
John Michael DixonUniversity of Edinburgh | UoE
John Michael Dixon
BSc, MBChB, MD, FRCS, FRCS(Ed), FRCP(Hon)
About
676
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33,710
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October 1989 - present
Publications
Publications (676)
Background: 80% of all breast cancers (BCs) are ER-positive (ER+). A significant number develop endocrine therapy resistance (ETR) . Clones develop in lymph nodes (LNs) which differ from the primary and these are implicated in ETR. A multiomics analysis of primary ER+ breast cancers, matched LN metastasis (LN+), if present, and matched recurrences...
Background: Neoadjuvant endocrine therapy (NET) in postmenopausal women (PMW) with large or locally advanced oestrogen receptor (ER)-rich breast cancer allows more women to be treated by breast-conserving surgery (BCS). A comprehensive analysis of the factors affecting clinical response to NET and the long-term safety of this strategy has been stud...
The majority of breast cancers are oestrogen receptor-positive (ER+). In ER+ cancers, oestrogen acts as a disease driver, so these tumours are likely to be susceptible to endocrine therapy (ET). ET works by blocking the hormone’s synthesis or effect. A significant number of patients diagnosed with breast cancer will have the spread of tumour cells...
Background: 80% of all breast cancers (BCs) are ER-positive (ER+). Not all respond to adjuvant endocrine therapy (aET) and a significant number develop endocrine resistance and recur. The basis for primary and acquired endocrine resistance is poorly understood. A multiomics analysis of primary ER+ BCs matched with recurrences on or after completion...
Background:
Limited level 1 evidence is available on the omission of radiotherapy after breast-conserving surgery in older women with hormone receptor-positive early breast cancer receiving adjuvant endocrine therapy.
Methods:
We performed a phase 3 randomized trial of the omission of irradiation; the trial population included women 65 years of...
Introduction
While endocrine therapy is the standard-of-care adjuvant treatment for hormone receptor-positive (HR+) breast cancers, there is also extensive evidence for the role of pre-operative (or neoadjuvant) endocrine therapy (NET) in HR+ postmenopausal women.
Areas covered
We conducted a thorough review of the published literature, to summari...
Background
Mondor's disease is a rare disorder characterised by thrombosis of superficial veins within the subcutaneous tissue of the breast and other organs. While factors such as trauma, infection, physical exertion, breast cancer and breast surgery have been implicated, in the majority no cause is identified.
Patients
Twenty patients presented...
Ribosomal RNA (rRNA) transcription by RNA polymerase I (Pol I) is a critical rate-limiting step in ribosome biogenesis, which is essential for cell survival. Despite its global function, disruptions in ribosome biogenesis cause tissue-specific birth defects called ribosomopathies, which frequently affect craniofacial development. Here, we describe...
Purpose:
Endocrine therapy resistance (ETR) remains the greatest challenge in treating patients with hormone receptor-positive breast cancer. We set out to identify molecular mechanisms underlying ETR through in-depth genomic analysis of breast tumors.
Experimental design:
We collected pre-treatment and sequential on-treatment tumor samples from...
IL6-like cytokines are a family of regulators with a complex, pleiotropic role in both the healthy organism, where they regulate immunity and homeostasis, and in different diseases, including cancer. Here we summarise how these cytokines exert their effect through the shared signal transducer IL6ST (gp130) and we review the extensive evidence on th...
Radiotherapy (RT) is an important treatment modality for the local control of breast cancer (BC). Unfortunately, not all patients that receive RT will obtain a therapeutic benefit, as cancer cells that either possess intrinsic radioresistance or develop resistance during treatment can reduce its efficacy. For RT treatment regimens to become persona...
Novel biomarkers are needed to continue to improve breast cancer clinical management and outcome. IL6-like cytokines, whose pleiotropic functions include roles in many hallmarks of malignancy, rely on the signal transducer IL6ST (gp130) for all their signalling. To date, 10 separate independent studies based on the analysis of clinical breast cance...
Treatment for HR+/HER2+ patients has been debated, as some tumors within this luminal HER2+ subtype behave like luminal A cancers, whereas others behave like non-luminal HER2+ breast cancers. Recent research and clinical trials have revealed that a combination of hormone and targeted anti-HER2 approaches without chemotherapy provides long-term dise...
Introduction
Excision biopsy has been the investigation of choice for patients presenting with pathological axillary lymphadenopathy without a breast abnormality. Core biopsy of nodes can provide sufficient tissue for diagnosis and has advantages in terms of morbidity and speed of diagnosis. This study evaluates the diagnostic accuracy of core biop...
Many patients with ER+ HER2− primary breast cancer are being deferred from surgery to neoadjuvant endocrine therapy (NeoET) during the COVID-19 pandemic. We have collated data from multiple international trials of presurgical endocrine therapy in order to provide guidance on the identification of patients who may have insufficiently endocrine-sensi...
PurposeThe goal of sentinel lymph node biopsy is to establish the presence or absence of cancer cells in regional axillary nodes. The number of sentinel nodes harvested from each patient varies. The aim of this study was to determine what factors influence the number of sentinel nodes excised at sentinel node biopsy.Methods
Data from 426 patients w...
Introduction
Recent years have seen a large increase in the proportion and number of sling-assisted, implant-based breast reconstructions. These are associated with significant rates of loss of the reconstruction. Various methods have been suggested to reduce this loss rate. One such method is the use of operating theatres with laminar flow. The ma...
Background: Invasive lobular carcinoma (ILC) is the second most common histological subtype of breast cancer and exhibits a number of clinico-pathological characteristics distinct from the more common invasive ductal carcinoma (IDC). Despite these differences, ILC is treated in the same way as IDC. We set out to identify alterations in the tumor mi...
Background
Invasive lobular carcinoma (ILC) is the second most common histological subtype of breast cancer and exhibits a number of clinico-pathological characteristics that are distinct from the more common invasive ductal carcinoma (IDC). Despite these differences, ILC is treated in the same way as IDC. We set out to identify alterations in the...
Purpose:
Fulvestrant, the first-in-class selective estrogen receptor (ER) degrader (SERD), is clinically effective in patients with ER+ breast cancer, but it has administration and pharmacokinetic (PK) limitations. Pharmacodynamic (PD) data suggests complete ER degradation is not achieved at fulvestrant's clinically feasible dose. This pre-surgica...
Background: A sentinel lymph node in breast cancer surgery is defined as a blue node or a “hot” radioactive node and includes nodes other than the hottest node providing that they contain at least 10% of the radioactivity of the hottest node. The false negative rate of SLNB in breast cancer surgery falls as the number of sentinel nodes removed incr...
Background: 80% of all breast cancers (BCs) are ER+. Not all respond to endocrine therapy (ET) and many eventually develop resistance. An in-depth genomic analysis of cancers that acquired resistance (aR) to multiple sequential lines of ET after an initial period of response has been performed.
Patients: A unique cohort of tissues from 20 post-meno...
Background: The ER+/HER2+ subtype accounts for up to 10% of all breast cancers (BCs) and most are treated with surgery followed by adjuvant chemotherapy with Herceptin +/- radiotherapy then adjuvant endocrine therapy (ET) to reduce the recurrence risk. Despite this it is clear that not all ER+/HER2+ patients gain benefit from the addition of chemot...
Background: Radiotherapy (RT) plays an important role in the multimodal treatment of breast cancer (BC). Despite improvements in the accuracy of delivering radiation to specific biological target volumes, the clinical response of BC to RT is still affected by intrinsic/acquired radioresistance. These resistant cancer cells can contribute to the dev...
Background: Estrogen receptor positive (ER+) breast cancer is routinely treated with endocrine therapies targeting the ER axis. However, primary and secondary resistance ultimately limits the use of these agents. Fulvestrant (FULV) is the first-in-class selective ER degrader (SERD) clinically effective in patients with ER+ breast cancer, both naïve...
Background: Ductal carcinoma in situ (DCIS) lesions are non-obligate precursors to invasive breast cancer (IBC). With the ultimate goal of preventing the development of invasive disease, DCIS is typically treated by breast-conserving surgery (BCS). Adjuvant radiotherapy (RT) is given for high-grade disease to reduce the risk of in-breast tumour rec...
Background: Endocrine therapy (ET) is an effective treatment of estrogen receptor positive (ER+) breast cancer (BC). However, not all ER+ cancers respond to ET and many eventually acquire resistance. Genomic aberrations in ESR1 have been reported to play a role in resistance to treatment. ESR1 mutations (ESRMs), reported in 10-50% of metastatic or...
Background:
High-throughput transcriptomics has matured into a very well established and widely utilised research tool over the last two decades. Clinical datasets generated on a range of different platforms continue to be deposited in public repositories provide an ever-growing, valuable resource for reanalysis. Cost and tissue availability norma...
Endocrine therapy is important for management of patients with estrogen receptor (ER) positive breast cancer, however positive ER staining does not reliably predict therapy response. We assessed the potential to improve prediction of response to endocrine treatment of a novel test that quantifies functional ER pathway activity from mRNA levels of E...
Background
Despite ER positive IHC staining, some patients do not respond to neoadjuvant endocrine therapy, suggesting that ER staining lacks specificity to predict response. We developed a method to infer a quantitative signal transduction pathway activity score (PAS) from mRNA levels (microarray, qPCR) of pathway-associated transcription factor t...
[This corrects the article DOI: 10.1371/journal.pone.0053292.].
Introduction
Accurate assessment of estrogen receptor (ER) expression is crucial to ensure that patients with early breast cancer are accurately identified for appropriate treatment with endocrine therapy. Reverse transcriptase polymerase chain reaction (RT-PCR), compared with immunohistochemistry (IHC), may provide a more precise indication of ER...
Background:In breast cancer (BC), radiotherapy (RT) is used adjuvantly to prevent recurrence and also in the palliative setting. Clinical signs of RT response are often not apparent for several weeks post-treatment and we currently lack tools to predict or monitor tumor response to RT early during treatment. The aim was to identify tumor-secreted b...
Background: ER+/HER2+ accounts for up to 10% of all breast cancers (BCs) and most are treated with endocrine therapy (ET) after surgery to reduce the recurrence risk. We developed and validated an immunohistochemistry (IHC) based test (EA2Clin) that incorporates baseline IL6ST, clinical variables and on-treatment measurement of MCM4. Responders (Rs...
Background: Transcriptomic analyses of clinical samples can help improve our understanding of disease aetiology, drug effectiveness, assign molecular subtypes and derive prognostic signatures for clinical decision-making. The success of early microarray studies relied heavily on sample quality and predominantly fresh frozen (FF) tissues to generate...
Background: The majority of patients with early-stage estrogen receptor positive (ER+) breast cancer (BC) are treated with adjuvant endocrine therapy (ET) after surgery to reduce the risk of recurrence. Recently, we have developed and validated an immunohistochemistry (IHC) based assay (EndoAdjuvant2 Clinical; EA2Clin) that measures pre-treatment I...
Background: Ductal carcinoma (DCIS) is a heterogeneous precursor, non-invasive breast lesion. There is a lack of specific DCIS molecular predictors of in breast tumour recurrence (IBTR) or progression to invasive breast cancer (IBC) after breast conserving surgery (BCS) +/- radiotherapy (RT). The aim of this was to identify novel biomarkers and com...
Background: Approximately 70% of breast cancers (BCs) are estrogen receptor positive (ER+). Not all ER+ cancers respond to endocrine therapy (ET) and many eventually develop acquired resistance. Next-generation sequencing (NGS) has shown ESR1 mutations (ESRMs) are present in 10-50% of recurrent/metastatic cancers treated with aromatase inhibitors (...
Background: Around 70% of all breast cancers (BCs) are estrogen receptor positive (ER+), but some do not respond to endocrine therapy (ET) and many eventually develop resistance. ESR amplification (ESRA) linked to an increase in ESR1 gene expression is known to occur in some cancers that are endocrine resistant. However, the incidence of ESRA has b...
Background: The role of neoadjuvant endocrine therapy (NET) for ER+ DCIS is an area of evolving study. It may allow down-sizing prior to surgery, converting DCIS requiring mastectomy to disease suitable for breast conservation surgery (BCS). Here we report the results from the first European single-institution series of its type.
Methods: Data were...
Background
The risk of recurrence for endocrine-treated breast cancer patients persists for many years or even decades following surgery and apparently successful adjuvant therapy. This period of dormancy and acquired resistance is inherently difficult to investigate; previous efforts have been limited to in-vitro or in-vivo approaches. In this stu...
Introduction: In breast cancer, estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) are essential biomarkers to predict response to endocrine and anti-HER2 therapies, respectively. In metastatic breast cancer, the use of these receptors and targeted therapies present additional challenges: temporal heterogeneity, together wit...
Background
The risk of recurrence for endocrine-treated breast cancer patients persists for many years or even decades following surgery and apparently successful adjuvant therapy. This period of dormancy and acquired resistance is inherently difficult to investigate, previous efforts have been limited to in vitro or in vivo approaches. In this stu...
Background: Ductal carcinoma (DCIS) of the breast represents a heterogeneous group of precursor, non-invasive breast lesions. Currently we lack accurate tools to stratify DCIS patients according to inherent risk of in breast tumour recurrence (IBTR) or progression to invasive breast cancer (IBC).Most DCIS patients are treated by breast-conversing s...
Background: 70% of all breast cancers (BCs) are ER+. Not all ER+ cancers respond to endocrine therapy (ET) and many eventually develop resistance. The aim was to perform in-depth genomic analysis of both primary resistant BCs, that do not respond to ET, and cancers which progress (>40% increase in size) after an initial response as they acquire res...
Introduction: IL6ST is regarded as a putative ER target gene. Recently it has been recognised as a key biomarker for prediction of response to endocrine therapy (ET), having been included as the primary biomarker in our EA2Clin test and as an ER-signalling gene in the EndoPredict test. In both tests higher IL6ST expression is associated with a bett...
Background:Neoadjuvant therapy (NET) in women with large or locally advanced estrogen receptor(ER)-rich breast cancers (BC) allows the option of breast-conserving surgery (BCS) + radiotherapy (RT). The aim was to study the long term safety of this strategy.
Methods: 280 postmenopausal women (median age 77, range 50-95, table 1) with ER-rich BC had...
Background: The majority of patients with early-stage estrogen receptor positive (ER+) breast cancer (BC) are treated with adjuvant endocrine therapy (ET) after primary surgery to reduce the risk of recurrence. A variety of tests are available to predict outcomes on ET but most require gene-level measurements and are expensive. Recently, we develop...
Background: Approximately 40% of ER+ breast cancer present with nodal metastasis. To date, there has been no comparison of the molecular response of primary cancers and metastases to ET. Recent evidence suggests that nodal metastases have different clones and subclones compared to the primary tumour. The aim of this study is to characterise the mol...
Purpose of Review
Pre-operative endocrine therapy can be used to down-stage large or locally advanced breast cancers in ER+ disease. In the last four decades, it has evolved from a treatment perceived as an alternative to surgery for those too unfit to undergo surgery or chemotherapy, to the present day where it is a valuable and valid option in th...
During the secretory phase of their life-cycle, ameloblasts are highly specialized secretory cells whose role is to elaborate an extracellular matrix that ultimately confers both form and function to dental enamel, the most highly mineralized of all mammalian tissues. In common with many other “professional” secretory cells, ameloblasts employ the...
Introduction:
Ductal Carcinoma in situ (DCIS) represents 5% of symptomatic and 20-30% of screen detected cancers. Breast conserving surgery (BCS) ± radiotherapy is performed in over 70% of women with DCIS. What constitutes an adequate margin for BCS remains unclear.
Methods:
A single institution follow up study has been conducted of 466 patients...
Development of the secondary palate involves a complex series of embryonic events which, if disrupted, result in the common congenital anomaly cleft palate. The secondary palate forms from paired palatal shelves which grow initially vertically before elevating to a horizontal position above the tongue and fusing together in the midline via the medi...
Cleft palate is a common congenital disorder that affects up to 1 in 2500 live births and results in considerable morbidity to affected individuals and their families. The aetiology of cleft palate is complex with both genetic and environmental factors implicated. Mutations in the transcription factor p63 are one of the major individual causes of c...
Krt5-tTA;pTRE-ΔNp63α bi-transgenic mice exhibit sub-mucous cleft palate.
(A) In neonatal wild-type mice, the medial edge epithelia have degenerated to allow mesenchymal continuity across the secondary palate. (B) In contrast, in 50% of neonatal Krt5-tTA;pTRE-ΔNp63α mice, the medial edge epithelia remain intact leading to sub-mucous cleft palate (ar...
Time-lapse imaging of palatal shelves dissected from mKrt17-GFP transgenic mice.
The periderm exhibits a migratory phenotype allowing completion of palatal fusion in wild-type mice. The video is a series of representative images taken at the same Z position over a 24-hour culture period.
(MP4)
Time-lapse imaging of palatal shelves dissected from mKrt17-GFP;Tgfb3-/- embryos in which the secondary palate remains cleft.
No migration of the periderm cells was observed. The video is a series of representative images taken at the same Z position over a 24-hour culture period.
(MP4)
Genes encoding proteins implicated in cell adhesion that are differentially-expressed in wild-type versus p63-/- mice.
(XLSX)
Results of the microarray analysis of palatal shelves dissected from E14.5 wild-type versus Krt5-tTA;pTRE-ΔNp63α mice.
(XLSX)
Histological analysis of E15.0 wild-type, Tgfb3-/- and Tgfb3-/-;p63+/- mice.
Representative images taken from serial sections of wild-type, Tgfb3-/- and Tgfb3-/-;p63+/- embryos in the anterior (A-C), mid (D-F) and posterior (G-I) regions of the palate at E15.0. p: palatal shelves; t: tongue. Scale bars: 250 μm.
(TIF)
Genome-wide distribution of ΔNp63α binding sites in the secondary palate.
(A) RNA-seq analysis indicates that transcripts encoding ΔNp63 isoforms predominate in the developing secondary palate. Transcript reads are indicated by black bars. (B) ChIP-qPCR validation of p63-bound sites. Fold-enrichment for each binding region was calculated relative t...
Percentage of proliferative cells in the palatal shelves of E14.5wild-type and Krt5-tTA;pTRE-ΔNp63α embryos.
Proliferative cells were assessed by anti-BrdU immunostaining and the percentages calculated for the epithelium, mesenchyme and total palate. No significant differences were found between the wild-type controls and the Tgfb3-/-;p63+/- embryo...
Sequences of the oligonucleotide primers used in the study.
(XLSX)
Percentage of proliferative cells in the palatal shelves of wild-type and Krt5-tTA;pTRE-ΔNp63α bi-transgenic mice at E13.5.
Proliferative cells were assessed by phosphohistone 3 immunostaining and the percentages calculated for the epithelium, mesenchyme and total palate. No significant differences were found between the wild-type littermate contro...
Time-lapse imaging of palatal shelves dissected from mKrt17-GFP;Tgfb3-/-;p63+/-embryos.
Reducing p63 dosage in Tgfb3-/- mice restores periderm migration and palatal fusion thereby rescuing the cleft palate phenotype. The video is a series of representative images taken at the same Z position over a 24-hour culture period.
(MP4)
A list of 104 genes that exhibit diametric expression with down-regulation in the p63 loss-of-function (p63-/-) microarray analysis and up-regulation in the Krt5-tTA;pTRE-ΔNp63α microarray analysis.
(XLSX)
Palatal development in E13.5 wild-type, Tgfb3-/- and Tgfb3-/-;p63+/- mice.
(A—C) The palatal shelves of wild-type, Tgfb3-/- and Tgfb3-/-;p63+/- mice lie in a vertical position lateral to the tongue. (D—I) While the basal epithelial cells are proliferative and express E-cadherin and p63, there is no evidence of cell death. (J—L) In all genotypes, th...
Percentage of proliferative cells in the palatal shelves of wild-type and Tgfb3-/-;p63+/- embryos at E14.5.
Proliferative cells were assessed by phosphohistone 3 immunostaining and the percentages calculated for the epithelium, mesenchyme and total palate. No significant differences were found between the wild-type littermate controls and the Tgfb3...
Development of the palatal shelves in E13.5 Krt5-tTA;pTRE-ΔNp63α bi-transgenic mice.
(A, B) The palatal shelves of wild-type and Krt5-tTA;pTRE-ΔNp63α embryos lie in a vertical position lateral to the tongue. (C, D) In both genotypes, the palatal epithelia consist of a keratin 14-positive basal layer covered by a distinct keratin 17-positive layer o...
Histological analysis of E15.0 wild-type and Krt5-tTA;pTRE-ΔNp63α bi-transgenic mice.
Representative images taken from serial sections of wild-type and Krt5-tTA;pTRE-ΔNp63α bi-transgenic embryos in the anterior (A-C), mid (D-F) and posterior (G-I) regions of the palate at E15.0. C, F and I are magnified regions of the boxes represented in B, E and...
Classification of the 6295 genomic regions bound by ΔNp63α in the palatal shelves of wild-type embryos.
(XLSX)
Results of the microarray analysis of palatal shelves dissected from E14 wild-type versus p63-/- mice.
(XLS)