• Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer

      Eccles, Suzanne A.; Aboagye, Eric O.; Ali, Simak; Anderson, Annie S.; Armes, Jo; Berditchevski, Fedor; Blaydes, Jeremy P.; Brennan, Keith; Brown, Nicola J.; Bryant, Helen E.; et al. (BioMed Central, 2013-10-01)
      Introduction: Breast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice. Methods More than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer ‘stem’ cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account. Results The 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease; (9) developing interventions and support to improve the survivorship experience; (10) a continuing need for clinical material for translational research derived from normal breast, blood, primary, relapsed, metastatic and drug-resistant cancers with expert bioinformatics support to maximise its utility. The proposed infrastructural enablers include enhanced resources to support clinically relevant in vitro and in vivo tumour models; improved access to appropriate, fully annotated clinical samples; extended biomarker discovery, validation and standardisation; and facilitated cross-discipline working. Conclusions With resources to conduct further high-quality targeted research focusing on the gaps identified, increased knowledge translating into improved clinical care should be achievable within five years.
    • Generation of anisotropic strain dysregulates wild-type cell division at the interface between host and oncogenic tissue.

      Moruzzi, Megan; Nestor-Bergmann, Alexander; Goddard, Georgina K; Tarannum, Nawseen; Brennan, Keith; Woolner, Sarah; email: sarah.woolner@manchester.ac.uk (2021-06-03)
      Epithelial tissues are highly sensitive to anisotropies in mechanical force, with cells altering fundamental behaviors, such as cell adhesion, migration, and cell division. It is well known that, in the later stages of carcinoma (epithelial cancer), the presence of tumors alters the mechanical properties of a host tissue and that these changes contribute to disease progression. However, in the earliest stages of carcinoma, when a clonal cluster of oncogene-expressing cells first establishes in the epithelium, the extent to which mechanical changes alter cell behavior in the tissue as a whole remains unclear. This is despite knowledge that many common oncogenes, such as oncogenic Ras, alter cell stiffness and contractility. Here, we investigate how mechanical changes at the cellular level of an oncogenic cluster can translate into the generation of anisotropic strain across an epithelium, altering cell behavior in neighboring host tissue. We generated clusters of oncogene-expressing cells within otherwise normal in vivo epithelium, using Xenopus laevis embryos. We find that cells in kRas , but not cMYC, clusters have increased contractility, which introduces radial stress in the tissue and deforms surrounding host cells. The strain imposed by kRas clusters leads to increased cell division and altered division orientation in neighboring host tissue, effects that can be rescued by reducing actomyosin contractility specifically in the kRas cells. Our findings indicate that some oncogenes can alter the mechanical and proliferative properties of host tissue from the earliest stages of cancer development, changes that have the potential to contribute to tumorigenesis. [Abstract copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.]