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1.  Cost-Effective Screening for Breast Cancer Worldwide: Current State and Future Directions 
Affordability of healthcare is highly limited by its skyrocketing cost. Access to screening and diagnostic medical equipment and medicine in developing countries is inadequate for the majority of the population. There is a tremendous worldwide need to detect breast cancer at its earliest stage. These needs must be balanced by the ability of countries to provide breast cancer screening technology to their populations. We reviewed the diagnostic accuracy, procedure cost and cost-effectiveness of currently available technique for breast screening and diagnosis including clinical breast examination mammography, ultrasound, magnetic resonance imaging, biopsy and a new modality for cancer diagnostics termed elasticity imaging that has emerged in the last decade. Clinical results demonstrate that elasticity imaging even in its simplest and least sophisticated versions, like tactile imaging, has significant diagnostic potential comparable and exceeding that of conventional imaging techniques. In view of many countries with limited resources, effective yet less expensive modes of screening must be considered worldwide. The tactile imaging is one method that has the potential to provide cost-effective breast cancer screening and diagnostics.
PMCID: PMC2613364  PMID: 19578481
breast cancer; screening; cost-effectiveness; elastography
2.  Molecular targets of breast cancer: AKTing in concert 
Despite significant advancement in the diagnosis and treatment of breast cancer, many patients succumb to this disease. The elucidation of aberrant signaling pathways that lead to breast cancer should help develop more effective therapeutic strategies. The Akt signaling pathway plays an important role in the development and progression of breast cancer. Overexpression/activation of Akt has been associated with poor prognosis and resistance to hormonal and chemotherapy. Although mutations in Akt are rare in breast cancer, the activity of Akt is regulated by hormones, growth factors, growth factor receptors, oncogenes and tumor suppressor genes that are often deregulated in breast cancer. The objective of this commentary is to discuss recent literature on how activation of Akt by various signaling pathways contributes to breast cancer and confers resistance to current therapy.
PMCID: PMC2678835  PMID: 19430575
Akt; PTEN; mTOR; breast cancer therapy
3.  Cost-Effective Screening for Breast Cancer Worldwide: Current State and Future Directions 
Affordability of healthcare is highly limited by its skyrocketing cost. Access to screening and diagnostic medical equipment and medicine in developing countries is inadequate for the majority of the population. There is a tremendous worldwide need to detect breast cancer at its earliest stage. These needs must be balanced by the ability of countries to provide breast cancer screening technology to their populations. We reviewed the diagnostic accuracy, procedure cost and cost-effectiveness of currently available technique for breast screening and diagnosis including clinical breast examination, mammography, ultrasound, magnetic resonance imaging, biopsy and a new modality for cancer diagnostics termed elasticity imaging that has emerged in the last decade. Clinical results demonstrate that elasticity imaging even in its simplest and least sophisticated versions, like tactile imaging, has significant diagnostic potential comparable and exceeding that of conventional imaging techniques. In view of many countries with limited resources, effective yet less expensive modes of screening must be considered worldwide. The tactile imaging is one method that has the potential to provide cost-effective breast cancer screening and diagnostics.
PMCID: PMC2613364  PMID: 19578481
breast cancer; screening; cost-effectiveness; elastography
5.  A Research Agenda for Appearance Changes Due to Breast Cancer Treatment 
Breast cancer is one of the most prevalent forms of cancer in the US. It is estimated that more than 180,000 American women will be diagnosed with invasive breast cancer in 2008. Fortunately, the survival rate is relatively high and continually increasing due to improved detection techniques and treatment methods. However, maintaining quality of life is a factor often under emphasized for breast cancer survivors. Breast cancer treatments are invasive and can lead to deformation of the breast. Breast reconstruction is important for restoring the survivor’s appearance. However, more work is needed to develop technologies for quantifying surgical outcomes and understanding women’s perceptions of changes in their appearance. A method for objectively measuring breast anatomy is needed in order to help both the breast cancer survivors and their surgeons take expected changes to the survivor’s appearance into account when considering various treatment options. In the future, augmented reality tools could help surgeons reconstruct a survivor’s breasts to match her preferences as much as possible.
PMCID: PMC3085417  PMID: 21655363
breast cancer; 3D imaging of breast; computer-assisted image analysis; quality of life
6.  Tumor Microvasculature: Endothelial Leakiness and Endothelial Pore Size Distribution in a Breast Cancer Model 
Tumor endothelial leakiness is quantified in a rat mammary adenocarcinoma model using dynamic contrast enhancement MRI and contrast agents of widely varying sizes. The contrast agents were constructed to be of globular configuration and have their uptake rate into tumor interstitium be driven by the same diffusion process and limited only by the availability of endothelial pores of passable size. It was observed that the endothelial pore distribution has a steep power law dependence on size, r−β, with an exponent of −4.1. The model of large pore dominance in tumor leakiness as reported in some earlier investigation with fluorescent probes and optical chamber methods is rejected for this tumor model and a number of other tumor types including chemically induced tumors. This steep power law dependence on size is also consistent with observations on human breast cancer.
PMCID: PMC3091400  PMID: 21655376
dynamic contrast enhancement MRI; tumor endothelial leakiness; endothelial pore sizes; tumor microvasculature
7.  Podosomes and Invadopodia: Related structures with Common Protein Components that May Promote Breast Cancer Cellular Invasion 
Summary:
A rate-limiting step in breast cancer progression is acquisition of the invasive phenotype, which can precede metastasis. Expression of cell-surface proteases at the leading edge of a migrating cell provides cells with a mechanism to cross tissue barriers. A newly appreciated mechanism that may be relevant for breast cancer cell invasion is the formation of invadopodia, well-defined structures that project from the ventral membrane and promote degradation of the extracellular matrix, allowing the cell to cross a tissue barrier. Recently, there has been some controversy and discussion as to whether invadopodia, which are associated with carcinoma cells, are related to a similar structure called podosomes, which are associated with normal cells. Invadopodia and podosomes share many common characteristics, including a similar size, shape, subcellular localization and an ability to promote invasion. These two structures also share many common protein components, which we outline herein. It has been speculated that podosomes may be precursors to invadopodia and by extension both structures may be relevant to cancer cell invasion. Here, we compare and contrast the protein components of invadopodia and podosomes and discuss a potential role for these proteins and the evidence that supports a role for invadopodia and podosomes in breast cancer invasion.
PMCID: PMC3085414  PMID: 21655365
invadopodia; podosomes; invasion; breast cancer
8.  Circumareolar Mastopexy with Multiple Glandular Plications for Symmetry of the Contra-Lateral Breast, in Patients Undergoing Breast Reconstruction with Prosthesis. Experience on 50 Cases 
Summary:
4 years experience on 50 cases using the Elliott’s technique for symmetrization of the contra-lateral breast in patients undergoing breast reconstruction with an anatomical prosthesis is presented in this paper.
The Elliott’s technique with its double superior and horizontal plication is a suitable and long-lasting procedure for patients with small-moderate ptotic breast and elastic skin, who wish to have a simple procedure and an immediate result with minimal scars.
PMCID: PMC3091399  PMID: 21655375
breast reconstruction with prosthesis; symmetrization; mastopexy
9.  Molecular Targets of Breast Cancer: AKTing in Concert 
Despite significant advancement in the diagnosis and treatment of breast cancer, many patients succumb to this disease. The elucidation of aberrant signaling pathways that lead to breast cancer should help develop more effective therapeutic strategies. The Akt signaling pathway plays an important role in the development and progression of breast cancer. Overexpression/activation of Akt has been associated with poor prognosis and resistance to hormonal and chemotherapy. Although mutations in Akt are rare in breast cancer, the activity of Akt is regulated by hormones, growth factors, growth factor receptors, oncogenes and tumor suppressor genes that are often deregulated in breast cancer. The objective of this commentary is to discuss recent literature on how activation of Akt by various signaling pathways contributes to breast cancer and confers resistance to current therapy.
PMCID: PMC2678835  PMID: 19430575
Akt; PTEN; mTOR; breast cancer therapy
10.  Computer-Aided Detection of Breast Cancer – Have All Bases Been Covered? 
The use of computer-aided detection (CAD) systems in mammography has been the subject of intense research for many years. These systems have been developed with the aim of helping radiologists to detect signs of breast cancer. However, the effectiveness of CAD systems in practice has sparked recent debate. In this commentary, we argue that computer-aided detection will become an increasingly important tool for radiologists in the early detection of breast cancer, but there are some important issues that need to be given greater focus in designing CAD systems if they are to reach their full potential.
PMCID: PMC3085409  PMID: 21655364
computer-aided detection; breast cancer; mammography; radiology
11.  The Cell Surface Estrogen Receptor, G Protein- Coupled Receptor 30 (GPR30), is Markedly Down Regulated During Breast Tumorigenesis 
Background:
GPR30 is a cell surface estrogen receptor that has been shown to mediate a number of non-genomic rapid effects of estrogen and appear to balance the signaling of estrogen and growth factors. In addition, progestins appear to use GPR30 for their actions. Therefore, GPR30 could play a critical role in hormonal regulation of breast epithelial cell integrity. Deregulation of the events mediated by GPR30 could contribute to tumorigenesis.
Methods:
To understand the role of GPR30 in the deregulation of estrogen signaling processes during breast carcinogenesis, we have undertaken this study to investigate its expression at mRNA levels in tumor tissues and their matched normal tissues. We compared its expression at mRNA levels by RT quantitative real-time PCR relative to GAPDH in ERα”—positive (n = 54) and ERα”—negative (n = 45) breast cancer tissues to their matched normal tissues.
Results:
We report here, for the first time, that GPR30 mRNA levels were significantly down-regulated in cancer tissues in comparison with their matched normal tissues (p < 0.0001 by two sided paired t-test). The GPR30 expression levels were significantly lower in tumor tissues from patients (n = 29) who had lymph node metastasis in comparison with tumors from patients (n = 53) who were negative for lymph node metastasis (two sample t-test, p < 0.02), but no association was found with ERα, PR and other tumor characteristics.
Conclusions:
Down-regulation of GPR30 could contribute to breast tumorigenesis and lymph node metastasis.
PMCID: PMC3091398  PMID: 21655374
breast tumorigenesis; estrogen signaling; G protein coupled receptor 30 (GPR30); cell surface estrogen receptor and lymph node metastasis
12.  The MUC1 Cytoplasmic Tail and Tandem Repeat Domains Contribute to Mammary Oncogenesis in FVB Mice 
Background:
Though the importance of the transmembrane mucin MUC1 in mammary oncogenesis has long been recognized, the relative contributions of the cytoplasmic tail and tandem repeat domains are poorly understood.
Methods:
To address this, mouse models of mammary carcinogenesis were created expressing full-length, cytoplasmic tail-deleted, or tandem repeat-deleted MUC1 constructs.
Results:
Overexpression of full-length MUC1 resulted in tumor formation in young mice (≤12 months); however, loss of either the cytoplasmic tail or the tandem repeat domain abrogated this oncogenic capacity. Aged mice in all strains developed late-onset mammary tumors similar to those previously described for the FVB background.
Conclusions:
This study is the first spontaneous cancer model to address the relative importance of the cytoplasmic tail and tandem repeat domains to MUC1-driven mammary oncogenesis, and suggests that both of these domains are essential for tumor formation.
PMCID: PMC3091404  PMID: 21655373
MUC1; breast cancer; mouse models; cytoplasmic tail; tandem repeat; mucin
13.  G-Protein Inwardly Rectifying Potassium Channel 1 (GIRK1) Knockdown Decreases Beta-Adrenergic, MAP Kinase and Akt Signaling in the MDA-MB-453 Breast Cancer Cell Line 
Previous data from our laboratory have indicated that there is a functional link between the beta-adrenergic receptor signaling pathway and the G-protein inwardly rectifying potassium channel (GIRK1) in breast cancer cell lines and that these pathways are involved in growth regulation of these cells. To determine functionality, MDA-MB-453 breast cancer cells were stimulated with ethanol, known to open GIRK channels. Decreased GIRK1 protein levels were seen after treatment with 0.12% ethanol. In addition, serum-free media completely inhibited GIRK1 protein expression. This data indicates that there are functional GIRK channels in breast cancer cells and that these channels are involved in cellular signaling. In the present research, to further define the signaling pathways involved, we performed RNA interference (siRNA) studies. Three stealth siRNA constructs were made starting at bases 1104, 1315, and 1490 of the GIRK1 sequence. These constructs were transfected into MDA-MB-453 cells, and both RNA and protein were isolated. GIRK1, β2-adrenergic and 18S control levels were determined using real-time PCR 24 hours after transfection. All three constructs decreased GIRK1 mRNA levels. However, β2 mRNA levels were unchanged by the GIRK1 knockdown. GIRK1 protein levels were also reduced by the knockdown, and this knockdown led to decreases in beta-adrenergic, MAP kinase and Akt signaling.
PMCID: PMC3091401  PMID: 21655370
GIRK; siRNA; breast cancer; real-time PCR; MAP kinase; Akt; beta-adrenergic
14.  Comparison and Identification of Estrogen-Receptor Related Gene Expression Profiles in Breast Cancer of Different Ethnic Origins 
The interactions between genetic variants in estrogen receptor (ER) have been identified to be associated with an increased risk of breast cancer. Available evidence indicates that genetic variance within a population plays a crucial role in the occurrence of breast cancer. Thus, the comparison and identification of ER-related gene expression profiles in breast cancer of different ethnic origins could be useful for the development of genetic variant cancer therapy. In this study, we performed microarray experiment to measure the gene expression profiles of 59 Taiwanese breast cancer patients; and through comparative bioinformatics analysis against published U.K. datasets, we revealed estrogen-receptor (ER) related gene expression between Taiwanese and British patients. In addition, SNP databases and statistical analysis were used to elucidate the SNPs associated with ER status. Our microarray results indicate that the expression pattern of the 65 genes in ER+ patients was dissimilar from that of the ER- patients. Seventeen mutually exclusive genes in ER-related breast cancer of the two populations with more than one statistically significant SNP in genotype and allele frequency were identified. These 17 genes and their related SNPs may be important in population-specific ER regulation of breast cancer. This study provides a global and feasible approach to study population-unique SNPs in breast cancer of different ethnic origins.
PMCID: PMC3091396  PMID: 21655371
estrogen receptor; breast cancer; microarray; gene expression profile
15.  A Decade of Change: An Institutional Experience with Breast Surgery in 1995 and 2005 
Introduction:
With the adoption of routine screening mammography, breast cancers are being diagnosed at earlier stages, with DCIS now accouting for 22.5% of all newly diagnosed breast cancers. This has been attributed to both increased breast cancer awareness and improvements in breast imaging techniques. How have these changes, including the increased use of image-guided sampling techniques, influenced the clinical practice of breast surgery?
Methods:
The institutional pathology database was queried for all breast surgeries, including breast reconstruction, performed in 1995 and 2005. Cosmetic procedures were excluded. The results were analysed utilizing the Chi-square test.
Results:
Surgical indications changed during 10-year study period, with an increase in preoperatively diagnosed cancers undergoing definitive surgical management. ADH, and to a lesser extent, ALH, became indications for surgical excision. Fewer surgical biopsies were performed for indeterminate abnormalities on breast imaging, due to the introduction of stereotactic large core biopsy. While the rate of benign breast biopsies remained constant, there was a higher percentage of precancerous and DCIS cases in 2005. The overall rate of mastectomy decreased from 36.8% in 1995 to 14.5% in 2005. With the increase in sentinel node procedures, the rate of ALND dropped from 18.3% to 13.7%. Accompanying the increased recognition of early-stage cancers, the rate of positive ALND also decreased, from 43.3% to 25.0%.
Conclusions:
While the rate of benign breast biopsies has remained constant over a recent 10-year period, fewer diagnostic surgical image-guided biopsies were performed in 2005. A greater percentage of patients with breast cancer or preinvasive disease have these diagnoses determined before surgery. More preinvasive and Stage 0 cancers are undergoing surgical management. Earlier stage invasive cancers are being detected, reflected by the lower incidence of axillary nodal metastases.
PMCID: PMC3091402  PMID: 21655372
breast cancer; breast surgery; sentinel nodes; breast cancer trends; breast radiology
16.  Reversed Expression of the JAK/STAT Pathway Related Proteins Prolactin Receptor and STAT5a in Normal and Abnormal Breast Epithelial Cells 
The JAK/STAT pathway is important for cellular metabolism. One component, STAT5a, is activated in the breast upon prolactin to prolactin receptor (PRLR) binding facilitating the transcription of genes involved in lobule development. STAT5a was previously found to be expressed in most normal breast epithelial cells but not in many in situ or invasive carcinomas except secretory carcinomas which retain STAT5a expression. This report examines the JAK/STAT pathway in the breast through the detection of PRLR and STAT5a. Fifty breast tissues, including benign secretory change, microglandular adenosis, usual and atypical hyperplasia and in situ and invasive ductal carcinoma both usual and secretory, were obtained from the files of the Armed Forces Institute of Pathology. Sections were immunostained with antibodies to PRLR and STAT5a. PRLR was minimally detected on the surface of a few normal breast epithelial cells whereas STAT5a was greatly expressed in over 80% of normal cell nuclei. PRLR was also minimally detected in secretory carcinomas expressing STAT5a. However, the opposite pattern was seen in breast carcinomas lacking STAT5a expression. PRLR was abundantly expressed in these cells. This reversed expression may indicate a JAK/STAT pathway disturbance that could play a role in the initiation or maintenance of an abnormal breast phenotype.
PMCID: PMC3091403  PMID: 21655368
STAT5a; prolactin receptor; immunohistochemistry; breast; secretory
17.  The Reality in the Surveillance of Breast Cancer Survivors—Results of a Patient Survey 
Background:
International guidelines for the surveillance of breast cancer patients recommend a minimized clinical follow-up including routine history and physical examination and regularly scheduled mammograms. However, the abandonment of scheduled follow-up examinations in breast cancer survivors remains a contradiction to established follow-up guidelines for other solid tumours.
Patients and Methods:
We report the patients’ view on the basis of a survey performed in two separate geographical areas in Germany. The questionnaires were sent out to 2.658 patients with a history of breast cancer.
Results:
A total of 801 patients (30.1%) responded to the questionnaire. The results of the survey can be summarized in two major categories: First, necessity for surveillance was affirmed by a majority (>95%), and 47.8% of the organized patients answered that there was a need for more intensive diagnostic effort during follow-up. The main expectation from an intensified follow-up was the increased feeling of security as expressed by >80% of the women. Second, the present survey indicates that most of the regularly scheduled follow-up visits were expanded using extensive laboratory and imaging procedures exceeding the quantity of examinations recommended in the present follow-up guidelines.
Conclusion:
Despite the fact that only one third of the patients responded to the questionnaire, the survey indicates that a majority of physicians who treated these patients still do not accept the present follow-up guidelines. To some extent this may be explained by the observation that patients and possibly also their doctors trust that intensified follow-up increases diagnostic security and survival. Since considerable changes in the treatment options of breast cancer have been made during the last decades a new trial of investigations in follow-up is warranted.
PMCID: PMC3104718  PMID: 21655369
breast cancer; follow-up; guidelines; surveillance
18.  In Search of Breast Cancer Culprits: Suspecting the Suspected and the Unsuspected 
I would like to welcome breast cancer research community to the first editorial of our newest journal “Breast Cancer: Basic and Clinical Research”. In pursuit of breast cancer culprits, we have come a long way since the early 90’s when the first breast cancer susceptibility gene BRCA1 was mapped and cloned. In the past few years, several new loci associated with the various degree of breast cancer risk have been identified using “Candidate Gene Association Study (CGAS) and Genome-Wide Association Study (GWAS)” approaches. This editorial is meant to quickly glance over recent findings of these population-based association studies.
PMCID: PMC3104717  PMID: 21655367

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