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Watkins J.,Breakthrough Breast Cancer Research Unit | Watkins J.,King's College London | Watkins J.,Life Sciences Partners | Weekes D.,Breakthrough Breast Cancer Research Unit | And 33 more authors.
Cancer Discovery | Year: 2015

Triple-negative breast cancers (TNBC) are characterized by a wide spectrum of genomic alterations, some of which might be caused by defects in DNA repair processes such as homologous recombination (HR). Despite this understanding, associating particular patterns of genomic instability with response to therapy has been challenging. Here, we show that allelic-imbalanced copy-number aberrations (AiCNA) are more prevalent in TNBCs that respond to platinum-based chemotherapy, thus providing a candidate predictive biomarker for this disease. Furthermore, we show that a high level of AiCNA is linked with elevated expression of a meiosis-associated gene, HORMAD1. Elevated HORMAD1 expression suppresses RAD51-dependent HR and drives the use of alternative forms of DNA repair, the generation of AiCNAs, as well as sensitizing cancer cells to HR-targeting therapies. Our data therefore provide a mechanistic association between HORMAD1 expression, a specific pattern of genomic instability, and an association with response to platinumbased chemotherapy in TNBC. SIGNIFICANCE: Previous studies have shown correlation between mutational “scars” and sensitivity to platinums extending beyond associations with BRCA1/2 mutation, but do not elucidate the mechanism. Here, a novel allele-specific copy-number characterization of genome instability identifies and functionally validates the inappropriate expression of the meiotic gene HORMAD1 as a driver of HR deficiency in TNBC, acting to induce allelic imbalance and moderate platinum and PARP inhibitor sensitivity with implications for the use of such “scars” and expression of meiotic genes as predictive biomarkers. © 2015 AACR.


Ng T.,Guys Medical School Campus | Ng T.,Breakthrough Breast Cancer Research Unit | Irshad S.,Guys Medical School Campus | Irshad S.,Breakthrough Breast Cancer Research Unit | Stebbing J.,Imperial College London
Oncogene | Year: 2013

The multifunctional roles of BRCA1 include its ability to regulate transcriptional processes that control differentiation at multiple levels, as well as functioning as a tumor suppressor. Data herein demonstrate that germline mutations in Brca1 impair luminal cell lineage and mammary development, with its deficiency converting ER-positive luminal tumors into basal-like cancers. Heterozygous mutations in Brca1 lead to downregulation of a number of luminal differentiation genes, explaining how it suppresses basal-like tumors, also highlighting its importance outside of its known highly publicized role in DNA repair. © 2013 Macmillan Publishers Limited All rights reserved.


Tutt A.,Breakthrough Breast Cancer Research Unit | Robson M.,Sloan Kettering Cancer Center | Garber J.E.,Dana-Farber Cancer Institute | Domchek S.M.,University of Pennsylvania | And 11 more authors.
The Lancet | Year: 2010

Background Olaparib, a novel, orally active poly(ADP-ribose) polymerase (PARP) inhibitor, induced synthetic lethality in BRCA-deficient cells. A maximum tolerated dose and initial signal of efficacy in BRCA-deficient ovarian cancers have been reported. We therefore assessed the efficacy, safety, and tolerability of olaparib alone in women with BRCA1 or BRCA2 mutations and advanced breast cancer. Methods Women (aged ≥18 years) with confirmed BRCA1 or BRCA2 mutations and recurrent, advanced breast cancer were assigned to two sequential cohorts in a phase 2 study undertaken in 16 centres in Australia, Germany, Spain, Sweden, the UK, and the USA. The first cohort (n=27) was given continuous oral olaparib at the maximum tolerated dose (400 mg twice daily), and the second (n=27) was given a lower dose (100 mg twice daily). The primary efficacy endpoint was objective response rate (ORR). This study is registered with ClinicalTrials.gov, number NCT00494234. Findings Patients had been given a median of three previous chemotherapy regimens (range 1-5 in cohort 1, and 2-4 in cohort 2). ORR was 11 (41%) of 27 patients (95% CI 25-59) in the cohort assigned to 400 mg twice daily, and six (22%) of 27 (11-41) in the cohort assigned to 100 mg twice daily. Toxicities were mainly at low grades. The most frequent causally related adverse events in the cohort given 400 mg twice daily were fatigue (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), nausea (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), vomiting (grade 1 or 2, three [11%]; grade 3 or 4, three [11%]), and anaemia (grade 1 or 2, one [4%]; grade 3 or 4, three [11%]). The most frequent causally related adverse events in the cohort given 100 mg twice daily were nausea (grade 1 or 2, 11 [41%]; none grade 3 or 4) and fatigue (grade 1 or 2, seven [26%]; grade 3 or 4, one [4%]). Interpretation The results of this study provide positive proof of concept for PARP inhibition in BRCA-deficient breast cancers and shows a favourable therapeutic index for a novel targeted treatment strategy in patients with tumours that have genetic loss of function of BRCA1-associated or BRCA2-associated DNA repair. Toxicity in women with BRCA1 and BRCA2 mutations was similar to that reported previously in those without such mutations.


Jensen K.S.,Copenhagen University | Binderup T.,Rigshospitalet | Binderup T.,Copenhagen University | Jensen K.T.,Copenhagen University | And 12 more authors.
EMBO Journal | Year: 2011

Exposure of metazoan organisms to hypoxia engages a metabolic switch orchestrated by the hypoxia-inducible factor 1 (HIF-1). HIF-1 mediates induction of glycolysis and active repression of mitochondrial respiration that reduces oxygen consumption and inhibits the production of potentially harmful reactive oxygen species (ROS). Here, we show that FoxO3A is activated in hypoxia downstream of HIF-1 and mediates the hypoxic repression of a set of nuclear-encoded mitochondrial genes. FoxO3A is required for hypoxic suppression of mitochondrial mass, oxygen consumption, and ROS production and promotes cell survival in hypoxia. FoxO3A is recruited to the promoters of nuclear-encoded mitochondrial genes where it directly antagonizes c-Myc function via a mechanism that does not require binding to the consensus FoxO recognition element. Furthermore, we show that FoxO3A is activated in human hypoxic tumour tissue in vivo and that FoxO3A short-hairpin RNA (shRNA)-expressing xenograft tumours are decreased in size and metabolically changed. Our findings define a novel mechanism by which FoxO3A promotes metabolic adaptation and stress resistance in hypoxia. © 2011 European Molecular Biology Organization | All Rights Reserved.


MacNeill M.,Western General Hospital | Arnott I.,Western General Hospital | Thomas J.,Western General Hospital | Thomas J.,Breakthrough Breast Cancer Research Unit
Journal of Clinical Pathology | Year: 2011

Aims: To compare the predictive values of axillary ultrasound (US) combined with fine needle aspiration (FNA) cytology with tumour size (T stage) and grade in the preoperative staging of breast cancer. More precise definition of axillary FNA reporting nomenclature is also presented. Patients and Methods: 314 patients: 119 patients had suspicious US investigated by FNA, 195 patients had normal US not investigated further preoperatively. This study examined the node-positive and node-negative cases in these two groups, calculating predictive values for cytology, US, T stage and tumour grade, and tested comparisons for significance. Results: Axillary FNA has a positive predictive value of 84.8% compared with US (66.7%). The difference is significant (p=0.008). Negative US has a negative predictive value of 81.0% compared with a negative predictive value for cytology of 66.7%, but the difference is not significant (p=0.08). 43% of patients with unsatisfactory cytology were node positive. Of 195 patients with negative axillary US, 37 (19%) had metastatic nodal disease. Fewer than 20% of these patients had micrometastases alone. Tumour size and grade influenced node status in US-suspicious cases only. Conclusion: Axillary FNA adds significantly to the positive predictive value provided by US. US gives false-negative results in 19% of cases and only a small proportion of these can be explained by micrometastases. Unsatisfactory cytology needs to be repeated because of a high rate of positive nodes in this group.

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