Disulfiram/copper complex inhibiting NFκB activity and potentiating cytotoxic effect of gemcitabine on colon and breast cancer cell lines

Most of the gemcitabine (dFdC) resistant cell lines manifested high NF?B activity. The NF?B activity can be induced by dFdC and 5-FU exposure. The chemosensitizing effect of disulfiram (DS), an anti-alcoholism drug and NF?B inhibitor, and copper (Cu) on the chemoresistant cell lines was examined. The DS/Cu complex significantly enhanced the cytotoxicity of dFdC (resistant cells: 12.2–1085-fold) and completely reversed the dFdC resistance in the resitant cell lines. The dFdC-induced NF?B activity was markedly inhibited by DS/Cu complex. The data from this study indicated that DS may be used in clinic to improve the therapeutic effect of dFdC in breast and colon cancer patients.

Structural and Functional Analysis of the Caspase –dependent and –independent Domains of the X-linked Inhibitor of Apoptosis Protein in Inflammatory Breast Cancer Tumor Biology

Inflammatory breast cancer (IBC) is an extremely rare but highly aggressive form of breast cancer characterized by the rapid development of therapeutic resistance leading to particularly poor survival. Our previous work focused on the elucidation of factors that mediate therapeutic resistance in IBC and identified increased expression of the anti-apoptotic protein, X-linked inhibitor of apoptosis protein (XIAP), to correlate with the development of resistance to chemotherapeutics. Although XIAP is classically thought of as an inhibitor of caspase activation, multiple studies have revealed that XIAP can also function as a signaling intermediate in numerous pathways. Based on preliminary evidence revealing high expression of XIAP in pre-treatment IBC cells rather than only subsequent to the development of resistance, we hypothesized that XIAP could play an important signaling role in IBC pathobiology outside of its heavily published apoptotic inhibition function. Further, based on our discovery of inhibition of chemotherapeutic efficacy, we postulated that XIAP overexpression might also play a role in resistance to other forms of therapy, such as immunotherapy. Finally, we posited that targeting of specific redox adaptive mechanisms, which are observed to be a significant barrier to successful treatment of IBC, could overcome therapeutic resistance and enhance the efficacy of chemo-, radio-, and immuno- therapies. To address these hypotheses our objectives were: 1. to determine a role for XIAP in IBC pathobiology and to elucidate the upstream regulators and downstream effectors of XIAP; 2. to evaluate and describe a role for XIAP in the inhibition of immunotherapy; and 3. to develop and characterize novel redox modulatory strategies that target identified mechanisms to prevent or reverse therapeutic resistance.

Using various genomic and proteomic approaches, combined with analysis of cellular viability, proliferation, and growth parameters both in vitro and in vivo, we demonstrate that XIAP plays a central role in both IBC pathobiology in a manner mostly independent of its role as a caspase-binding protein. Modulation of XIAP expression in cells derived from patients prior to any therapeutic intervention significantly altered key aspects IBC biology including, but not limited to: IBC-specific gene signatures; the tumorigenic capacity of tumor cells; and the metastatic phenotype of IBC, all of which are revealed to functionally hinge on XIAP-mediated NFκB activation, a robust molecular determinant of IBC. Identification of the mechanism of XIAP-mediated NFκB activation led to the characterization of novel peptide-based antagonist which was further used to identify that increased NFκB activation was responsible for redox adaptation previously observed in therapy-resistant IBC cells. Lastly, we describe the targeting of this XIAP-NFκB-ROS axis using a novel redox modulatory strategy both in vitro and in vivo. Together, the data presented here characterize a novel and crucial role for XIAP both in therapeutic resistance and the pathobiology of IBC; these results confirm our previous work in acquired therapeutic resistance and establish the feasibility of targeting XIAP-NFκB and the redox adaptive phenotype of IBC as a means to enhance survival of patients.

Lost in Translation? Russian Media Portrayals and Laypersons’ Interpretations of Angelina Jolie’s Breast Cancer Discourse

In May 2013, Angelina Jolie revealed that because she had a family history of breast and ovarian cancer and carried a rare BRCA gene mutation, she had undergone a preventive double mastectomy. Media coverage has been extensive around the world, including in Russia, not an English-language country, where all global news is inevitably filtered by translation. After examining the reactions of Russian mass media and members of the public to Jolie’s disclosure, I consider what transformations have occurred with Jolie’s message in the process of cross-cultural transfer. I explore the mass media portrayal of Jolie’s announcement, laypersons’ immediate and prolonged reactions, and the reflections of patients involved directly in the field of hereditary breast cancer. To my knowledge, this multifaceted and bilingual project is the first conceptualization of Jolie’s story as it has been translated in a different sociocultural environment. I start with examination of offline and online publications that appeared in Russia within two months after Jolie’s announcement. In this part of my analysis, I conceptualize the representation of Jolie’s case in Russian mass media and grasp what sociocultural waves were generated by this case among general lay audiences. Another part of my study contains the results of qualitative in-depth interviews. Eight women with a family history of hereditary breast cancer were recruited to participate in the research. The findings represent Jolie’s case through the eyes of Russian women with the same gene mutation as Jolie. Consolidating my findings, I argue that Jolie’s announcement was misinterpreted and misrepresented by Russian mass media, as well as misunderstood by a considerable part of the media audience. Jolie’s perspective on hereditary breast cancer mostly remained unheard among members of the Russian public. I make suggestions about the reasons for such a phenomenon, and demonstrate how Jolie’s case is implicated in politics, economics, and the culture of contemporary Russia.

Effects of a positive emotion-based adjuvant psychological therapy in colorectal cancer patients: a pilot study

Objective: To examine the effectiveness of an “Enhancing Positive Emotions Procedure” (EPEP) based on positive psychology and cognitive behavioral therapy in relieving distress at the time of adjuvant chemotherapy treatment in colorectal cancer patients (CRC). It is expected that EPEP will increase quality of life and positive affect in CRC patients during chemotherapy treatment intervention and at 1 month follow-up.Method: A group of 24 CRC patients received the EPEP procedure (intervention group), whereas another group of 20 CRC patients did not receive the EPEP (control group). Quality of life (EORTC-QLQC30), and mood (PANAS) were assessed in three moments: prior to enter the study (T1), at the end of the time required to apply the EPEP (T2, 6 weeks after T1), and, at follow-up (T3, one-month after T2). Patient’s assessments of the EPEP (improving in mood states, and significance of the attention received) were assessed with Lickert scales.Results: Insomnia was reduced in the intervention group. Treatment group had better scores on positive affect although there were no significantly differences between groups and over time. There was a trend to better scores at T2 and T3 for the intervention group on global health status, physical, role, and social functioning scales. Patients stated that positive mood was enhanced and that EPEP was an important resource.Conclusions: CRC patients receiving EPEP during chemotherapy believed that this intervention was important. Furthermore, EPEP seems to improve positive affect and quality of life. EPEP has potential benefits, and its implementation to CRC patients should be considered.

Late cardiac effects of chemotherapy in breast cancer survivors treated with adjuvant doxorubicin: 10-year follow-up

Doxorubicin (Dox), a mainstay of adjuvant breast cancer treatment, is associated with cardiac toxicity in the form of left ventricular dysfunction (LVD), LV diastolic dysfunction, or LV systolic dysfunction. Study objectives were to evaluate the prevalence of LVD in long-term breast cancer survivors treated with Dox and determine if brain-type natriuretic peptide (BNP) may help identify patients at risk for LVD. Patients who participated in prospective clinical trials of adjuvant Dox-based chemotherapy for breast cancer with a baseline left ventricular (LV) ejection fraction evaluation from 1999 to 2006 were retrospectively identified from the St Vincent's University Hospital database. Patients were invited to undergo transthoracic echocardiography, BNP analysis, and cardiovascular (CV) risk factor assessment. LVDD was defined as left atrial volume index >34 mL/m(2) and/or lateral wall E prime <10 m/s, and LVSD as LVEF <50 %. Of 212 patients identified, 154 participated, 19 patients had died (no cardiac deaths), and 39 declined. Mean age was 60.7 [55:67] years. A majority of the patients (128, 83 %) had low CV risk (0/1 risk factors), 21 (13.6 %) had 2 RFs, and 5 (3.2 %) ≥3 RFs. BMI was 27.2 ± 4.9 kg/m(2). Median Dox dose was 240 mg/m(2) [225-298]; 92 patients (59.7 %) received ≤240 mg/m(2) and 62 (40.3 %) > 240 mg/m(2). Baseline LVEF was 68.2 ± 8 %. At follow-up of 10.8 ± 2.2 years, LVEF was 64.4 ± 6 %. Three (1.9 %) subjects had LVEF <50 % and one (0.7 %) had LVDD. Dox >240 mg/m2 was associated with any LVEF drop. BNP levels at follow-up were 20.3 pg/ml [9.9-36.5] and 21.1 pg/ml [9.8-37.7] in those without LVD and 61.5 pg/ml [50-68.4] in those with LVD (p = 0.04). Long-term prospective data describing the impact of Dox on cardiotoxicity are sparse. At over 10 years of follow-up, decreases in LVEF are common, and dose related, but LVD as defined is infrequent (2.6 %). Monitoring with BNP for subclinical LVD needs further evaluation.

ARB: Phase II window of opportunity study of short-term preoperative treatment with enzalutamide in ER-positive and triple-negative breast cancer

The androgen receptor (AR) is expressed in 60-80% of breast cancers (BC) across all molecular phenotypes, with a higher incidence in oestrogen receptor positive (ER+) BC compared to ER negative tumours. In ER+ disease, AR-expression has been linked to endocrine resistance which might be reversed with combined treatment targeting ER and AR. In triple negative BCs (TNBC), preclinical and clinical investigations have described a subset of patients that express the AR and are sensitive to androgen blockade, providing a novel therapeutic target. Enzalutamide, a potent 2nd generation anti-androgen, has demonstrated substantial preclinical and clinical anti-tumour activity in AR+ breast cancer. Short-term preoperative window of opportunity studies are a validated strategy for novel treatments to provide proof-of-concept and define the most appropriate patient population by directly assessing treatment effects in tumour tissue before and after treatment. The ARB study aims to assess the anti-tumour effects of enzalutamide in early ER+ breast cancer and TNBC, to identify the optimal target population for further studies and to directly explore the biologic effects of enzalutamide on BC and stromal cells. Methods: ARB is an international, investigator sponsored WOO phase II study in women with newly diagnosed primary ER+ BC or AR+ TNBC of ≥ 1cm. The study has two cohorts. In the ER+ cohort, postmenopausal patients will be randomised 2:1 to receive either enzalutamide (160mg OD) plus exemestane (50mg OD) or exemestane (25mg OD). In the TNBC cohort, AR+ will receive single agent treatment with enzalutamide (160mg OD). Study treatment is planned for 15–29 days, followed by surgery or neo-adjuvant therapy. Tissue and blood samples are collected before treatment and on the last day of study treatment. The primary endpoint is inhibition of tumour-cell proliferation, as measured by change in Ki67 expression, determined centrally by 2 investigators. Secondary endpoints include induction of apoptosis (Caspase3), circulating hormone levels and safety. ARB aims to recruit ≈235 patients from ≈40 sites in the UK, Germany, Spain and USA. The study is open to recruitment.

Breast cancer outcomes following predictive BRCA testing in Northern Ireland

Objectives: Since 1995, BRCA testing has identified 445 women in Northern Ireland who carry a pathogenic BRCA1/2 mutation, without breast cancer (bca) at testing. This study examined outcomes with reference to management, bca risk, and incidence following positive predictive testing. Methods: Patients were identified from the regional genetics database. Electronic clinical records were used to obtain management and outcome details. Median follow-up was to bca diagnosis, risk-reducing mastectomy (rrm), death, or last follow-up. Results: 169 women had a BRCA1 mutation, and 276 BRCA2. ■ BRCA1 cohort: Median follow-up post-testing was 3 years. 56 Women (33%) had rrm, and 12 are awaiting rrm (total 68, 40%) at a median age of 36 years. 12 Women (7%) developed bca, at a median of 2 years following testing. 4 Women were diagnosed with bcas incidentally at rrm. 7 Patients had bilateral mastectomies following a cancer diagnosis. 1 Woman developed bca following rrm (1.7%). Three deaths were reported: 1 breast cancer (1.7%), 1 ovarian cancer (1.7%), and 1 with no recorded breast/ovarian cancer diagnosis. ■ BRCA2 cohort: Median follow-up post-testing was 6 years. rrm was carried out in 75 women (27%), with 20 awaiting rrm (total 95, 35%); median age: 39 years. 16 Women developed bca (5.8%), at a median of 5 years from testing. 6 Women were diagnosed with cancer incidentally at rrm; 9 women had bilateral mastectomy following diagnosis, and 1 developed bca following rrm (1.3%). Five deaths were reported: 1 bca, 1 ovarian cancer, and 3 with no recorded breast/ovarian cancer diagnosis. Conclusions: The uptake of rrm following predictive BRCA testing in Northern Ireland is comparable with that reported elsewhere. The incidence of bca following rrm is low (<2%) in our cohort, with low breast and ovarian cancer–specific mortality following positive predictive testing.

HER2 in high-risk rectal cancer patients treated in EXPERT-C, a randomized phase II trial of neoadjuvant capecitabine and oxaliplatin (CAPOX) and chemoradiotherapy (CRT) with or without cetuximab.

BACKGROUND: HER2 is an established therapeutic target in breast and gastric cancers. The role of HER2 in rectal cancer is unclear, as conflicting data on the prevalence of HER2 expression in this disease have been reported. We evaluated the prevalence of HER2 and its impact on the outcome of high-risk rectal cancer patients treated with neoadjuvant CAPOX and CRT±cetuximab in the EXPERT-C trial. PATIENTS AND METHODS: Eligible patients with available tumour tissue for HER2 analysis were included. HER2 expression was determined by immunohistochemistry (IHC) in pre-treatment biopsies and/or surgical specimens (score 0-3+). Immunostaining was scored according to the consensus panel recommendations on HER2 scoring for gastric cancer. Tumours with equivocal IHC result (2+) were tested for HER2 amplification by D-ISH. Tumours with IHC 3+ or D-ISH ratio ≥2.0 were classified as HER2+. The impact of HER2 on primary and secondary end points of the study was analysed. RESULTS: Of 164 eligible study patients, 104 (63%) biopsy and 114 (69%) surgical specimens were available for analysis. Only 3 of 104 (2.9%) and 3 of 114 (2.6%) were HER2+, respectively. In 77 patients with paired specimens, concordance for HER2 status was found in 74 (96%). Overall, 141 patients were assessable for HER2 and 6 out of 141 (4.3%) had HER2 overexpression and/or amplification. The median follow-up was 58.6 months. HER2 was not associated with a difference in the outcome for any of the study end points, including in the subset of 90 KRAS/BRAF wild-type patients treated±cetuximab. CONCLUSIONS: Based on the low prevalence of expression as recorded in the EXPERT-C trial, HER2 does not appear to represent a useful therapeutic target in high-risk rectal cancer. However, the role of HER2 as a potential predictive biomarker of resistance to anti-EGFR-based treatments and a therapeutic target in anti-EGFR refractory metastatic colorectal cancer (CRC) warrants further investigation. TRIAL REGISTRATION: ISRCTN Register: 99828560.

Activation of STING-Dependent Innate Immune Signaling By S-Phase-Specific DNA Damage in Breast Cancer

BACKGROUND: Previously we identified a DNA damage response-deficient (DDRD) molecular subtype within breast cancer. A 44-gene assay identifying this subtype was validated as predicting benefit from DNA-damaging chemotherapy. This subtype was defined by interferon signaling. In this study, we address the mechanism of this immune response and its possible clinical significance.

METHODS: We used immunohistochemistry (IHC) to characterize immune infiltration in 184 breast cancer samples, of which 65 were within the DDRD subtype. Isogenic cell lines, which represent DDRD-positive and -negative, were used to study the effects of chemokine release on peripheral blood mononuclear cell (PBMC) migration and the mechanism of immune signaling activation. Finally, we studied the association between the DDRD subtype and expression of the immune-checkpoint protein PD-L1 as detected by IHC. All statistical tests were two-sided.

RESULTS: We found that DDRD breast tumors were associated with CD4+ and CD8+ lymphocytic infiltration (Fisher's exact test P < .001) and that DDRD cells expressed the chemokines CXCL10 and CCL5 3.5- to 11.9-fold more than DNA damage response-proficient cells (P < .01). Conditioned medium from DDRD cells statistically significantly attracted PBMCs when compared with medium from DNA damage response-proficient cells (P < .05), and this was dependent on CXCL10 and CCL5. DDRD cells demonstrated increased cytosolic DNA and constitutive activation of the viral response cGAS/STING/TBK1/IRF3 pathway. Importantly, this pathway was activated in a cell cycle-specific manner. Finally, we demonstrated that S-phase DNA damage activated expression of PD-L1 in a STING-dependent manner.

CONCLUSIONS: We propose a novel mechanism of immune infiltration in DDRD tumors, independent of neoantigen production. Activation of this pathway and associated PD-L1 expression may explain the paradoxical lack of T-cell-mediated cytotoxicity observed in DDRD tumors. We provide a rationale for exploration of DDRD in the stratification of patients for immune checkpoint-based therapies.

A Qualitative Assessment of Breast Cancer Advocates in Bolivia, Colombia, Ecuador and Peru

Thesis (Master's)--University of Washington, 2016-06

Toll-like receptor 9 in breast cancer

The innate immune system recognizes microbial features leading to the activation of the adaptive immune system. The role of Toll-like receptor 9 (TLR9) is to recognize microbial DNA. In addition to immune cells, TLR9 is widely expressed in breast cancer in addition to other cancers. Breast cancer is the most common cancer in women, affecting approximately one in eight in industrialized countries. In the clinical setting, breast cancer is divided into three clinical subtypes with type-specific treatments. These subtypes are estrogen receptor (ER)-positive, HER2-positive and triple-negative (TNBC) breast cancer. TNBC is the most aggressive subtype that can be further divided into several subtypes. TNBC tumors lack ER, progesterone receptor and HER2 receptor. Therefore, the current clinically used targeted therapies are not suitable for TNBC treatment as TNBC is a collection of diseases rather than one entity. Some TNBC patients are cured with standard chemotherapy, while others rapidly die due to the disease. There are no clinically used iomarkers which would help in predicting which patients respond to chemotherapy. During this thesis project, we discovered a novel good-prognosis TNBC subtype. These tumors have high TLR9 expression levels. Our findings suggest that TLR9 screening in TNBC patient populations might help to identify the patients that are at the highest risk regarding a relapse. To gain better understanding on the role of TLR9 in TNBC, we developed an animal model which mimicks this disease. We discovered that suppression of TLR9 expression in TNBC cells increases their invasive properties in hypoxia. In line with the clinical findings, TNBC cells with low TLR9 expression also formed more aggressive tumors in vivo. TLR9 expression did not, however, affect TNBC tumor responses to doxorubicin. Our results suggest that tumor TLR9 expression may affect chemotherapyrelated immune responses, however, this requires further investigation. Our other findings revealed that DNA released by chemotherapy-killed cells induces TLR9-mediated invasion in living cancer cells. Normally, extracellular self-DNA is degraded by enzymes, but during massive cell death, for example during chemotherapy, the degradation machinery may be exhausted and self-DNA is taken up into living cells activating TLR9. We also discovered that the malaria drug chloroquine, an inhibitor of autophagy and TLR9 signalling does not inhibit TNBC growth in vivo, independently of the TLR9 status. Finally, we found that ERα as well as the sex hormones estrogen and testosterone regulate TLR9 expression and activity in breast cancer cells in vitro. As a conclusion, we suggest that TLR9 is a potential biomarker in TNBC. ------- Sisäsyntyisen immuniteetin tehtävä on tunnistaa mikrobien molekyylirakenteita, mikä saa aikaan adaptiivisen immuunijärjestelmän aktivoitumisen. Tollin kaltainen reseptori 9 (TLR9) on dna:ta tunnistava sisäsyntyisen immuniteetin reseptori, jota ilmennetään myös useissa syövissä, kuten rintasyövässä. Rintasyöpä on naisten yleisin syöpä, johon joka kahdeksas nainen sairastuu elämänsä aikana. Kliinisesti rintasyöpä jaotellaan kolmeen alatyyppiin, joista kolmoisnegatiivinen rintasyöpä on aggressiivisin. Tämän tyypin syövät eivät ilmennä hormonireseptoreja (estrogeeni- ja progesteronireseptori) tai HER2-reseptoria. Tästä johtuen kolmoisnegatiivisten potilaiden hoitoon ei voida käyttää rintasyövän nykyisten hoitosuositusten mukaisia täsmähoitoja. Kolmoisnegatiivinen rintasyöpä ei kuitenkaan ole yksi sairaus, koska molekyylitasolla sen on osoitettu koostuvan lukuisista, biologialtaan erilaisista syöpämuodoista. Tällä hetkellä kliinisessä käytössä ei ole biomarkkeria, jonka avulla kolmoisnegatiivisen rintasyövän alatyypit voisi erottaa toisistaan. Löysimme uuden kolmoisnegatiivisen syövän alatyypin, joka ilmentää vain vähän TLR9-proteiinia. Tällä alatyypillä on erittäin huono ennuste ja tulostemme perusteella TRL9-tason selvittäminen voisi seuloa huonoennusteiset syövät kolmoisnegatiivisten syöpien joukosta. Kehitimme eläinmallin, jolla voidaan tutkia matalan ja korkean TLR9-tason vaikutuksia kolmoisnegatiivisten kasvainten hoitovasteeseen. Toinen löytömme oli, että kemoterapialla tapettujen syöpäsolujen dna saa aikaan elävien syöpäsolujen TLR9-välitteistä invaasiota. Normaalisti entsyymit hajoittavat yksilön oman solunulkoisen dna:n. Erikoistilanteissa, kuten syöpähoitojen yhteydessä, jolloin solukuolema on massiivista, elimistön oma koneisto ei ehdi tuhoamaan solunulkoista dna:ta ja sitä voi kertyä eläviin soluihin, joissa se aktivoi TLR9:n. Kolmanneksi havaitsimme, että malarialääke klorokiini, joka estää TLR9:n toimintaa ja jolla on syövänvastaisia vaikutuksia soluviljelyolosuhteissa, ei estänyt TLR9-positiivisten tai TLR9-negatiivisten kasvainten kasvua käyttämässämme eläinmallissa. Neljänneksi soluviljelykokeittemme tulokset osoittivat, että sukupuolihormonit estrogeeni ja testosteroni sekä estrogeenireseptori osallistuvat TLR9:n ilmentymisen ja aktiivisuuden säätelyyn. Tuloksemme osoittavat, että TLR9 potentiaalinen biomarkkeri kolmoisnegatiivisessa rintasyövässä.

Potential Therapeutic Targets in Triple Negative Breast Cancer

Triple negative breast cancers (TNBC) are often described as biologically aggressive tumors, with poorer survival compared to other breast cancer subtypes. The fact that TNBC lacks an obvious target like estrogen receptor and HER2 represents a major challenge in the management of these patients. Genomic analyses have revealed that TNBC comprises a diverse group of cancers, which have distinct molecular profiles and different prognosis. These studies also highlighted molecular aberrations that could serve as potential treatment targets. On the other hand, a high percentage of TNBCs express some important surface receptors that have been already exploited in the development of promising targeted therapies, which are currently tested in clinical trials. In this review, we will provide an overview on the molecular diversity of TNBC with special emphasis on the evolving role of some potential biomarkers that may be utilized in the near future.

Pathological validation and significance of micrometastasis in sentinel nodes in primary breast cancer

In embracing a multidisciplinary approach to the management of patients with sentinel node biopsy in breast cancer, the pathologist task is to screen sentinel nodes for possible metastasis. The consequences of missing sentinel node micrometastasis can directly influence treatment strategies, and this screening therefore has to be performed with more attention than usual. There is presently great diversity in the histopathological work-up of sentinel nodes, with many centres employing additional techniques such as immunohistochemistry, reverse transcription polymerase chain reaction or flow cytometry in addition to routine haematoxylin and eosin staining. In this review, we address the pathological validation and significance of micrometastasis in sentinel node biopsy in primary breast cancer

Breast cancer

Breast cancer remains one of the leading causes of cancer morbidity and mortality. Despite significant advances in treatment of breast cancer a substantial proportion of women affected by this disease succumb to it. Survival of patients with advanced disease, chemoresistant tumors or a suboptimal response to endocrine therapy is significantly shortened. Hence, further understanding of disease pathogenesis is required to enhance the arsenal of approaches to cure this deadly ailment. Recent advances in biochemistry, molecular cell biology and cancer research highlighted the importance of dysregulation of protein synthesis, translation, in the development and progression of tumors. This dysregulation appears to take place at an early stage of translation, called translation initiation, that is a highly controlled and rate-limiting step of the protein synthesis. In this chapter we summarize decades of knowledge accumulated in regards to the role of translation and its regulation in the development and progression of breast cancer. We then extensively discuss applications of this knowledge in diagnosis and treatment of breast cancer.

Pathologically confirmed breast cancer in Malawi: a descriptive study: Clinical profile of breast cancer

Background Breast cancer is the most common female cancer in Africa, yet no published studies have investigated breast cancer in Malawi. Understanding the clinical profile of breast cancer is important to develop early diagnosis efforts. Aim To describe clinical and pathological characteristics of breast specimens from a pathology laboratory at a national teaching hospital. Methods Secondary analysis of pathology reports from July 2011 to September 2013. Results Among 85 breast cancer cases, 55% were < 50 years. Median tumor size was 4 cm and 49% were grade 3. Median symptom duration was eight months. Conclusions Malawian women with breast cancer commonly have long symptom durations prior to diagnosis, young age, and poorly differentiated tumors. Improved clinical and pathological characterization, including hormone receptor status, are urgently needed to better understand this disease in Malawi.