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.

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.

Women with increased risk of breast cancer have the treatment options of chemoprevention, surveillance or prophylactic mastectomy (PM). This article will focus on PM. PM should only be undergone after a detailed risk assessment and consultation with the patient's entire medical team, including a psychologist. PM will either be bilateral or contralateral. Bilateral PM is usually recommended to women who have a genetic predisposition for breast cancer. Research has shown that PM was 98.6% effective in preventing breast cancer in BRCA1 or BRCA2 mutation carriers. Contralateral PM (CPM) is a treatment option not often recommended to women who are being treated for breast cancer. While research has shown that CPM can offer a 95% risk reduction to contralateral breast cancer recurrence, the low risk of developing a contralateral breast cancer in the first place (0.6%) means that CPM would actually offer little benefit to most patients. However, it should be noted that the efficacy of PM for patients with invasive lobular carcinoma is controversial and further research is needed. The optimal surgical technique for removing the most breast tissue is total mastectomy, while new techniques of ‘skin sparing’ mastectomy will allow a better cosmetic outcome following reconstruction.

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.

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.

Insulin-like growth factor I (IGF-I) and its main binding protein 3 (IGFBP-3) are multi-regulatory peptides important in tumour cell growth and survival. In the circulation, they occur in large quantities and are readily measured. Across a population, concentrations vary and this may impact on risk of cancers common in western societies. Emerging epidemiological evidence supports the notion that higher levels of IGF-I are associated with increased risk of pre-menopausal, but not post-menopausal, breast cancer. Higher levels of IGFBP-3 may also predict for increased risk of pre-menopausal breast cancer, but this is contrary to the conventional view that this peptide is tumour protective. Nutritional and lifestyle factors, important in breast cancer risk, also inter-relate with circulating levels of IGF-I, but in many circumstances, the relationships are complex. It is becoming increasingly important that the clinical breast oncologist understands the physiology of the IGF system and its potential role in cancer risk assessment and prevention.

The cyclooxygenase (COX) enzymes catalyse the rate-limiting step of conversion from arachidonic acid to prostaglandins (PGs). The enzyme exists in two isoforms COX-1 and COX-2. The inducible COX-2 isoform has been shown to be present in up to 80% of breast cancers, high expression correlating with low rates of apoptosis, increased angiogenesis and poor prognosis. Both non-steroidal anti-inflammatory drugs (NSAIDs) and selective inhibitors to COX-2 have been associated with anti-tumoural properties, decreasing the rates of tumour growth, increasing apoptosis and inhibiting angiogenesis. A variety of cellular mechanisms have been suggested, but the exact mechanisms of action remain unclear. COX-2 inhibitors have the potential to be used either alone, or in combination with other agents such as aromatase inhibitors (AIs), monoclonal antibodies (i.e. trastuzumab) or chemotherapeutic agents as novel therapeutic strategies against breast cancer. However the potential cardiac toxicity of the COX-2 selective compounds needs to be fully addressed, with the future development of either safe dosing regimes or new compounds.

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.

The estrogen receptor-alpha (ER-α) is a Type I nuclear receptor that is over-expressed in the majority of human breast cancers and plays a significant role in the development and progression of these cancers. As estrogen plays important roles in the etiology of breast cancer and the growth of established ER-α expressing cancers, intense interest has been generated in understanding the mechanisms by which ER-α signaling is regulated physiologically and using this knowledge to develop interventions to inhibit ER-α signaling. These efforts have met with some success in the development of pharmacologic agents that can reduce breast cancer risk, prevent recurrence of established cancers, and treat advanced cancers with considerably less side effects than cytotoxic chemotherapy. Here, we will review some of the mechanisms that operate to inhibit ER-α signaling and describe how pharmacologic agents and dietary factors interact with ER-α to block its activity. In the process of reviewing these mechanisms, we will highlight their clinical implications.

With advanced detection methods now allowing cancers to be found at earlier and earlier stages, new treatment methods to deal with these early stage cancers are also emerging. Radioguided occult lesion localisation (ROLL), a technique pioneered in 1996, is a useful method for localisation of impalpable breast tumours with results superior to those obtained by wire localisation and comparable to those achieved by surgery of palpable lesions. ROLL allows for the precise localisation necessary to optimise the cosmetic outcome in breast conserving surgery without jeopardising sufficient free tissue margins. ROLL can also be used in conjunction with sentinel node biopsy (SNB) using either the same or different radioactive tracer. For all these reasons, ROLL is an important development in breast cancer treatment.

Breast cancer is one of the leading causes of cancer mortality in women in developed countries even though most women with the disease die of other causes. Postoperative adjuvant chemotherapy with anthracycline-based regimens has been proven to decrease the risk of relapse and cancer-related mortality in women with early stage breast cancer contributing to the improving survival seen with this disease. The taxanes have been effective additions to several adjuvant regimens based on recent prospective randomized studies. In the quest to further improve outcomes with adjuvant chemotherapy, dose and schedule modifications based on kinetic models have been compared with standard regimens. In this paper we review of several key trials testing a specific modification called ‘dose-dense’ chemotherapy.

Although much has been written about overdiagnosis in mammographical screening, analytical estimates of the extent of overdiagnosis are rare in the literature. Estimates specific to ductal carcinoma in situ (DCIS) and the implications for future invasive disease are even more difficult to find. In this paper, we review studies of incidence of DCIS within breast screening programmes and its association with subsequent incidence of invasive breast cancer. Although sparse, published results suggest that the majority of DCIS cases have the propensity to progress to invasive disease.

Chemoprevention with tamoxifen and oophorectomy are thought to be effective in decreasing the incidence of breast cancer in women at increased risk for the disease. There is mounting data supporting the idea that hormonal interventions that reduce estrogen exposure to breast epithelium, such as prophylactic oophorectomy and tamoxifen, are effective in breast cancer prevention in both BRCA1 and BRCA2 mutations carriers. Several recent studies directly address the protective effect of tamoxifen and oophorectomy in BRCA mutation carriers and suggest that these endocrine manipulations decrease the risk of primary and secondary breast cancers. Ongoing studies aim to better define the effect of tamoxifen in these very high-risk women and determining whether factors, such as earlier age of use or prior prophylactic oophorectomy, impact tamoxifen's effect. Based on existing data, we recommend that women with deleterious mutations in BRCA1 or BRCA2 be informed of the beneficial effect of oophorectomy on breast cancer risk and that women who choose breast cancer screening instead of prophylactic mastectomy be offered tamoxifen as a prevention option.

Endocrine adjuvant therapy for breast cancer has been associated with a decrease in bone mineral density (BMD) and bone loss. For aromatase inhibitors, this bone loss is likely to be the most significant limitation to their long-term use. Treatments traditionally used to counteract his effect include exercise and supplementation with calcium and vitamin D. A newer treatment is the use of bisphosphonates, a class of drugs that reduce osteoclast activity. Clinical trials currently underway to examine the effect of bisphosphonate treatment on breast cancer patients have shown improvement in bone strength. Additional benefits of bisphosphonates, currently under study, give this class of drugs an important role to play in the treatment of cancer treatment-induced bone loss.

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.

There is an established increased risk of secondary malignancy following radiation therapy for cancer in childhood or as a young adult. Breast cancer poses a particular problem as the population risk is significant and screening methods are available raising the question of possible screening interventions for women who are at high lifetime risk.

Historical assumptions concerning the optimal fractionation schedules for women with breast cancer are being challenged by the early results of randomised clinical trials. Multiple small fractions of 2.0 Gy or less are optimal for squamous cell carcinomas, which are clearly less sensitive to fraction size than the surrounding dose-limiting normal tissues. Breast cancer may be different in showing comparable sensitivity to fraction size as the healthy tissues of the breast and underlying ribcage. If this is confirmed, it means that fewer, larger fractions confer the same benefit as standard 2.0 Gy schedules, provided appropriate downward corrections are made to the total dose. The approach also lends itself to tests of acceleration, shorter treatment times being of obvious interest to patients and possibly of therapeutic benefit in their own right.

Bone metastases frequently occur in advanced breast cancer patients and once incorporated into bone have profound effects on bone physiology. Bisphosphonates are potent inhibitors of osteoclastic function and are becoming increasingly important for the management of patients with breast cancer. They affect the ability of cancer cells to accelerate bone turnover and as a result control pain and reduce the risk of pathological fracture.

Furthermore ongoing clinical trials are investigating the role of bisphosphonates as an adjuvant therapy in high-risk breast cancer patients with an aim to prevent bone metastasis.

This article reviews the mechanisms of bone metastasis and will discuss present and future developments for the monitoring and treatment of metastatic bone disease.