Prostate‐specific antigen found in Type I breast cyst fluids is a secretory product of the apocrine cells lining breast gross cysts

Prostatespecific antigen (PSA), a serine protease thought to be exclusively produced by the prostate epithelial cells, has been recently found in human breast tissues and fluids. PSA in breast cancer is associated with the presence of steroidhormones and receptors, and its presence seems to be a favourable prognostic indicator. In order to clarify whether the cells lining breast cysts may represent the source of PSA found in human breast cyst fluid, we performed an ultrastructural immunolocalization of PSA in the cells surrounding Type I breast cysts, obtained from breast cyst fluids of women affected by breast gross cystic disease, the most commonly occurring benign breast lesions associated with increased cancer risk. These apocrine cells show morphological features typical of actively synthesizing and secreting cells, and a PSA labelling distributed on free ribosomes, RER cisternae, and secretory granules, indicating that the metabolically active apocrine cells lining the Type I cysts are responsible for the production and secretion of PSA in Type I breast cyst fluids. The synthesis and intracystic accumulation of this serine protease in biosynthetically active apocrine Type I cysts can play an important role in the natural history of breast gross cystic disease as well as in the mechanism of cyst evolution.     

Prostate specific antigen: a useful screening test?

The role of prostate specific antigen (PSA) as a screening test for prostate cancer is controversial. Proponents of screening emphasize that early detection can lead to discovery of organ-confined disease and the potential for cure. Opponents point to the lack of credible evidence that screening is associated with a decrease in mortality. In addition, population-based screening (with subsequent diagnosis and treatment in many men) can be associated with considerable morbidity and mortality in the context of a disease that is often not fatal. This report examines the limitations of PSA as a screening test and supports an approach using "verbal informed consent" to identify patients who should be tested.     

Immunohistochemical labelling for prostate–specific antigen in breast carcinomas

Immunohistochemical detection of prostate–specific antigen (PSA) is an aid in determining the prostatic origin of metastatic cells. However, small amounts of PSA have also been found in non–prostatic tissues and tumors, for example in some breast carcinomas, by highly sensitive immunofluorometric methods, but also by immunohistochemistry. Our aim was to evaluate the prevalence and prognostic value of histologically confirmed PSA immunoreactivity in breast carcinoma.Sections of formalin–fixed, paraffin–embedded samples from 171 breast carcinomas were immunostained for PSA. The staining results were compared with the mitotic activity, tumor size, histological grade, steroid receptors and follow–up data. For analysis the material was divided into subgroups according to the patients' age (pre- and postmenopausal). PSA was found by immunohistochemistry in 54 (32) breast carcinomas. In survival analysis of the whole patient material PSA positivity did not show prognostic value. Among premenopausal patients concomitant estrogen receptor and PSA–negativity proved to be associated with high risk of breast cancer death (RR 6.2), also after adjustment for tumor size, histological grade, and axillary lymph node status. Among postmenopausal patients PSA positivity was associated with progesterone receptor positivity and high differentiation but not with age, nodal status, or mitotic activity. PSA can be detected by immunohistochemistry in a considerable number of breast carcinomas. PSA immunoreactivity alone does not seem to have any value as general prognosticator of breast carcinoma patients. However, concomitant absence of PSA and estrogen receptors was an indicator of unfavourable prognosis among premenopausal patients.     

Prostate specific antigen as a clinical biomarker for prostate cancer: what's the take home message?

Prostate specific antigen (PSA) continues to be challenged as a legitimate clinical biomarker in early detection of prostate cancer due to lack of specificity for malignant transformation. Skepticism surrounding the utility of serum PSA as a clinical marker is not new and many questioned its initial use in widespread prostate cancer screening due to non-specific expression and low predictive value for cancer detection. Despite these initial concerns, serum PSA measurement along with digital rectal examination (DRE) is currently the accepted practice for prostate cancer screening in the United States with hundreds of thousands of men undergoing serum PSA measurement annually. In contrast to its role for early detection, serum PSA measurement as a surrogate for prostate cancer recurrence (biochemical failure) following curative intent therapy has consummate clinical utility in post-treatment surveillance. As thousands of men each year are aggressively treated for potentially curable prostate cancer, development of simple and effective diagnostic tools for detecting treatment failures should be an important area of biomedical and clinical investigation. We have constructed and tested a home-based prostate cancer surveillance device for use by patients to detect PSA from blood obtained by finger stick. Our initial results suggest that home based PSA testing is feasible and may have clinical utility in management of men treated for prostate cancer.     

Symptomatic suprasellar endodermal cyst, possibly originating from the Seessel’s pouch, containing fluid with a high carcinoembryonic antigen level

A 32-year-old man presented with a rapidly progressive decrease in visual acuity and diplopia. Magnetic resonance imaging (MRI) revealed a suprasellar cystic mass extending to the upper part of the clivus. The content of this cyst showed a slightly higher signal intensity than that of his cerebrospinal fluid (CSF) on T1-weighted images. The cyst stretched the pituitary stalk, but a normal pituitary signal was observed. The cyst wall was maximally resected under neuroendoscopy, which yielded fluid contents that were white and mucous like, with a carcinoembryonic antigen (CEA) level 1,400 ng/ml or higher. On light microscopy, one to two layers of epithelial cells with cylindrical nuclei on loose connective tissue lined the cyst cavity. These cells were positive for periodic acid-Schiff, CEA, and cytokeratin 7 and negative for cytokeratin 20. On electron microscopy, epithelial cells showed many short microvilli with coating material. The cytoplasm was rich in electron-dense material, and dense intercellular adhesion was observed, but neither goblet cells nor cilia were present. On the basis of MRI features, cytokeratin expression patterns and electron microscopic findings, the patient was considered to have a suprasellar endodermal cyst derived from Seessel’s pouch.     

Associations of serum 25-hydroxyvitamin D with overall and breast cancer–specific mortality in a multiethnic cohort of breast cancer survivors

Purpose

Despite limited evidence on the association of vitamin D with outcomes in breast cancer survivors, some clinicians advise breast cancer patients to use vitamin D supplements. More evidence is needed to inform these recommendations.

Methods

In the Health, Eating, Activity, and Lifestyle study, we examined associations of post-treatment serum concentrations of 25-hydroxyvitamin D (25(OH)D) on overall and breast cancer–specific mortality in 585 breast cancer survivors from western Washington State, New Mexico, and Los Angeles County. 25(OH)D was measured in stored blood collected 2 years post-enrollment. Outcomes were ascertained from the Surveillance, Epidemiology, and End Results registries and medical records. Cox proportional hazards models were fit to assess associations of serum 25(OH)D with overall and breast cancer–specific mortality.

Results

After a median follow-up of 9.2 years; 110 women died, including 48 from breast cancer. Standard cut points classified 211 (31.6 %) women as serum 25(OH)D deficient (<20 ng/mL), 189 (32.2 %) as insufficient (20–30 ng/mL), and 185 (36.2 %) as sufficient (>30 ng/mL). Compared to women with deficient 25(OH)D, those in the sufficient ranges had a decreased risk of overall mortality (age-adjusted HR = 0.58; 95 % CI 0.36–0.96); however, multivariate adjustments attenuated the association (HR = 0.90; 95 % CI 0.50–1.61). No association was found between serum 25(OH)D and breast cancer–specific mortality (sufficient: HR = 1.21; 95 % CI 0.52–2.80) in multivariate models.

Conclusion

In this breast cancer cohort, higher serum 25(OH)D may be associated with improved survival, but results were not statistically significant and must be interpreted with caution. The potential prognostic effect of vitamin D from diet, supplements, or both should be evaluated in future larger studies with additional endpoints from breast cancer patients.     

Wnt5a signaling — A new and attractive target for specific anticancer therapy

Wnt signaling has been shown to engage a multifunctional pathway that is involved in the regulation of a wide variety of normal and pathologic processes, including embryogenesis, differentiation and tumorigenesis. Recent studies have demonstrated that Wnt5a expression is frequently seen in various human cancers. In contrast to the transforming members of the Wnt family, shown to be upregulated in many cancers, the role of Wnt5a is still controversial in its expression in different tumors. There is increasing evidence that Wnt5a has tumor suppressor function in some malignancies, and in addition, it elicits promigratory and proinvasive effects via the planar cell polarity pathway, which suggests that Wnt5a might be an effective marker for the progression and prognosis of tumors. Obviously, the outcome of Wnt5a signaling is dependent on a multitude of variables, ranging from receptors, downstream effectors and inhibitors, to external influences coming from the tumor microenvironment. This review will focus on the role of Wnt5a signaling and, as a consequence, provide an outline describing the expression and functions of Wnt5a in cancer progression.     

The clinical impact of breast scintigraphy acquired with a breast specific γ-camera (BSGC) in the diagnosis of breast cancer: incremental value versus mammography

We investigated the clinical impact of breast scintigraphy acquired with a breast specific γ-camera (BSGC) in the diagnosis of breast cancer (BC) and assessed its incremental value over mammography (Mx). A consecutive series of 467 patients underwent BSGC scintigraphy for different indications: suspicious lesions on physical examination and/or on US/MRI negative at Mx (BI-RADS 1 or 3), characterization of lesions suspicious at Mx (BI-RADS 4), preoperative staging in lesions highly suggestive of malignancy at Mx (BI-RADS 5). Definitive histopathological findings were obtained in all cases after scintigraphy: 420/467 patients had BC, while 47/467 patients had benign lesions. The scintigraphic data were correlated to Mx BI-RADS category findings and to histology. The incremental value of scintigraphy over Mx was calculated. Scintigraphy was true-positive in 97.1% BC patients, detecting 96.2% of overall tumor foci, including 91.5% of carcinomas ≤10 mm, and it was true-negative in 85.1% of patients with benign lesions. Scintigraphy gave an additional value over Mx in 141/467 cases (30.2%). In particular, scintigraphy ascertained BC missed at Mx in 31 patients with BI-RADS 1 or 3, including 26 patients with heterogeneously/high dense breast (19/26 with tumors ≤10 mm) and detected additional clinically occult ipsilateral or controlateral tumor foci (all <10 mm) or the in situ component sited around invasive tumors in 77 BC patients with BI-RADS 4 or 5, changing surgical management in 18.2% of these cases; moreover, scintigraphy ruled out malignancy in 33 patients with BI-RADS 4. BSGC scintigraphy proved a highly sensitive diagnostic tool, even in small size carcinoma detection, while maintaining a high specificity. The procedure increased both the sensitivity of Mx, especially in dense breast and in multifocal/multicentric disease, and the specificity as well as it better defined local tumor extension, thus guiding the surgeon to a more appropriate surgical treatment.     

Concurrent chemoradiotherapy for locally advanced breast cancer—time for a new paradigm?

Background

In cases of locally advanced breast cancer (labc), preoperative (“neoadjuvant”) therapy was traditionally reserved to render the patient operable. More recently, neoadjuvant therapy, particularly chemotherapy, is being used in patients with operable disease to increase the opportunity for breast conservation. Despite the increasing use of preoperative chemotherapy, rates of pathologic complete response, a surrogate marker for disease-free survival, remain modest in patients with locally advanced disease and particularly so when the tumour is estrogen or progesterone receptor–positive and her2-negative. A new paradigm for labc patients is needed. In other solid tumours (for example, rectal, esophageal, and lung cancers), concurrent chemoradiotherapy (ccrt) is routinely used in neoadjuvant and adjuvant treatment protocols alike.

Results

The literature suggests that ccrt in labc patients with inoperable disease is associated with response rates higher than would be anticipated with systemic therapy alone.

Conclusions

Ongoing trials in this field are eagerly awaited to determine if ccrt should become the new paradigm.     

TrkC: a new predictive marker in breast cancer?

Available data involve neurotrophins and their receptors in carcinomas. Quantitative evaluation of these molecules in these tumors might be useful as prognostic marker and eventual treatments. Our study on 40 mammary tumors tries to correlate expression of these molecules and prognosis. Immunohistochemistry for NGF, BDNF, NT3, TrkA, TrkB, TrkC, and p75 was used. Patient's age, histopathology, Bloom-Richardson grading, estrogen and progesterone receptors, Ki-67 index, HER-2, p53 were evaluated. Statistics found inverse relationship between grading and TrkC expression. We found significantly higher TrkC expression in Grade I than in Grade III tumors. Rise in TrkC expression could indicate good prognosis.     

α-Parvin,a pseudopodial constituent,promotes cell motility and is associated with lymph node metastasis of lobular breast carcinoma

Invasive lobular carcinoma (ILC) is more frequently lymph node positive than is invasive ductal carcinoma (IDC), and ILC cell infiltration shows distinctive histological characteristics, suggesting the action of ILC-specific invasion molecules. To identify such a molecule, we used a proteomic approach in the pseudopodia of MDA-MB-231 breast cancer cells. A pseudopodial constituent was identified using excimer laser ablation, two-dimensional difference gel electrophoresis, mass spectroscopy, and immunocytofluorescence. MDA-MB-231 cells were modified to express various levels of this constituent by transient transfection and were examined for pseudopodia formation and migratory abilities using wound healing and two-chamber assays. Immunohistochemical positivity of human breast cancer cells (56 ILCs and 21 IDCs) was compared with clinicopathological variables. An actin-binding adaptor protein, α-parvin, was found to localize to pseudopodia and to form focal adhesions in cells not induced to extend pseudopodia. Pseudopodial length and density and migratory abilities correlated with α-parvin expression. Twenty-one (37.5 %) ILCs stained positive for α-parvin, whereas the results were negative for all 21 IDCs (P < 0.001). α-Parvin positivity in ILC was significantly associated with lymphatic invasion (P = 0.038) and lymph node metastasis (P = 0.003) in univariate analyses and to lymph node metastasis (P = 0.020) in multivariate analyses. α-Parvin, a pseudopodial constituent, was found to promote migration of breast cancer cells and to be expressed exclusively by ILC, suggesting that α-parvin is an ILC-specific invasion molecule that may have clinical utility as a biomarker for aggressive subsets of ILC.     

Three-dimensional in vitro tissue culture models of breast cancer — a review

Three-dimensional (3D) in vitro breast tumour models have an invaluable role in tumour biology today providing some very important insights into breast cancer. As well as increasing our understanding of homeostasis, cellular differentiation and tissue organization they provide a well defined environment for cancer research in contrast to the complex host environment of an in vivo model. With the recent availability of relevant stromal elements together with the vast array of extracellular matrix constituents available, in vivo like microenvironments can be recreated. These tissue like structures more realistically model the structural architecture and differentiated function of breast cancer than a cellular monolayer providing in vivo like responses to therapeutic agents. Three dimensional in vitro models allow the study of cell-cell and cell-extracellular matrix interactions, in addition to the influence of the microenvironment on cellular differentiation, proliferation, apoptosis and gene expression. Due to their enormous potential 3D cultures are currently being exploited by many other branches of biomedical science with therapeutically orientated studies becoming the major focus of research. In return great progress in 3D culture techniques have been made, largely due to this greater interaction. At present they are being used in studies ranging from investigating the role of adhesion molecules (e.g., E-cadherin) in invasion/metastasis; VEGF and angiogenesis, to tissue modelling and remodelling. Progress in the development of complex 3D culture systems is more productive than ever, however further research is vital.