Majority Of Breast Carcinomas Research Articles

Multi-modal imaging probe for EpCAM overexpressed in breast cancer

Breast cancer is a highly lethal and aggressive form of cancer. Early-stager diagnosis and intraoperative guidance are important endeavors for reducing associated morbidity and mortality among breast cancer patients. Epithelial cell adhesion molecule (EpCAM) is aberrantly expressed in the majority of breast carcinoma, making it an attractive imaging biomarker. Herein, we have designed novel EpCAM-targeting peptides (denoted as YQ-S) for precise breast carcinoma detection. The greater binding affinity of the designed peptide YQ-S2 over YQ-S1 and the reported peptide SNF was displayed on different cell lines with flow cytometry analysis, showing a positive correlation with the expression of EpCAM. Besides, YQ-S2 displayed an ideal biosafety profile with no evidence of any acute toxicity. Thus, YQ-S2 was chosen to represent YQ-S. By linking with the near-infrared fluorescent dye (MPA), we further developed the EpCAM-targeting probe (YQ-S2-MPA) for real-time imaging and fluorescence-guided resection of breast cancer tumors. In vivo imaging of the MCF-7 tumor-bearing model demonstrated higher tumor uptake of YQ-S2-MPA compared with that of SNF-MPA. The maximum tumor-to-normal tissue signal ratio of YQ-S2-MPA was 5.1, which was about 2 times that of SNF-MPA. Meanwhile, the metastatic lesions in 4T1 lung metastasis, and lymph node metastasis (LNM) mice were successfully detected under this imaging system. Notably, YQ-S2-MPA had excellent performance in surgical navigation studies in the preclinical models. Moreover, we exploited the 99mTc-HYNIC-YQ-S2 to localize EpCAM positive tumors successfully. These data proved that YQ-S2 can distinguish EpCAM-positive orthotopic and metastatic tumors from surrounding normal tissues accurately, and possesses the clinical potential as a surgical navigation probe.

ПРОГНОСТИЧНЕ ЗНАЧЕННЯ ЕКСПРЕСІЇ РЕЦЕПТОРІВ АНДРОГЕНІВ У ХВОРИХ НА РАК ГРУДНОЇ ЗАЛОЗИ

The review discusses the importance of the expression of androgen receptor (AR) in patients with breast cancer (BC). AR is expressed in normal tissues of the breast and in most of the molecular sub-types of BC. AR are located with estrogen (ER) and progesterone (PR) receptors in epithelial cells, but not in the stroma of breast. Up to this date there is no common opinion about the role of the lev-el of androgens and their metabolites in biological fluids samples in the development of BC. Hy-pothesis, that androgens are directly involved in BC cancerogenesis, is based on the presence of AR in the majority of breast carcinomas. AR expression was higher in ER positive subtypes (90% Lu-minal A, 70-90% Luminal B and lower in ER negative subtypes (60% HER2, 10-50% triple- nega-tive cancer. The opinion prevails, that patients with tumours positive to АR, are characterised by a better prognosis than negative to AR. The most aggressive type of BC is triple-negative breast can-cer (TNBC), characterized by high proliferative activity and doesn’t respond to the hormonal thera-py. Оne of the aims of the present study is to explore the clinical significance of AR and provide evidence for AR-directed treatment in TNBC. In recent years, the issue of targeted therapy for AR expression has been actively discussed. In a study by Gucalp et al (2013), the efficacy of bicalutam-ide in patients with AR + THNBC with AR expression ≥ 10%, ER-, PR- was determined. Twenty-six patients received 150 mg of bicalutamide daily, and 19% patients had improvements in the gen-eral condition. In a preclinical study of the effect of Enzalutamide and Bicalutamide in ER + (AR +) BC, it has been shown that Enzalutamide is more effective than Tamoxifen because it reduces proliferation in both ER + BC and ER- BC patients.

Histopathological and immunohistochemical characteristics of breast carcinomas in Uyo, subtropical region of Africa

Background: There is a relative dearth of data for immunohistochemical characteristics of breast carcinomas in cancer registries of Nigeria and some parts of Africa. A descriptive hospital based study, done over a year, involving three hospitals in Uyo rendering breast cancer care.
 Objective: To determine the immunohisto chemical-expression pattern of oestrogen receptor, progesterone receptor, and human epidermal receptor 2 and their relationship with histopathological features of invasive breast carcinomas in Uyo, Akwa Ibom State.
 Materials and methods: Each specimen with an accompanying completely filled coded proforma form containing clinical characteristics of patients with breast cancer was received at the Histopathology Department for subsequent histopathological and immunohistochemical analysis.
 Results: The age range for patients with breast carcinoma was 23 -70 years with a mean age at presentation of43.07 ± 11.19 years. Invasive ductal carcinoma was the commonest histological type accounting for 86.9 % of all breast cancer. Positivity for oestrogen receptors, progesterone receptors and Her-2 were seen in 18.0 %, 14.8 % and 32.8 % of breast carcinomas respectively. Majority of breast carcinomas were triple negative phenotype (62.3 %).
 Conclusion: Majority of the invasive breast carcinomas in our environment were triple negative phenotype (62.3 %).

Histopathological and Immunohistochemical Characteristics of Breast Carcinomas in Uyo, Subtropical Region of Africa

Background: There is a relative dearth of data for immunohistochemical characteristics of breast carcinomas in cancer registries of Nigeria and some parts of Africa. A descriptive hospital based study, done over a year, involving three hospitals in Uyo rendering breast cancer care.
 Objective: To determine the immunohistochemical-expression pattern of oestrogen receptor, progesterone receptor, and human epidermal receptor 2 and their relationship with histopathological features of invasive breast carcinomas in Uyo, Akwa Ibom State.
 Materials and methods: Each specimen with an accompanying completely filled coded proforma form containing clinical characteristics of patients with breast cancer was received at the Histopathology Department for subsequent histopathological and immunohistochemical analysis.
 Results: The age range for patients with breast carcinoma was 23 -70 years with a mean age at presentation of 43.07 ± 11.19 years. Invasive ductalcarcinoma was the commonest histological type accounting for 86.9 % of all breast cancer. Positivity for oestrogen receptors, progesterone receptors and Her-2 were seen in 18.0%, 14.8% and 32.8% of breast carcinomas respectively. Majority of breast carcinomas were triple negative phenotype (62.3%).Conclusion: Majority of the invasive breast carcinomas in our environment were triple negative phenotype (62.3%).

BRCA1 expression and its association with histological typing, grade, ER, PR, HER2 in carcinoma of breast

Breast cancer is the most commonly diagnosed cancer in female worldwide. BRCA 1 is located predominantly in nucleus. BRCA 1 is associated with breast cancer. Materials and Methods: This was retroprospective study, 50 known cases of breast carcinoma were analysed in Muzaffarnagar Medical College, Muzaffarnagar. Observation and Results: The age range of patients was from 28-70 years and mean age of patients was 50.24 years. Majority of breast carcinoma were above 45 years of age (64%) and of upper outer quadrant (52%) and of grade II (48%). Invasive carcinoma of no special type (NST) formed the majority of cases (82%) followed by Invasive lobular carcinoma (6%). Altered BRCA 1 expression was seen in ER, PR and HER 2 negative cases. Conclusions: Invasive Carcinoma of no special type was the commonest morphological type. Majority of cases of breast carcinoma were of grade II. Keywords: BRCA 1, Invasive Carcinoma NST, ER, PR, Her 2 neu, IHC.

Immunohistochemical Expression of Cyclooxygenase-2 (COX-2) in Breast Cancer

Background: breast cancer (BC) is the most common type of diagnosed cancers in women. It is still the second leading cause of cancer-related death among women after lung cancer all over the world. Breast cancer is the first of top ten cancers in Egypt. It ranks as the first malignancy affecting females, contributing 30% of all female cancers. It affects 1 in 14 women during their life time. Aim: This study investigated the association between cyclooxygenase-2 (COX-2) expression in female breast cancer versus the expression of ER, PR, as well as its association with other established prognostic indicators like age, tumor size, lymph nodal status, stage, grade, lymphovascular invasion, insitu component and histological subtype, and aims to validate the role of overexpression of COX-2 as a prognostic marker in female patients with breast cancer in Egypt. Results: High significant correlation was found between lymph node metastasis, negative ER and PR cases and COX-2 expression. No significant correlation could be detected between age, tumor size, site, histologic type, grade, insitu component, LVI and COX-2 expression. Conclusion: Cyclooxygenase-2 has poor prognostic parameter in breast cancer, as it is over expressed in majority of breast carcinoma, especially with lymph node metastasis, ER and PR negative hormone receptor.

RATE OF MALIGNANT BREAST CANCER AMONG WOMEN WITH BREAST MASS ATTENDING ALDEWANIYAH TEACHING HOSPITALS: A CROSS-SECTIONAL STUDY

Objective: The problems of breast mass, pain, or discharge are extremely common in the Iraqi population, as well as, globally. However, the trend in most health-care institutions is that most breast lesions are of benign biologic behavior and among true neoplastic lesions. Marital status has been linked to the outcome of breast malignancy; however, the link is controversial.Thus, the aim of the present study is to make a clear insight into the true incidence rate of carcinoma and their risk factors.Materials and Methods: The study was designed to be a cross-sectional study involving a cohort of 182 Iraqi women with the breast mass. Patients were selected in a systemic random way from the population of patients already visiting the surgical consultation clinic and ward and oncology unit in Al-Dewaniyah teaching hospital in Al-Diwaniyah province, Iraq.Result: The present study showed that the most breast lesions (82%) were benign, and the most frequent one was a fibroadenoma (37.4%). Malignant lesions accounted for a small percentage (17.4%). Mean age of patients with carcinoma was 49.78±7.58 years and most all cases occurred after 20 years of age and that 87.5% of cases were seen after the age of 40. Majority of breast carcinoma were of invasive ductal carcinoma. No significant association was seen between the clinical behavior of breast mass and marital status; however, malignant clinical behavior showed significant association with age.Conclusion: The incidence rate of malignant breast lesions in Iraqi women with breast mass is similar to that seen worldwide and that age is the main risk factor that predicts the malignant clinical behavior of a breast mass.

Knockdown delta-5-desaturase in breast cancer cells that overexpress COX-2 results in inhibition of growth, migration and invasion via a dihomo-\u03b3-linolenic acid peroxidation dependent mechanism

BackgroundCyclooxygenase-2 (COX-2), the inducible COX form, is a bi-functional membrane-bound enzyme that typically metabolizes arachidonic acid (downstream ω-6 fatty acid) to form 2-series of prostaglandins known to be involved in cancer development. Overexpression of COX-2 has been found in a majority of breast carcinomas, and has also been associated with increased severity and the development of the metastasis. Our lab recently demonstrated that COX-2 can also metabolize dihomo-γ-linolenic acid (DGLA, a precursor of ω-6 arachidonic acid) to produce an anti-cancer byproduct, 8-hydroxyoctanoic acid (8-HOA) that can inhibit growth and migration of colon and pancreatic cancer cells. We thus tested whether our strategy of knocking down delta-5-desaturase (D5D, the key enzyme that converts DGLA to arachidonic acid) in breast cancer cells overexpressing COX-2 can also be used to promote 8-HOA formation, thereby suppressing cancer growth, migration, and invasion.MethodsSiRNA and shRNA transfection were used to knock down D5D expression in MDA-MB 231 and 4 T1 cells (human and mouse breast cancer cell lines expressing high COX-2, respectively). Colony formation assay, FITC Annexin V/PI double staining, wound healing and transwell assay were used to assess the effect of our strategy on inhibition of cancer growth, migration, and invasion. GC/MS was used to measure endogenous 8-HOA, and western blotting was performed to evaluate the altered key protein expressions upon the treatments.ResultsWe demonstrated that D5D knockdown licenses DGLA to inhibit growth of breast cancer cells via promoting formation of 8-HOA that can inhibit histone deacetylase and activate cell apoptotic proteins, such as procaspase 9 and PARP. Our strategy can also significantly inhibit cancer migration and invasion, associated with altered expression of MMP-2/− 9, E-cadherin, vimentin and snail. In addition, D5D knockdown and DGLA supplementation greatly enhanced the efficacy of 5-fluorouracil on breast cancer growth and migration.ConclusionsConsistent to our previous studies on colon and pancreatic cancer, here we demonstrate again that the high level of COX-2 in breast cancer cells can be capitalized on inhibiting cancer growth and migration. The outcome of this translational research could guide us to develop new anti-cancer strategy and/or to improve current chemotherapy for breast cancer treatment.

Monte Carlo simulation studies for the determination of microcalcification thickness and glandular ratio through dual-energy mammography

The majority of breast carcinomas can be associated to the presence of calcifications before the development of a mass. However, the overlapping tissues can obscure the visualization of microcalcification clusters due to the reduced contrast-noise ratio (CNR). In order to overcome this complication, one potential solution is the use of the dual-energy (DE) technique, in which two different images are acquired at low (LE) and high (HE) energies or kVp to highlight specific lesions or cancel out tissue background. In this work, the DE features were computationally studied considering simulated acquisitions from a modified PENELOPE Monte Carlo code. The employed irradiation geometry considered typical distances used in digital mammography, a CsI detection system and an updated breast model composed of skin, microcalcifications and glandular and adipose tissues. The breast thickness ranged from 2 to 6cm with glandularities of 25%, 50% and 75%, where microcalcifications with dimensions from 100 up to 600μm were positioned. In general, results pointed an efficiency index better than 87% for the microcalcification thicknesses and better than 95% for the glandular ratio. The simulations evaluated in this work can be used to optimize the elements from the DE imaging chain, in order to become a complementary tool for the conventional single-exposure images, especially for the visualization and estimation of calcification thicknesses and glandular ratios.

Mammaglobin-A Immunohistochemistry in Primary Central Nervous System Neoplasms and Intracranial Metastatic Breast Carcinoma

Metastases represent the most common type of intracranial neoplasm. In women, 30% of such tumors derive from breast carcinoma. In neurosurgical cases with ambiguous cellular morphology and/or limited biopsy material, immunohistochemistry (IHC) is often performed to distinguish metastases from primary central nervous system (CNS) neoplasms. IHC for mammaglobin-A (MGA), a protein expressed in a majority of breast carcinomas, is commonly applied in this setting, but its utility for distinguishing primary CNS neoplasms from metastatic breast carcinoma is unknown; the reactivity of MGA in primary and metastatic CNS neoplasms has never been described. Here, we describe the frequency and patterns of IHC reactivity for MGA in metastatic and primary CNS neoplasms from patients with well-documented histories of breast carcinoma. Following a published protocol previously applied to non-CNS neoplasms, MGA staining of moderate to strong intensity within 5% or more of a neoplasm was considered positive. On the basis of these criteria, 3 of 12 (25.0%) glioblastomas, 1 of 10 (10.0%) meningiomas, and 47 of 95 (49.5%) metastases were positive. Importantly, the cytoarchitectural staining characteristics among all 4 MGA-positive primary CNS neoplasms (cytoplasmic and nuclear) differed from those of the metastases (cytoplasmic and membranous). These findings suggest that MGA IHC staining intensity and distribution can distinguish metastases from primary CNS neoplasms (P=0.0086) in women with a history of breast carcinoma but also indicate that cytologic staining patterns must be interpreted for more accurate tumor classification.

The prognostic potential of keratin 18 in breast cancer associated with tumor dedifferentiation, and the loss of estrogen and progesterone receptors

The differential expression profiling with breast normal and tumor tissues, and a breast cancer cell line led to identification of cytokeratin 18 (KT18) gene over-expressed in breast cancer. The expression pattern of KT18 in breast cancer was compared to those of conventional tumor markers such as proliferating cell nuclear antigen (PCNA) and minichromosome maintenance protein 3 (MCM3). Their expression patterns in breast cancer were almost identical, suggesting that KT18 might be useful for detection of proliferating fractions in the breast cancer. The immunohistochemical analyses on the tissue microarray consisting of invasive ductal carcinomas revealed that the up-regulation of KT18 is observed in a majority of breast carcinomas whereas its down-regulation also occurs at a less frequency. Of particular interest, KT18 down-regulation was associated with histologically poorly differentiated carcinomas than well differentiated carcinomas. In addition, it was also significantly associated with the loss of estrogen receptor (ER) and progesterone receptor (PR), the prognostic markers of the breast cancer (P < 0.05), while not with HER2, tumor size, and lymph node metastasis. This result suggests that KT18 correlated with ER and PR may be utilized for the prognosis of breast cancer. Furthermore, the forced down-regulation of KT18 enhanced the growth of tumor xenografts in vivo and invasiveness in vitro. Therefore, our findings suggest that loss of KT18 expression might be a good indicator of the poor prognosis of the breast cancer and it may play an active role in the breast tumorigenesis.

LIMK2 is a crucial regulator and effector of Aurora-A-kinase-mediated malignancy

Aurora A is overexpressed in majority of breast carcinomas. With the exception of BRCA1 and PHLDA1, no oncogenic Aurora A substrates are known in breast cancer. In this study, a chemical genetic approach was used to identify malignant targets of Aurora A, which revealed LIMK2 as a novel Aurora A substrate. Aurora A regulates LIMK2 kinase activity, subcellular localization and protein levels by direct phosphorylation at S283, T494 and T505. In response, LIMK2 also positively regulates the level of Aurora A, thereby engaging in a positive-feedback loop, promoting Aurora-A-mediated oncogenic pathways. Most importantly, LIMK2 ablation fully abrogates Aurora-A-mediated tumorigenesis in nude mice, suggesting that LIMK2 is a key oncogenic effector of Aurora A. Furthermore, LIMK2 ablation acts synergistically with inhibition of Aurora A in promoting cell death. Finally, Aurora-A-mediated upregulation of LIMK2 appears to be a common mechanism in many cancers. LIMK2 inhibition or ablation is therefore an alternative approach for modulating Aurora A deregulation in cancer.

PHLDA1 is a crucial negative regulator and effector of Aurora A kinase in breast cancer

Aurora A kinase is overexpressed in the majority of breast carcinomas. A chemical genetic approach was used to identify the malignant targets of Aurora A, which revealed pleckstrin-homology-like domain protein PHLDA1 as an Aurora A substrate. PHLDA1 downregulation is a powerful prognostic predictor for breast carcinoma, which was confirmed in our study. We further show that downregulation of PHLDA1 is associated with estrogen receptor (ER) expression in breast carcinoma. Aurora A directly phosphorylates PHLDA1 leading to its degradation. PHLDA1 also negatively regulates Aurora A, thereby triggering a feedback loop. We demonstrate the underlying mechanisms by which PHLDA1 upregulation strongly antagonizes Aurora-A-mediated oncogenic pathways, thereby revealing PHLDA1 degradation as a key mechanism by which Aurora A promotes breast malignancy. Thus, not surprisingly, PHLDA1 upregulation acts synergistically with Aurora A inhibition in promoting cell death. PHLDA1 overexpression might therefore be an alternative method to modulate Aurora A deregulation in breast carcinoma. Finally, this study led to the discovery of a mutation in the Aurora A active site that renders it amenable to the chemical genetic approach. Similar mutations are required for Aurora B, suggesting that this modified approach can be extended to other kinases that have hitherto not been amenable to this methodology.

Association between blood groups and breast cancer subtype.

e11041 Background: The majority of breast carcinomas are the luminal type, which has the higher levels of estrogen receptor, tend to be low grade with a favorable prognosis. Altered glycosylation, a common feature of cancer cells, is related with both expressions of HER2/neu and ABO blood groups. The present study was designed to investigate the association between blood groups and the risk of luminal-type breast cancer. Methods: 1652 patients with breast cancer were analyzed retrospectively. Variables studied included age at diagnosis, menopausal status, estrogen, progesterone and HER2/neu receptor status, TNM stage and ABO blood type with Rh status. Results: Patient age ranged from 20 to 89 years, with a mean 49.1±11.6 years. 48.4% of patients were premenopausal and 45% were postmenopausal. Estrogen receptor (ER) was positive in 71.9%, progesterone receptor (PR) was positive in 72.6% and HER2/neu receptor was positive in 22.1% of the patients. The most frequent blood types in breast cancer were A Rh positive (28.8%), 0 Rh positive (21.3%) and B Rh positive (9.8%), respectively. According to TNM stage, patients with blood group A and 0 had significantly fewer nodal metatasis (p=0.023, p=0.004; respectively), and patients with blood group 0 had significantly smaller tumor size (p=0.048) than other blood subgroups. Patients with blood group 0 had significantly higher levels of ER (p=0.036) and PR (p=0.045). There was no association between HER2/neu status, and ABO blood group or Rh status. Conclusions: Women with breast cancer were more likely to have blood type of A and 0. Blood type of 0 blood was found to be associated with luminal-type breast cancer and an earlier tumor stage. Further studies are required to sort out the relationships between blood types and breast cancer risk and prognosis.

Loss of Annexin A1 Expression in Breast Cancer Progression

Annexin A1 (ANXA1) is a potential marker of development of breast cancer. However, previous studies of ANXA1 expression in primary breast carcinoma and lymph node metastasis have yielded conflicting results. Therefore, to accurately characterize the ANXA1 expression pattern, we used microarray analysis and matched patient samples to evaluate progressive alterations in ANXA1 protein expression during malignant transformation and metastasis. We constructed a tissue microarray using 82 pairs of primary breast cancers and lymph node metastases from archival materials. We also identified 21 cases of breast carcinoma for which a single slide contained the entire progression from benign breast tissue, carcinoma in situ, to invasive carcinoma. Immunohistochemical staining for ANXA1 and various prognostic markers was performed. Microarray analysis revealed that ANXA1 expression was lost in 79% of breast carcinomas, and there was no difference in ANXA1 expression between primary breast carcinoma and lymph node metastasis. Most ANXA1-negative tumors were positive for estrogen and progesterone receptors but negative for HER2/neu and epidermal growth factor receptor. In contrast, most ANXA1-positive tumors were negative for estrogen, progesterone, and HER2/neu. In the whole tissue sections, ANXA1 is heterogeneously expressed in benign epithelium and is lost in both in situ carcinoma and invasive carcinoma. The lack of ANXA1 expression in the majority of breast carcinomas and the early loss of ANXA1 expression in in situ carcinoma, which is maintained in both invasive and metastatic tumors, suggests a possible role for ANXA1 in the early events of malignant transformation.

In situ production of sex steroids in human breast carcinoma

It is well known that sex steroids are closely involved in the growth of human breast carcinomas, and the great majority of breast carcinomas express sex steroid receptors. In particular, recent studies have demonstrated that estrogens and androgens are locally produced and act in breast carcinoma tissues without release into plasma. Blockade of intratumoral estrogen production potentially leads to an improvement in the prognosis of invasive breast carcinoma patients, and, therefore, it is important to obtain a better understanding of sex steroid-producing enzymes in breast carcinoma. In this review, we summarize recent studies on tissue concentration of sex steroids and expression of enzymes related to intratumoral production of estrogens [aromatase, steroid sulfatase (STS), and 17beta-hydroxysteroid dehydrogenase type 1 (17betaHSD1)], and androgens (17betaHSD5 and 5alpha-reductase) in invasive and in situ (noninvasive) breast carcinomas, and discuss the significance of intratumoral production of sex steroids in breast carcinoma.

Histopathological characteristics of female breast carcinomas seen at the University of Port Harcourt Teaching Hospital, Port Harcourt, Nigeria

Breast carcinoma is an unpredictable disease in the sense that some patients may present with relatively early disease and die of widespread metastases within six months to one year, while others present with fairy advanced disease and yet survive longer. The aim of this study was to characterize breast carcinomas into prognostic groups using histological features. A total of 269 breast carcinomas in females received during a five-year period (January 1991 to December 1995 inclusive) were analyzed. Archive records (request forms and microscopic slides) of all breast malignancies diagnosed in the department of Anatomical Pathology of University of Port Harcourt Teaching Hospital were retrieved and evaluated with respect to histological type, histological grades, and mononuclear cell infiltration within the primary tumour. The modified Bloom-Richardson system of microscopic grading of breast carcinoma was used. The majority of carcinomas showed scanty or absent tubule formation (43.1%) and 59% of cases showed numerous mitotic figures. Forty-nine percent of carcinomas show poorly differentiated or anaplastic nuclei. The final tumour grade (FG) which is the summation of tubular pattern, nuclear pleomorphism and mitotic grades of each of the tumours reveals that 53% fall in FG3, 26% in FG2while only 21% fall in FG1. The majority of the breast carcinomas in this study, 58%, show scanty or absent mononuclear infiltration. The majority of breast carcinomas in this study are poorly differentiated invasive ductal carcinoma, "not otherwise specified" which exhibit high proliferation ratio and are associated with poor host cellular immune reaction. These attributes translate to poor prognosis.

Breast carcinoma in women 35 years and younger: a pathological study

To document the pathological features of breast carcinoma diagnosed in women aged 35 years or less. The files of the Department of Pathology, Singapore General Hospital, were searched for cases of breast cancer diagnosed in individuals aged 35 years or less between January 1993 and December 2004. Histological slides and pathology reports were retrieved and reviewed. Pathologic parameters of tumour size, histological grade, accompanying ductal carcinoma in situ (DCIS), lymphovascular invasion, nodal status, hormone receptor and c-erbB-2 profiles, were documented. Of 112 cases of breast cancer, 91 (81.3%) were invasive carcinomas, 17 (15.2%) pure DCIS, three (2.7%) were diagnosed on needle aspirates. No residual tumour was available for microscopic assessment in one (0.9%) patient who underwent bilateral mastectomy in our institution but had her initial surgery elsewhere. Invasive tumour size ranged from 0.3 to 11.5 cm (mean 2.7 cm, median 2.1 cm), with 84 (92.3%) infiltrative ductal, two (2.2%) lobular, two (2.2%) mucinous, two (2.2%) atypical medullary, and one (1.1%) mixed ductal-lobular. The majority were grade 3 (54 cases, 59.3%), with 24 (26.4%) grade 2 and 7 (7.7%) grade 1, while grading was not accomplished in six (6.6%) cases. Nodal status was positive in 39 (42.9%), negative in 25 (27.4%), unknown in the rest (27 cases, 29.7%). Oestrogen and progesterone receptors (ER, PR) were positive in 51 (61.4%) and 43 (51.8%) cases, respectively, out of 83 (91.2%) cases in which they were evaluated. c-erbB-2 immunostaining, carried out in 54 (59.3%) invasive cancers, showed positivity in 16 (29.6%) cases.DCIS cases ranged from 0.25 to 6.2 cm (mean 2.2 cm, median 2 cm) in size. Nuclear grade was low in seven (41.2%), intermediate in four (23.5%), and high in six (35.3%). The majority of breast carcinomas in young women are invasive, with T2 disease at presentation, and of poor histological grade. The recent rise in numbers suggests increased detection, plausibly due to improved awareness of breast disease among the younger female population. Pathogenetic causes that differ from breast carcinogenesis in older women have to be further clarified.

Frequent HIN-1 Promoter Methylation and Lack of Expression in Multiple Human Tumor Types

HIN-1 (high in normal-1) is a candidate tumor suppressor identified as a gene silenced by methylation in the majority of breast carcinomas. HIN-1 is highly expressed in the mammary gland, trachea, lung, prostate, pancreas, and salivary gland, and in the lung, its expression is primarily restricted to bronchial epithelial cells. In this report, we show that, correlating with the secretory nature of HIN-1, high levels of HIN-1 protein are detected in bronchial lavage, saliva, plasma, and serum. To determine if, similar to breast carcinomas, HIN-1 is also silenced in tumors originating from other organs with high HIN-1 expression, we analyzed its expression and promoter methylation status in lung, prostate, and pancreatic carcinomas. Nearly all prostate and a significant fraction of lung and pancreatic carcinomas showed HIN-1 hypermethylation, and the majority of lung and prostate tumors lacked HIN-1 expression. In lung carcinomas, the degree of HIN-1 methylation differed among tumor subtypes (P = 0.02), with the highest level of HIN-1 methylation observed in squamous cell carcinomas and the lowest in small cell lung cancer. In lung adenocarcinomas, the expression of HIN-1 correlated with cellular differentiation status. Hypermethylation of the HIN-1 promoter was also frequently observed in normal tissue adjacent to tumors but not in normal tissue from noncancer patients, implying that HIN-1 promoter methylation may be a marker of premalignant changes. Thus, silencing of HIN-1 expression and methylation of its promoter occurs in multiple human cancer types, suggesting that elimination of HIN-1 function may contribute to several forms of epithelial tumorigenesis.

Breast cell invasive potential relates to the myoepithelial phenotype.

On the basis of marker profile, the majority of breast carcinomas are thought to be derived from luminal epithelial cells; however, a subgroup of tumours with more mesenchymal characteristics are associated with a worse prognosis. The hypothesis of our study is that some breast carcinomas exhibit myoepithelial rather than pure mesenchymal differentiation and that acquisition of myoepithelial characteristics confers an aggressive phenotype. Pure luminal epithelial cells and fibroblasts are readily distinguished by many markers but distinguishing between myoepithelial and fibroblast cell lineages is more problematic. The markers found to be most discriminating in our study were CK14, alpha6beta4 integrin and the myoepithelial-associated desmosomal cadherin DSg3. These markers were applied to a series of breast cell lines and purified normal breast cell populations and the expression profile related to in vitro invasive behaviour. This demonstrated that expression of one or more myoepithelial markers by tumour cells (MDA MB 231, MDA MB 468, MDA MB 436) was associated with a high invasive capacity compared with cells with a pure luminal phenotype (MCF-7, T47D, ZR75). To address why myoepithelial characteristics are associated with higher invasion, the in vitro behaviour of normal myoepithelial cells and two other nontumourigenic breast cell lines (MCF-10A, HBL100) was also analysed. Primary myoepithelial cells from normal human breast exhibit a high invasive capacity when grown at low density, suggesting that invasive capacity is part of the myoepithelial phenotype. In keeping with this, both nontumourigenic cell lines exhibited features of the myoepithelial phenotype and a high invasive capacity. These results suggest that tumours that exhibit a myoepithelial phenotype may be clinically more aggressive because a high invasive capacity is intrinsic to the myoepithelial phenotype.