tamoxifen and hexylcarbamoyl 1-5-FU (HCFU) were given. During the administration period (30 months after surgery), a solitary pulmonary metastasis occurred. Three months after the start of S-1 (100 mg/body/day), the tumor disappeared on images. Thereafter she took S-1 orally for approximately 10 years, and the pulmonary metastatic focus maintained complete response. In addition, no recurrent focus was observed. The adverse events observed during S-1 treatment were nausea, low-grade neutropenia and pigmentation of fingers. All were mild, and S-1 could be continued. Our case illustrates two important characteristics of S-1. First, S-1 was effective even though this patient had a lung metastasis during adjuvant treatment with HCFU. S-1 is a combined formulation containing 5-chloro-2, 4-dihydroxypyrimidine (CDHP; gimestat), which inhibits an enzyme that metabolites 5-FU, dihydropyrimidine dehydrogenase (DPD). Therefore, high 5-FU concentrations are maintained with S-1, and S-1 may be effective in the patients who do not respond to other fluoropyrimidine agents. Second, since S-1 toxicity was mild, long-term treatment for approximately 10 years was possible. Since S-1 contains potassium oxonate (OXO; otastat), gastrointestinal toxicities, the main adverse events of 5-FU agents, could be reduced. The purpose of treatments for metastatic breast cancer is to maintain favorable quality of life (QOL), as well as to improve survival. S-1 could be a valuable agent for breast cancer treatments, since it showed clinical efficacy and mild toxicity, and can be given orally.     

Comparison of the expression levels of lysine-specific demethylase 1 and survival outcomes between triple-negative and non-triple-negative breast cancer

Lysine-specific demethylase 1 (LSD1) is a nuclear protein and the first histone demethylase to be identified. LSD1 is an evolutionarily conserved member of the FAD-dependent amine oxidase family and serves an important role in controlling gene expression. LSD1 has been implicated in the tumorigenesis and progression of several types of human cancer; however, to the best of our knowledge, the expression levels and clinical significance of LSD1 in triple-negative breast cancer (TNBC) and non-triple-negative breast cancer (NTNBC) have not been investigated in detail. Therefore, the present study aimed to compare the expression levels of LSD1 in TNBC and NTNBC to determine the prognostic significance of LSD1 in breast cancer. Previous studies have suggested that LSD1 may be involved in the carcinogenesis and progression of breast cancer; however, the findings of the present study indicated that LSD1 may not be a suitable molecular treatment target and auxiliary diagnostic indicator for TNBC and NTNBC.     

长链非编码 RNA AFAP1－AS1在乳腺癌中的表达及临床意义

目的：探讨长链非编码 RNA（long non －coding RNA,lncRNA）肌动蛋白纤维相关蛋白1－反义 RNA1（actinfilament －associated protein 1－antisense RNA1,AFAP1－AS1）在乳腺癌肿瘤组织中的表达情况及其临床意义。方法：采用荧光定量 PCR 方法检测76例乳腺癌组织及其对应癌旁组织中 AFAP1－AS1的表达情况。选取表达差异最大的5对组织,结合核浆分离的方法,检测 AFAP1－AS1在乳腺癌细胞中的表达位置。分析AFAP1－AS1表达与乳腺癌主要临床病理特征及患者生存曲线的相关性。通过 siRNA 干扰 AFAP1－AS1在乳腺癌细胞 SKBR －3、MCF －7中的表达,MTT 法检测其表达对乳腺癌细胞增殖的影响。结果：AFAP1－AS1在乳腺癌组织中的表达水平相较癌旁组织明显下调（P ＜0．05）,并且这一表达差异主要发生在细胞质。沉默AFAP1－AS1的表达会促进乳腺癌细胞增殖。同时,AFAP1－AS1在乳腺癌组织中的表达差异与临床分期和淋巴结转移有关（P ＜0．05）,且与患者生存率也明显相关（P ＜0．05）。结论：lncRNA AFAP1－AS1在乳腺癌组织中表达下调,影响乳腺癌细胞增殖,可能与乳腺癌的发生和发展有关,可能成为新的乳腺癌分子标志物。     

DBC1的研究进展

DBC1是近年来新发现的一种蛋白,属于小GTP酶类Rho家族的非典型成员。最初因为在乳腺癌组织中杂合性缺失被鉴定出来的。目前关于DBC1在乳腺癌上的研究报道尚少。本文对国内外关于该基因的有关研究进行综述,了解其分子机制,基因表达情况。     

GSTM1 and GSTT1 Genetic Polymorphisms and Breast Cancer Risk in Selected Filipino Cases

Background: The association of genetic polymorphisms with cancer development has been shown to be race- andtumor site-specific. Thus, this study aimed to determine whether polymorphisms in the GSTM1 and GSTT1 genesare associated with breast cancer among selected Filipinos. Methods: A total of 136 histologically confirmed breastcancer cases were age- and sex-matched with 136 clinically healthy controls. Genomic DNA extracted from bloodsamples of participants were screened for GSTM1 and GSTT1 genetic polymorphisms by multiplex PCR. Results:The frequency of null genotypes among the cases (GSTM1: n=78; 57.4%; GSTT1: n=61; 44.9%) was not significantlydifferent (p>0.05) from the controls (GSTM1: n=93; 68.4%; GSTT1: n=59; 43.4%). It was also demonstrated that riskfor breast cancer was increased in passive smokers carrying the GSTM1 null (OR=2.56; 95% CI=1.38-4.75) or GSTT1positive (OR=2.00; 95% CI=1.05-3.83) genotypes. Moreover, risk was decreased in alcohol users carrying the GSTT1null (OR=0.39; 95% CI=0.16-0.97) genotype. Conclusion: This study suggests that variants of GSTM1 and GSTT1may not be risk factors for breast cancer development among Filipinos. However, the risk may be increased when thesegenotypes were combined with lifestyle or environmental factors.     

HLA-DRB 1 alleles and the susceptibility of Iranian patients with breast cancer

Breast cancer is considered a major malignancy among women worldwide. The contribution of genetic elements to the onset of familial breast cancer has already been established. The current study investigate the alfele frequency of HLA-DRB 1 in 36 primary operable female breast cancer patients from southern Iran by polymerase chain reaction using sequence specific primers (PCR-SSP). Results were compared with those of 36 female control subjects. Statistical analysis was performed and P values were determined for each character. Our results indicated that the frequency of HLA-DRB 1*12 allele is significantly higher in the patient group (p<0.03) compared to the control group. In addition, HLA-DRB1*11 appeared to be as the most frequent allele in the control group (29.2%) and had approximately the same distribution among the patient group (22.5%).     

Differential levels of soluble intercellular adhesion molecule-1 (sICAM-1) in early breast cancer and benign breast lesions

To date, no soluble markers can discriminate benign from malignant breast lesion; therefore, to assess the diagnostic potential of circulating intercellular adhesion molecule-1 (sICAM-1), serum concentrations of sICAM-1 were quantitated in 230 consecutive patients that underwent surgery for breast neoplasias, utilizing an enzyme-linked immunosorbent assay. Histological diagnosis revealed that 177 patients had breast cancer and 53 had a benign breast disease. In the cancer patient group, 90 subjects had pTl tumors without (pT1N0M0, n=46) or with (pT1N1M0, n=41; pT1N2M0, n=3) regional lymph node metastases. Mean levels of serum sICAM-1 of patients with pT1 breast cancer, without or with regional lymph node involvement, were significantly (P<0.05) higher than those of patients with benign breast lesions and of 49 age-matched control subjects. Elevated levels of serum sICAM-1 were detected in 27/90 (30%) pTl breast tumors and in 1/53 (2%) benign breast lesions; thus, among subjects with high levels of sICAM-1, 96% had breast cancer. No significant correlation was found between levels of serum sICAM-1 and breast cancer progression. These observations, altogether, suggest that in the presence of a suspicious breast neoplasm the quantitative analysis of serum sICAM-1 can orient clinical diagnosis towards malignancy.     

Estrogen upregulation of BRCA1 expression with no effect on localization

Alterations in the expression of the breast and ovarian cancer susceptibility gene BRCA1 may contribute to the development of mammary and ovarian neoplasia. The sex-steroid estrogen modulates cell proliferation of normal and neoplastic breast and ovarian epithelial cells, but the role of estrogen regulation on the expression of BRCA1 remains to be defined. In this study, estrogen-regulated BRCA1 expression was examined in breast and ovarian cancer cells. Estrogen stimulated the proliferation of estrogen receptor (ER)–positive breast MCF-7, C7-MCF-7, and ovarian BG-1 cells as well as the expression of the estrogen-inducible pS2 gene. This was concomitant with upregulation of BRCA1 mRNA (2.5- to 5.0-fold) and a 3- to 10-fold induction of BRCA1 protein (230 kDa). Cell fractionation studies localized the BRCA1 protein to the nucleus in both unstimulated and estrogen-stimulated cells. The antiestrogen ICI-182780 inhibited estrogen-induced cell proliferation, BRCA1 mRNA induction, and BRCA1 protein expression in ER-positive cells. Conversely, estrogen did not influence expression of BRCA1 in HBL-100 cells that lacked the estrogen receptor, although the constitutive levels of BRCA1 mRNA (but not protein) in these cells were 5- to 30-fold higher than in other breast and ovarian cancer cells. Secretion of the BRCA1 protein into the cell medium did not account for the discrepancy between the mRNA and protein levels in HBL-100 cells. Proliferation of HBL-100 cells was not affected by either estrogen or ICI-182780. Taken together, these data support a role for the steroid estrogen and the involvement of the estrogen receptor pathway in the modulation of expression of BRCA1. We therefore propose that stimulation of cell proliferation may be a prerequisite for upregulation of BRCA1 in breast and ovarian cancer cells. Mol. Carcinog. 22:102–109, 1998. © 1998 Wiley-Liss, Inc. This article is a US Government work and, as such, is in the public domain in the United States of America.     

Collaboration of breast cancer clinic and genetic counseling division for BRCA1 and BRCA2 mutation family in Japan

BACKGROUND: BRCA1 and BRCA2 mutations cause high breast cancer incidence rates as high as 80% Although prophylactic therapy is still controversial, several prophylactic therapies have been proposed and tried for BRCA1 and BRCA2 mutation carriers. Prophylactic surgery, chemo-prevention and precise screening have been proposed as prophylactic therapy. All BRCA1 and BRCA2 mutation carriers need knowledge about their disease and the countermeasures that are used to protect against onset of disease. Counseling plays an important role in this regard for people with genetic diseases. Therefore, collaboration between breast cancer clinics and genetic counseling services is the most important issue in clinical practice. Our group consists of three national universities and a general hospital. In this article we describe our trial to construct a clinical system against hereditary breast cancer as an interim report for the Japanese Ministry of Health, Labour and Welfare. PATIENTS AND METHODS: Twenty familial breast cancer patients were registered in this study. The whole sequence of BRCA1 and BRCA2 were analyzed. If pathological mutations were detected, their first degree families were introduced to the counseling division at each institute when candidates visited counseling divisions. RESULTS AND DISCUSSION: Four cases of a deleterious mutation in BRCA1 or BRCA2 were detected among 20 cases. Their first degree relatives are now under consideration for visiting counseling divisions. The clinical system described in this study should play a role to protect BRCA1 or BRCA2 mutation carriers in Japan.     

Apaf－1在乳腺癌治疗中的作用及意义

乳腺癌的新辅助化疗不但可以降低临床分期、提升保乳率,还可以判断化疗药物的敏感性,并指导术后化疗用药,已逐渐成为乳腺癌综合治疗的首选。但仍有少数乳腺癌患者不能从新辅助化疗中受益,预测乳腺癌新辅助治疗的获益人群,是临床中亟待解决的问题。乳腺癌新辅助化疗后的细胞凋亡指数（apop-totic index,AI）是评估乳腺癌新辅助化疗疗效的关键因素,而Apaf－1作为凋亡途径的重要一员,在细胞凋亡中起到重要的作用。本文通过乳腺癌新辅助化疗后AI值的变化,并结合Apaf－1自身的结构、分布、在凋亡途径中的作用及在各肿瘤中的表达和化疗耐药性等角度,对Apaf－1在乳腺癌治疗中的作用及意义作一综述。     

胰岛素样生长因子-1在乳腺癌组织中的表达

Objective  We investigated the expression of insulin-like growth factor-1 (IGF-1) so as to explore its relationship with carcinogenesis and development of breast cancer. Methods  IGF-1 mRNA levels in tissues of breast cancer, adjacent breast cancer in 70 cases breast cancer patients were analyzed by RT-PCR with the normal breast tissues of paired breast as the control. Results  The level of IGF-1 mRNA expression in breast cancer tissues was significantly higher than that in the paired adjacent to breast cancer tissues, normal mammary gland tissues. The ration of IGF-1/β-actin were 0.679 ± 0.075, 0.463 ± 0.085, 0.305 ± 0.031, respectively. There was significant difference between different groups (P < 0.005). Expression of IGF-1 was associated with lymph node metastasis, pathological staging and estrogen receptor status of breast cancer and no significant relationship with tumor pathological grouping (P > 0.005). Conclusion  The high-level expression of IGF-1 in breast cancer tissues is correlated with carcinogenesis, development and metastasis of breast cancer.     

MTA1和nm23-H1蛋白表达与乳腺癌生物学行为之间的关系

目的探讨肿瘤转移相关基因（NTA1）和nm23-H1蛋白表达与乳腺癌生物学行为之间的关系。方法运用免疫组化S-P法检测56例乳腺癌组织中NTAl、nm23-H1蛋白的表达。结果56例乳腺癌组织中39例NTA1蛋白阳性表达,阳性率为69．6％,NTA1高表达与乳腺癌组织学分级、临床分期和淋巴结转移关系密切（P〈0．05）;3l例nm23-H1蛋白阳性表达,阳性率为55．4％,nm23-H1低表达与乳腺癌组织学分级、临床分期和淋巴结转移关系密切（P〈0．05）;乳腺癌组织中NTA1、nm23-H1蛋白表达呈负相关（P〈0．05）。结论NTA1和nm23-H1蛋白表达与乳腺癌分化程度、淋巴结转移和预后关系密切,可作为诊断乳腺癌患者转移复发的参考指标,并有望成为乳腺癌基因治疗的新靶点。     

WT1在乳腺癌中的研究进展

Wilms瘤基因1(Wilms' tumor gene 1,WT1)作为抑癌基因第一次在肾母细胞瘤(又称 Wilms瘤)中被描述,但后续的研究表明WT1基因在多种肿瘤中高表达,包括乳腺癌、肺癌、直肠癌,提示WT1可能具有癌基因的作用。多项研究显示,WT1与乳腺癌的发生、发展及预后密切相关。因此WT1有助于揭示乳腺癌发生发展的机制,并成为乳腺癌潜在的生物治疗靶位。本文就近年来WT1在乳腺癌中的研究进展予以综述。     

Germline 657del5 mutation in the NBS1 gene in breast cancer patients

In this report the proportion of consecutive and familial breast cancer cases harboring the 657del5 of exon 6 of the NBS1 gene was determined to assess whether it is associated with the increased risk of breast cancer development. The study consisted of 3 groups of patients: a series of consecutive 150 patients with histologically confirmed breast cancer, diagnosed under the age of 50 in the city of Szczecin; a series of 80 breast cancer patients with a family history of breast cancer in their first-degree relatives; and a series of 530 consecutive individuals without the diagnosis of breast cancer selected at random by family doctors from the city of Szczecin. Molecular examination included allele-specific PCR assay for the common Slavic NBS1 mutation (657del5), LOH analysis using denucleotide CA repeat microsatellite markers, haplotype analysis and sequencing. The NBS1 founder mutation was detected in 2 of 150 (1.3%) consecutive breast cancer cases diagnosed under the age of 50 years; in 3 of 80 familial breast cancer cases (3.7%); and in 3 of 530 individuals (0.6%) from the general population. Examination of tumor DNA from patients with the NBS1 mutation (groups A and B) revealed loss of heterozygosity (LOH) in all cases. Additional haplotype analysis revealed that allelic loss affects specifically wild-type alleles. The majority of probands with breast cancer and the NBS1 mutation had a positive family history of breast cancer in their first-degree relatives. It appears that the 657del5 mutation in exon 6 of the NBS1 gene is responsible for the occurrence of a small but significant proportion of familial breast cancer patients.