Discovery and Development of HDAC Inhibitors: Approaches for the Treatment of Cancer a Mini-review.

Histone deacetylase (HDAC) inhibitors have emerged as promising cancer therapeutics due to their ability to induce differentiation, cell cycle arrest, and apoptosis in cancer cells. In the present review, we have described the systemic discovery and development of HDAC inhibitors. Researchers across the globe have identified various small molecules like benzo[d][1,3]dioxol derivatives, belinostat analogs, pyrazine derivatives, quinazolin- 4-one-based derivatives, 2,4-imidazolinedione derivatives, acridine hydroxamic acid derivatives, coumarin derivatives, tetrahydroisoquinoline derivatives, thiazole-5-carboxamide, salicylamide derivatives, ß-peptoid- capped HDAC inhibitors, quinazoline derivatives, benzimidazole and benzothiazole derivatives, and ß- elemene scaffold containing HDAC inhibitors. Most of the scaffolds have shown attractive IC50 (µM) in various cell lines like HDAC1, HDAC2, HDAC6, PI3K, HeLa, MDA-MB-231, MCF-10A, MCF-7, U937, K562 and Bcr-Abl cell lines.

Clinical management of Kaposi sarcoma herpesvirus-associated diseases: an update on disease manifestations and treatment strategies.

INTRODUCTION: Kaposi sarcoma herpes virus (KSHV) is associated with several diseases including Kaposi sarcoma, a form of multicentric Castleman's disease, primary effusion lymphoma, and an inflammatory cytokine syndrome. These KSHV-associated diseases (KAD) can present with heterogenous signs and symptoms that are often associated with cytokine dysregulation that may result in multiorgan dysfunction. The inability to promptly diagnose and treat these conditions can result in long-term complications and mortality. AREAS COVERED: Existing epidemiological subtypes of existing KSHV-associated diseases, specifically Kaposi sarcoma as well as the incidence of several KSHV-associated disorders are described. We review the KSHV latent and lytic phases as they correlate with KSHV-associated diseases. Given the complicated presentations, we discuss the clinical manifestations, current diagnostic criteria, existing treatment algorithms for individual KAD, and when they occur concurrently. With emerging evidence on the virus and host interactions, we evaluate novel approaches for the treatment of KAD. An extensive literature search was conducted to support these findings. EXPERT OPINION: KSHV leads to complex and concurrent disease processes that are often underdiagnosed both in the United States and worldwide. New therapies that exist for many of these conditions focus on chemotherapy-sparing options that seek to target the underlying viral pathogenesis or immunotherapy strategies.

Granulomatous mastitis secondary to Corynebacterium requiring surgical intervention: a complicated diagnosis.

Corynebacterium species is a Gram-positive bacillus endogenous to human integument that has previously been associated with idiopathic granulomatous mastitis. The diagnosis and treatment of this bacteria may be complicated by inability to distinguish colonization from contamination and infection. We present an uncommon case of granulomatous mastitis associated with negative wound cultures requiring surgical intervention.

Long-term outcomes of pouch surveillance and risk of neoplasia in familial adenomatous polyposis.

BACKGROUND: Long-term pouch surveillance outcomes for familial adenomatous polyposis (FAP) are unknown. We aimed to quantify surveillance outcomes and to determine which of selected possible predictive factors are associated with pouch dysplasia. METHODS: Retrospective analysis of collected data on 249 patients was performed, analyzing potential risk factors for the development of adenomas or advanced lesions ( ≥ 10 mm/high grade dysplasia (HGD)/cancer) in the pouch body and cuff using Cox proportional hazards models. Kaplan-Meier analyses included landmark time-point analyses at 10 years after surgery to predict the future risk of advanced lesions. RESULTS: Of 249 patients, 76 % developed at least one pouch body adenoma, with 16 % developing an advanced pouch body lesion; 18 % developed an advanced cuff lesion. Kaplan-Meier analysis showed a 10-year lag before most advanced lesions developed; cumulative incidence of 2.8 % and 6.4 % at 10 years in the pouch body and cuff, respectively. Landmark analysis suggested the presence of adenomas prior to the 10-year point was associated with subsequent development of advanced lesions in the pouch body (hazard ratio [HR] 4.8, 95 %CI 1.6-14.1; P = 0.004) and cuff (HR 6.8, 95 %CI 2.5-18.3; P < 0.001). There were two HGD and four cancer cases in the cuff and one pouch body cancer; all cases of cancer/HGD that had prior surveillance were preceded by ≥ 10-mm adenomas. CONCLUSIONS: Pouch adenoma progression is slow and most advanced lesions occur after 10 years. HGD and cancer were rare events. Pouch phenotype in the first decade is associated with the future risk of developing advanced lesions and may guide personalized surveillance beyond 10 years.

Altered Mucosal Immune-Microbiota Interactions in Familial Adenomatous Polyposis.

INTRODUCTION: Familial adenomatous polyposis (FAP) is a condition caused by a constitutional pathogenic variant of the adenomatous polyposis coli gene that results in intestinal adenoma formation and colorectal cancer, necessitating pre-emptive colectomy. We sought to examine interaction between the mucosal immune system and commensal bacteria in FAP to test for immune dysfunction that might accelerate tumorigenesis. METHODS: Colonic biopsies were obtained from macroscopically normal mucosal tissue from 14 healthy donors and 13 patients with FAP during endoscopy or from surgical specimens. Intraepithelial and lamina propria lymphocytes were phenotyped. Intraepithelial microbes were labeled with anti-IgA/IgG and analyzed by flow cytometry. RESULTS: Proportions of resident memory CD103-expressing CD8 + and γδ T-cell receptor + intraepithelial lymphocytes were dramatically reduced in both the left and right colon of patients with FAP compared with healthy controls. In lamina propria, T cells expressed less CD103, and CD4 + CD103 + cells expressed less CD73 ectonucleotidase. IgA coating of epithelia-associated bacteria, IgA + peripheral B cells, and CD4 T-cell memory responses to commensal bacteria were increased in FAP. DISCUSSION: Loss of resident memory T cells and γδ T cells in mucosal tissue of patients with FAP accompanies intestinal microbial dysbiosis previously reported in this precancerous state and suggests impaired cellular immunity and tumor surveillance. This may lead to barrier dysfunction, possible loss of regulatory T-cell function, and excess IgA antibody secretion. Our data are the first to implicate mucosal immune dysfunction as a contributing factor in this genetically driven disease and identify potentially critical pathways in the etiology of CRC.

Fluctuating methylation clocks for cell lineage tracing at high temporal resolution in human tissues.

Molecular clocks that record cell ancestry mutate too slowly to measure the short-timescale dynamics of cell renewal in adult tissues. Here, we show that fluctuating DNA methylation marks can be used as clocks in cells where ongoing methylation and demethylation cause repeated 'flip-flops' between methylated and unmethylated states. We identify endogenous fluctuating CpG (fCpG) sites using standard methylation arrays and develop a mathematical model to quantitatively measure human adult stem cell dynamics from these data. Small intestinal crypts were inferred to contain slightly more stem cells than the colon, with slower stem cell replacement in the small intestine. Germline APC mutation increased the number of replacements per crypt. In blood, we measured rapid expansion of acute leukemia and slower growth of chronic disease. Thus, the patterns of human somatic cell birth and death are measurable with fluctuating methylation clocks (FMCs).

Presentation, management and outcomes of ileoanal pouch cancer: a single-centre experience.

AIM: This study aimed to determine the clinical presentation, management and outcomes for patients with ileoanal pouch cancer. METHOD: Patients who were diagnosed with ileoanal pouch cancer were identified from our polyposis registry (1978-2019) and operative and referral records (2006-2019). Details of presentation, endoscopic surveillance, cancer staging and management were retrieved from hospital records. RESULTS: Eighteen patients were identified (12 with ulcerative colitis, one with Crohn's disease, three with familial adenomatous polyposis [FAP], two with dual diagnosis of FAP and inflammatory bowel disease). The median time from pouch formation to cancer diagnosis was 16.5 years (range 5-34 years) and the median age of the patient at pouch cancer diagnosis was 54 years (range 35-71 years). Eleven of the 18 patients were undergoing surveillance. Four of five FAP patients developed pouch cancer whilst on surveillance. Eight patients were asymptomatic at the time of pouch cancer diagnosis. Two patients had complete clinical response following chemoradiotherapy. Fourteen patients underwent pouch excision surgery (eight with exenteration). Median survival was 54 months; however, only eight patients had outcomes available beyond 24 months follow-up. CONCLUSIONS: Pouch cancer can occur in patients despite routine surveillance and without symptoms, and survival is poor. Centralization of 'high-risk' patients who require surveillance is recommended and a low threshold for referral to centres that can provide expert investigation and management is advised.

Practical management of polyposis syndromes.

Hereditary bowel tumours are usually part of a distinct syndrome which require management of both intestinal and extra-intestinal disease. Polyposis syndromes include: Familial adenomatous polyposis, MUTYH-associated polyposis, Serrated polyposis syndrome, Peutz-Jeghers syndrome, Juvenile polyposis syndrome and PTEN-hamartomatous syndromes. Of all colorectal cancers (CRC), 5%-10% will be due to an underlying hereditary CRC syndrome. Diagnosis and management of polyposis syndromes is constantly evolving as new scientific and technological advancements are made with respect to identifying causative genes and increased sophistication of endoscopic therapy to treat polyps. This, in addition to data yielded from meticulous record-keeping by polyposis registries has helped to guide management in what are otherwise relatively rare conditions. These data help guide clinical management of patients and their 'at-risk' relatives. Diagnosis is both genetic where possible but clinical recognition is key in the absence of an identifiable causative gene. Furthermore, some syndromes can overlap which can additionally complicate diagnosis. The principle goals of polyposis management are first to manage and treat the presenting patient and then to identify 'at-risk' patients, through screening and predictive genetic testing, endoscopic surveillance to allow therapy and guide surgical prophylaxis. Due to the complexity of diagnosis and management, patients and their families should be referred to a genetics centre or a polyposis registry where dedicated management can take place.

Correction to: Buthionine sulfoximine sensitizes antihormone-resistant human breast cancer cells to estrogen-induced apoptosis.

After the publication of this work [1] an error was noticed in Fig. 3a and Fig. 5a.

Management of Slipped Gastric Bands via Creation of a De Novo Tunnel and Band Replacement: a Single-Centre Experience.

BACKGROUND: A lack of clarity remains over the optimal strategy for the management of laparoscopic adjustable gastric band (LAGB) slippage, which, although rare (around 3% in our experience), can when acute result in obstruction, gastric erosion or ischaemia. Typically, slipped bands are removed acutely. The aim of this study was to explore outcomes following immediate or delayed resiting of slipped LAGBs in a single centre, comparing simple repositioning with retunnelling and replacement. METHODS: A retrospective analysis of computerised records, notes and prospectively maintained bariatric databases was undertaken to identify all patients with a slipped LAGB in a single centre. RESULTS: Thirty-two patients required operative intervention following a diagnosis of slipped LAGB (median time from initial LAGB insertion to slippage 2.9 years). Two (6%) patients underwent band removal and 30 (94%), band revision surgery (25 immediately and five at a planned but expedited procedure).Twenty-four (77%) patients underwent insertion of a new LAGB via a de novo retrogastric tunnel, five (21%) of which required further future operative intervention; whereas, six (23%) patients underwent repositioning of the existing LAGB within the same tunnel, five (83%) of which underwent further operative intervention (log-rank test p = 0.0001). Following LAGB revision, there was no significant further change in BMI (median + 1 kg/m2; range - 13 to + 10 kg/m2). CONCLUSION: Resiting of slipped LAGBs is safe and maintains weight loss. Although a significant risk of future operative intervention remains, this can be reduced via the creation of a de novo retrogastric tunnel for band resiting.

Collagen quantification in breast tissue using a 12-wavelength near infrared spectral tomography (NIRST) system.

A portable near infrared spectral tomography (NIRST) system was adapted for breast cancer detection and treatment monitoring with improved speed of acquisition for parallel 12 wavelengths of parallel frequency-domain (FD) and continuous-wavelength (CW) measurement. Using a novel gain adjustment scheme in the Photomultiplier Tube detectors (PMTs), the data acquisition time for simultaneous acquisition involving three FD and three CW wavelengths, has been reduced from 90 to 55 seconds, while signal variation was also reduced from 2.1% to 1.1%. Tomographic images of breast collagen content have been recovered for the first time, and image reconstruction approaches with and without collagen content included have been validated in simulation studies and normal subject exams. Simulations indicate that including collagen content into the reconstruction procedure can significantly reduce the overestimation in total hemoglobin, water and lipid by 8.9µM, 1.8% and 15.8%, respectively, and underestimates in oxygen saturation by 9.5%, given an average 10% background collagen content. A breast cancer patient with invasive ductal carcinoma was imaged and the reconstructed images show that the recovered tumor/background contrast in total hemoglobin increased from 1.5 to 1.7 when collagen was included in reconstruction.

Faecal calprotectin: factors affecting levels and its potential role as a surrogate marker for risk of development of Crohn's Disease.

BACKGROUND: Faecal calprotectin (FC) is one of the most widely used non-invasive tests for the diagnosis and assessment of Crohn's disease (CD) activity. Despite this, factors other than disease activity which affect levels have not been extensively reviewed. This is of importance when using FC in the diagnostic setting but also may be of utility in studying the aetiology of disease. OBJECTIVES: Our review outlines environmental risk factors that affect FC levels influencing diagnostic accuracy and how these may be associated with risk of developing CD. FC as a surrogate marker could be used to validate risk factors established in case control studies where prospective studies are not feasible. Proof of this concept is provided by our identification of obesity as being associated with elevated FC, our subsequent confirmation of obesity as risk factor for CD and the subsequent verification in prospective studies, as well as associations of lack of physical activity and dietary fibre intake with elevated FC levels and their subsequent confirmation as risk factors in prospective studies. CONCLUSION: We believe that FC is likely to prove a useful surrogate marker for risk of developing CD. This review has given a theoretical basis for considering the epidemiological determinants of CD which to date has been missing.

An observational study of comorbidity and healthcare utilisation among HIV-positive patients aged 50 years and over.

The number of HIV-positive people aged ≥50 years is rising each year. We measured the prevalence of non-infectious illnesses and their risk factors and described healthcare use in this UK population. A cross-sectional, observational study was conducted at an outpatient HIV specialist clinic in south east England. Patients age ≥50 years were invited to complete questionnaires measuring demographics, non-infectious illnesses, medication use, lifestyle and healthcare utilisation. The response rate was 67%. Of 299 participants, 84% reported ≥1 comorbid condition and 61% reported ≥2 (multimorbidity). Most commonly reported were high cholesterol, sexual dysfunction, hypertension and depression. In multivariate analyses, age, number of years HIV-positive and duration of antiretroviral therapy remained significant predictors of comorbidity when controlling for lifestyle factors (exercise, smoking and use of recreational drugs and alcohol). Use of non-HIV healthcare services was associated with increasing comorbidity, a longer duration of HIV and recreational drug use. The majority of HIV-patients aged ≥50 years reported multiple comorbidities and this was associated with polypharmacy and increased use of non-HIV services. Further research examining the quality, safety and patient experience of healthcare is needed to inform development of services to optimally meet the needs of older HIV-positive patients.

Splenic abscess rupture postappendicectomy.

The authors present a case of splenic abscess rupture postappendicectomy. Splenic abscess is rare with a reported incidence of 0.05%-0.7%. It is extremely unusual for a splenic abscess to result in splenic rupture. Contiguous spread, in this case from postappendix perforation, can cause splenic abscess formation. Postemergency splenectomy, the patient required admission to intensive therapy unit for 5 days but made a good postoperative recovery. This case is important to report as this is a rare postoperative complication of generalised peritonitis and this case highlights that astute diagnosis and management of the deteriorating surgical patient and rapid mobilisation of theatre are lifesaving.

The effect of simultaneous peripheral excision in breast conservation upon margin status.

BACKGROUND: Negative margins in breast conservation therapy (BCT) decrease local recurrence risk. Excision may be performed via two techniques: either as a single lumpectomy specimen or as a central segment with simultaneously resected peripheral segments (PSs). There is little data directly comparing these methods for their effect on margin status. MATERIALS AND METHODS: A retrospective review of all patients undergoing BCT for invasive breast cancer was conducted to evaluate and compare the two techniques. Presentation, pathologic characteristics, surgical technique, specimen volume, and final margin status were recorded. RESULTS: Among 259 cancers in 257 women, 33 had positive margins. A single segment was removed in 69 patients, while 190 patients had 1-6 PSs simultaneously removed. By univariate analysis, smaller tumor size (P = .017) and greater numbers of segments removed (P = .01) lowered the risk of positive margins. In a multivariate model, smaller tumor size (P = .0024), lack of EIC (P = .049), and greater numbers of segments removed (P = .0061) lowered the risk of margin positivity. Despite this last predictor, the total resected specimen volume did not increase with the number of PSs removed (P = .4). There was no residual tumor in 49.2% of PSs despite a compromised primary segment margin. CONCLUSIONS: Smaller tumor size, lack of EIC, and greater numbers of simultaneous PSs excised decrease the likelihood of positive margins, despite a lack of correlation between segment numbers and excised volume. These findings suggest that excision of simultaneous PSs may assist in achieving negative margins, in part, because of avoidance of pathologic artifact.

Experimental treatment of oestrogen receptor (ER) positive breast cancer with tamoxifen and brivanib alaninate, a VEGFR-2/FGFR-1 kinase inhibitor: a potential clinical application of angiogenesis inhibitors.

PURPOSE: Tamoxifen, a selective oestrogen receptor modulator (SERM), and brivanib alaninate, a vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor, are two target specific agents that result in a substantial decrease in tumour growth when given alone. Tamoxifen activates SERM stimulated breast and endometrial tumour growth. Tamoxifen and brivanib alaninate have side-effects that can affect therapeutic outcomes. The primary goal of the current study was to evaluate the therapeutic effects of lower doses of both agents when given in combination to mice with SERM sensitive, oestrogen stimulated tumour xenografts (MCF-7 E2 tumours). Experiments were conducted to evaluate the response of SERM stimulated breast (MCF-7 Tam, MCF-7 Ral) and endometrial tumours (EnCa 101) to demonstrate the activity of brivanib alaninate in SERM resistant models. EXPERIMENTAL DESIGN: In the current study, tumour xenografts were minced and bi-transplanted into the mammary fat pads of athymic, ovariectomised mice. Preliminary experiments were conducted to determine an effective oral dose of tamoxifen and brivanib alaninate that had minimal effect on tumour growth. Doses of 125 microg of tamoxifen and 0.05 mg/g of brivanib alaninate were evaluated. An experiment was designed to evaluate the effect of the two agents together when started at the time of tumour implantation. An additional experiment was done in which tumours were already established and then treated, to obtain enough tumour tissue for molecular analysis. RESULTS: Brivanib alaninate was effective at inhibiting tumour growth in SERM sensitive (MCF-7 E2) and SERM stimulated (EnCa 101, MCF-7 Ral, MCF-7 Tam) models. The effect of the low dose drug combination as an anti-tumour strategy for SERM sensitive (MCF-7 E2) in early treatment was as effective as higher doses of either drug used alone. In established tumours, the combination is successful at decreasing tumour growth, while neither agent alone is effective. Molecular analysis revealed a decreased phosphorylation of VEGFR-2 in tumours that were treated with brivanib alaninate and an increase in VEGFA transcription to compensate for the blockade of VEGFR-2 by increasing the transcription of VEGFA. Tamoxifen increases the phosphorylation of VEGFR-2 and this effect is abrogated by brivanib alaninate. There was also increased necrosis in tumours treated with brivanib alaninate. CONCLUSION: Historically, tamoxifen has a role in blocking angiogenesis as well as the blockade of the ER. Tamoxifen and a low dose of an angiogenesis inhibitor, brivanib alaninate, can potentially be combined not only to maximise therapeutic efficacy but also to retard SERM resistant tumour growth.

New hypotheses and opportunities in endocrine therapy: amplification of oestrogen-induced apoptosis.

AIMS: To outline the progress being made in the understanding of acquired resistance to long term therapy with the selective oestrogen receptor modulators (SERMs, tamoxifen and raloxifene) and aromatase inhibitors. The question to be addressed is how we can amplify the new biology of oestrogen-induced apoptosis to create more complete responses in exhaustively antihormone treated metastatic breast cancer. METHODS AND RESULTS: Three questions are posed and addressed. (1) Do we know how oestrogen works? (2) Can we improve adjuvant antihormonal therapy? (3) Can we enhance oestrogen-induced apoptosis? The new player in oestrogen action is GPR30 and there are new drugs specific for this target to trigger apoptosis. Similarly, anti-angiogenic drugs can be integrated into adjuvant antihormone therapy or to enhance oestrogen-induced apoptosis in Phase II antihormone resistant breast cancer. The goal is to reduce the development of acquired antihormone resistance or undermine the resistance of breast cancer cells to undergo apoptosis with oestrogen respectively. Finally, drugs to reduce the synthesis of glutathione, a subcellular molecule compound associated with drug resistance, can enhance oestradiol-induced apoptosis. CONCLUSIONS: We propose an integrated approach for the rapid testing of agents to blunt survival pathways and amplify oestrogen-induced apoptosis and tumour regression in Phase II resistant metastatic breast cancer. This Pharma platform will provide rapid clinical results to predict efficacy in large scale clinical trials.

Buthionine sulfoximine sensitizes antihormone-resistant human breast cancer cells to estrogen-induced apoptosis.

INTRODUCTION: Estrogen deprivation using aromatase inhibitors is one of the standard treatments for postmenopausal women with estrogen receptor (ER)-positive breast cancer. However, one of the consequences of prolonged estrogen suppression is acquired drug resistance. Our group is interested in studying antihormone resistance and has previously reported the development of an estrogen deprived human breast cancer cell line, MCF-7:5C, which undergoes apoptosis in the presence of estradiol. In contrast, another estrogen deprived cell line, MCF-7:2A, appears to have elevated levels of glutathione (GSH) and is resistant to estradiol-induced apoptosis. In the present study, we evaluated whether buthionine sulfoximine (BSO), a potent inhibitor of glutathione (GSH) synthesis, is capable of sensitizing antihormone resistant MCF-7:2A cells to estradiol-induced apoptosis. METHODS: Estrogen deprived MCF-7:2A cells were treated with 1 nM 17beta-estradiol (E2), 100 microM BSO, or 1 nM E2 + 100 microM BSO combination in vitro, and the effects of these agents on cell growth and apoptosis were evaluated by DNA quantitation assay and annexin V and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) staining. The in vitro results of the MCF-7:2A cell line were further confirmed in vivo in a mouse xenograft model. RESULTS: Exposure of MCF-7:2A cells to 1 nM E2 plus 100 microM BSO combination for 48 to 96 h produced a sevenfold increase in apoptosis whereas the individual treatments had no significant effect on growth. Induction of apoptosis by the combination treatment of E2 plus BSO was evidenced by changes in Bcl-2 and Bax expression. The combination treatment also markedly increased phosphorylated c-Jun N-terminal kinase (JNK) levels in MCF-7:2A cells and blockade of the JNK pathway attenuated the apoptotic effect of E2 plus BSO. Our in vitro findings corroborated in vivo data from a mouse xenograft model in which daily administration of BSO either as a single agent or in combination with E2 significantly reduced tumor growth of MCF-7:2A cells. CONCLUSIONS: Our data indicates that GSH participates in retarding apoptosis in antihormone-resistant human breast cancer cells and that depletion of this molecule by BSO may be critical in predisposing resistant cells to E2-induced apoptotic cell death. We suggest that these data may form the basis of improving therapeutic strategies for the treatment of antihormone resistant ER-positive breast cancer.

Selective estrogen receptor modulators and phytoestrogens.

Scientific achievements in the last two decades have revolutionized the treatment and prevention of breast cancer. This is mainly because of targeted therapies and a better understanding of the relationship between estrogen, its receptor, and breast cancer. One of these discoveries is the use of synthetic selective estrogen modulators (SERMs) such as tamoxifen in the treatment strategy for estrogen receptor (ER)-positive breast cancer. Hundreds of thousands of lives have been saved because of this advance. Not only is tamoxifen used in the treatment strategy for patients who have breast cancer, but also for prevention in high-risk premenopausal women. Another synthetic SERM, raloxifene, which was initially used to prevent osteoporosis, is also as effective as tamoxifen for prevention in high-risk postmenopausal women. In certain regions of the world, particularly in Asia, a low incidence of breast cancer has been observed. These women have diets that are high in soy and low in fat, unlike the Western diet. Interest in the protective effects of soy derivatives has led to the research of phytoestrogens and metabolites of soy that are described by some as natural SERMs. As a result, many clinical questions have been raised as to whether phytoestrogens, which are also found in other natural foods, can protect against breast cancer. This article reviews the development and role of the more common SERMs, tamoxifen and raloxifene. In addition, this paper will also highlight the emerging studies on phytoestrogens and their similarity and dissimilarity to SERMs.