Before the advent of diagnostic imaging, palpation was one of the main methods of clinical investigation for the evaluation of tumours. Malignant tumours feel harder that benign ones and this physical property is related to their coefficient of elasticity. Direct comparison of tissue images before and after application of a force is too crude a measure of elasticity except at extremes of differences in elasticity. Analysis of the raw imaging data, which contains very much more information than can be displayed for visual perception, can detect very much smaller differences in elasticity.

The radio frequency data of returning ultrasound echoes contain much more data than appears in an ultrasound image. Comparison, of the datasets of uncompressed tissue with compressed tissue, of a region of interest allows production of a strain (elasticity) image of that same region of interest. Change in tissue which is not visible on B-mode (greyscale) imaging can now be detected with real time strain imaging which is beginning to be developed on commercial ultrasound equipment. The information obtained with strain/elasticity imaging is now showing potential in influencing management of patients with breast problems.

Tissue microarrays have rapidly become a vital tool in the analysis of protein biomarkers on large patient cohorts. Composed of hundreds of miniature histologic tissue cores taken from patient tumors and arrayed in a grid pattern, tissue microarrays have great potential for automation. However, unlike DNA/RNA expression arrays, they contain spatial information, such that successful automation requires both the ability to quantitate and localize biomarkers within the tissue. This review traces tissue microarray analysis from the simplest of systems (visual inspection) to dedicated, automated quantitative analyzers capable of localizing biomarkers to sub-cellular compartments. It focuses on the importance of automating the process of tissue microarray analysis, while commenting on the inherent problems associated with both manual and automated analysis. Finally, it discusses the future of automated tissue microarray analysis, emphasizing the many areas of development and potential improvement.

Although having increased breast density is one of the strongest risk factors for breast cancer other than increased age and having a BRCA1 or BRCA2 mutation, it is still not clearly understood what that measure of risk is reflecting biologically. It has long been presumed based on indirect evidence that breast density is an indicator of cumulative hormone, particularly estrogen, exposure throughout one's life. However, there is growing evidence that the story may not be that simple. Recent studies suggest that stromal and epithelial proliferation and interaction, and the IGH-axis may all be involved in explaining the breast density and breast cancer risk association. Clearly for breast cancer research to advance it will be necessary to think beyond the presumed association that explains breast density only through estrogen pathways.

Synchronous bilateral invasive breast cancer is a rare event. The etiology of bilateral breast cancer is uncertain, but most evidence supports independent tumors and not metastasis spread from one of the primary tumors. The prognosis of bilateral breast cancer was once thought to be poor, but recent data has suggested a similar survival for bilateral breast cancers as compared to unilateral disease.

Delivering bad news to patients being evaluated for and diagnosed with breast cancer requires a unique blend of medical knowledge, compassion, and sensitivity. Although many of the techniques involved are intuitive, one can enhance these skills by incorporating a few simple concepts into the patient encounter. By combining these with an understanding of appropriate responses to possible patient reactions to the news, one can create a more effective groundwork for the patient’s recovery on both physical and emotional levels.

Numerous studies suggest that loss of E-cadherin is necessary to induce Epithelial–mesenchymal transition (EMT) and metastasis. Snail is a major contributor to EMTs. The Snail family of zinc-finger transcription factors interact with the E-cadherin promoter to repress transcription during EMT. The present article reviews the regulation of E-cadherin and discusses recent novel insights into the molecular basis in the process of EMT.

Physicians are testing minimally invasive ablation techniques to determine if they will be acceptable substitutes for surgical removal of primary breast tumors. In radiofrequency ablation (RFA), frictional heating of the tissue is caused by the rapid movement of ions attempting to follow a high frequency alternating current moving between two electrodes. Localization of a small electrode in the tumor is accomplished under ultrasound guidance, and a larger electrode pad is placed on the outside of the body. Five pilot studies have demonstrated that RFA can effectively ablate tumors up to 3 cm in size. In addition to treating small primary tumors, RFA may also be useful for consolidation therapy after lumpectomy, for treatment of inoperable tumors in end-stage patients, for treatment of locally advanced disease as a substitute for neoadjuvant chemotherapy, and for treatment of breast cancer metastases, such as bone, liver, and kidney. Clinical trials are needed to assess treatment outcomes and to monitor the long-term fate of ablated tissue.

Available mouse models of ductal carcinoma in situ (DCIS) and BRCA1-mutation-related breast cancer are reviewed. The best validated mouse models of human DCIS are the conditional estrogen receptor α in mammary tissue (CERM) model initiated by deregulated estrogen receptor α and the serial explant mouse model initiated by p53 deficiency. At present the most useful and best validated mouse model of BRCA1-mutation-related breast cancer uses the cre-lox system to make a conditional Brca1 deletion targeted to mammary epithelial cells. The major shortcoming of the non-conditional Brca1 models is the high incidence of non-mammary tumor development. The use of mammary gland transplants or explants from these mice into nude hosts is one approach that could be used to circumvent this deficiency. Development and validation of a Brca1-mutation-related mouse model of basal cell breast cancer is an important next step.

Histone acetylation is thought to facilitate binding of transcription factors (TFs) to specific target DNA sequences by destabilizing nucleosomes bound to the promoter region of a target gene. In addition, non-histone proteins including a subset of TFs and co-activators are acetylated by p300/CBP and P/CAF. The regulation of estrogen signaling by direct estrogen receptor alpha (ERα) post-translational modification reveals a novel role for histone acetyltransferase in hormone signaling. ERα is acetylated and phosphorylated and phosphorylation occurs at multiple sites in response to kinase signaling. The finding that mutations with the ERα hinge domain lysine residues enhance hormone sensitivity suggests these residues may be involved in ligand-dependent transcriptional repression or transcriptional attenuation. Phosphorylation and acetylation of the ER regulates hormone signaling and is being assessed for a role in resistance to anti-estrogen therapy of ERα-positive patients.

Over-expression or aberrant signalling of the erbB family members epidermal growth factor receptor (EGFR) and HER2 (erbB2/neu) have been associated with the pathogenesis of the malignant phenotype. In addition, high levels of EGFR and HER2 expression have been shown to correlate with poor prognosis and also implicated in disease progression. Signal transduction inhibitors (STIs) have been developed with specifically target these receptors and include the small molecule tyrosine kinase inhibitor gefitinib (IressaTM) which targets the EGFR and the humanised monoclonal antibody trastuzumab (HerceptinTM), which has anti-tumour activity against HER2. Studies however, have indicated that de novo or acquired resistance to these agents is a major clinical problem. Cancer cells are highly adaptive and can readily switch from one receptor signalling pathway to another in order to maintain growth or cell survival, a process paradoxically, that in many instances is induced by the anti-tumour agents themselves, ultimately limiting their activity and promoting resistance. Evidence is accumulating which demonstrates that signalling interplay occurs between the EGFR/HER2 and the insulin-like growth factor -1 receptor (IGF-1R) and the article will focus on the growth factor pathway switching that occurs between these receptors which can influence the effectiveness gefitinib and trastuzumab.

Phyllodes tumors of the breast are rare fibroepithelial neoplasms with variable malignant potential. Treatment is primarily surgical; the use of radiation therapy is controversial. Here, we present the case of a 29-year-old female with a histologically malignant phyllodes tumor of the breast initially treated with wide local excision. At 18 months following surgery the patient experienced a local recurrence, which displayed sarcomatous degeneration on pathological examination. The patient subsequently underwent a total mastectomy and adjuvant radiation therapy. We discuss the decision to employ radiation therapy in the management of the patient's tumor.

Despite the fact that breast cancer is predominantly a disease of postmenopausal women, there have been no uniform recommendations for both locoregional and systemic therapy for women over 70. Until recently, older women have been excluded from clinical trials. This study is the first randomized trial that addresses the use of radiation therapy following lumpectomy in a favorable cohort of elderly women.

Treatment principles of breast cancer in males are derived from studies performed among females, while the low incidence in males has so far precluded such studies. The therapy recommendations for males therefore lack the solid evidence, frequently present for females with breast cancer. The primary breast cancer diagnosis in males is not infrequently in stage III/IV and at higher age, thereby requiring multiprofessional and multimodal management including preoperative therapy and adjuvant therapies based on the tumour’s biological characteristics and the clinical circumstances. The majority of male breast cancer tumours are oestrogen-receptor positive and adjuvant/neoadjuvant tamoxifen is therefore recommended, surgery is frequently radical mastectomy and adjuvant radiotherapy should likely be used on wider indications. Chemotherapy should be considered both in the adjuvant and metastatic setting for receptor-negative cancers and for patients with biologically aggressive disease. Trastuzumab should be offered to patients with Her-2/neu-positive disease, while the use of aromatase inhibitors is more uncertain due to differences in the hormonal environment in males.

Citation of original article:

C. Wang et al. Cancer Research 2005; 65(15): 6557–6567.

Abstract of the original article:

The cyclin D1 gene is frequently overexpressed in human breast cancer and is capable of inducing mammary tumorigenesis when overexpressed in transgenic mice. The BRCA1 breast tumor susceptibility gene product inhibits breast cancer cellular growth and the activity of several transcription factors. Herein, cyclin D1 antagonized BRCA1-mediated repression of estrogen receptor α(ERα)-dependent gene expression. Cyclin D1 repression of BRCA1 function was mediated independently of its cyclin-dependent kinase, retinoblastoma protein, or p160 (SRC-1) functions in human breast and prostate cancer cells. In vitro, cyclin D1 competed with BRCA1 for ERα binding. Cyclin D1 and BRCA1 were both capable of binding ERα in a common region of the ERα hinge domain. A novel domain of cyclin D1, predicted to form a helix-loop-helix structure, was required for binding to ERα and for rescue of BRCA1-mediated ERα transcriptional repression. In chromatin immunoprecipitation assays, 17β-estradiol (E2) enhanced ERα and cyclin D1 recruitment to an estrogen response element (ERE). Cyclin D1 expression enhanced ERα recruitment to an ERE. E2 reduced BRCA1 recruitment and BRCA1 expression inhibited E2-induced ERα recruitment at 12 h. Cyclin D1 expression antagonized BRCA1 inhibition of ERα recruitment to an ERE, providing a mechanism by which cyclin D1 antagonizes BRCA1 function at an ERE. As cyclin D1 abundance is regulated by oncogenic and mitogenic signals, the antagonism of the BRCA1-mediated ERα repression by cyclin D1 may contribute to the selective induction of BRCA1-regulated target genes.

Tissue-specific stem cells play a key role in organ homoeostasis. They are relatively well characterized in systems which undergo constant proliferation and production of differentiated cells, including the haemopoietic system, skin and intestine. However, little is known about the role and regulation of stem cells in the mammary gland. This review briefly summarizes the current understanding of the role of breast-specific stem cells in normal and cancerous tissues, and how this may identify new targets for breast cancer prevention and therapy.