6 research outputs found

    Biological basis for novel mesothelioma therapies

    Get PDF
    Funder: British Lung Foundation (BLF); doi: https://doi.org/10.13039/501100000351Funder: Royal Society through a University Research Fellowship and the Engineering and Physical Sciences Research Council (EPRSC)Funder: China Scholarship Council (CSC); doi: https://doi.org/10.13039/501100004543Abstract: Mesothelioma is an aggressive cancer that is associated with exposure to asbestos. Although asbestos is banned in several countries, including the UK, an epidemic of mesothelioma is predicted to affect middle-income countries during this century owing to their heavy consumption of asbestos. The prognosis for patients with mesothelioma is poor, reflecting a failure of conventional chemotherapy that has ultimately resulted from an inadequate understanding of its biology. However, recent work has revolutionised the study of mesothelioma, identifying genetic and pathophysiological vulnerabilities, including the loss of tumour suppressors, epigenetic dysregulation and susceptibility to nutrient stress. We discuss how this knowledge, combined with advances in immunotherapy, is enabling the development of novel targeted therapies

    Progestins used for hormonal contraception in Switzerland: study of their effects on the breast epithelium

    No full text
    Breast cancer is the most commonly diagnosed cancer and the most common cause of cancer death among women. Hormones have been shown to have a key role in breast development and carcinogenesis. Repeated activation of progesterone receptor (PR) signaling as it occurs during menstrual cycles is important in cancer risk. Through hormonal contraception many women are exposed to synthetic PR agonists, progestins, either on their own or in combination with the synthetic estrogen receptor (ER) agonist, ethinyl estradiol (EE). Progestins vary in their chemical structures and biological activities. Epidemiological studies show that hormonal contraceptions increase the risk of breast cancer but to date there have been few studies that analyze specific progestins regarding the breast cancer risk they confer. We hypothesized that different progestins have distinct abilities to induce cell proliferation and to modulate gene expression in the breast epithelium and this may ultimately have different effects on breast cancer risk. To test the hypothesis that different progestins currently used in hormonal contraceptions in Switzerland have distinct abilities to induce the expression of important mediators of PR action, receptor activator of NF-ĂŽÂşB ligand (RANKL) and Wnt4, we employed mouse mammary gland organoids and human breast tissue microstructures. We find that androgenic progestins strongly induce RANKL and Wnt4 whereas anti-androgenic progestins fail to do so. To test the ability of different progestins currently used in hormonal contraceptions in Switzerland to induce cell proliferation in human breast epithelium, we humanized mouse mammary gland using intraductal injection of human breast epithelial cells obtained from reduction mammoplasty surgery. We show that breast epithelial cells maintain hormone receptor expression and remain hormone responsive in this approach. We find that the androgenic progestins, Gestodene and Levonorgestrel, promote cell proliferation over two months more than progesterone. Furthermore, we show that Androgen receptor (AR) inhibition abrogates promegestone-induced RANKL induction and reduces cell proliferation induced by androgenic progestin, LNG. We also show that activation of AR signaling through DHT exposure is sufficient to induce proliferation of human breast epithelial cells. Thus, different progestins have different biological effects on the breast epithelium that appear to be related to their androgenic activities

    Variably Scaled Kernels Improve Classification of Hormonally-Treated Patient-Derived Xenografts

    No full text
    Little is known about the biological functions which are exerted by hormone receptors in physiological conditions. Here, we made use of the Mouse INtraDuctal (MIND) model, an innovative patient-derived xenograft (PDX) model, to characterize global gene expression changes, which are triggered by stimulation of dihydrotestosterone (DHT) and progesterone (P4) in vivo. Fast and clever mathematical tools are needed to analyze increasing numbers of complex datasets. We generated hormone receptor-specific list of genes which were then used to test the classification performance obtained by different machine-learning algorithms in the frame of our labelled PDXs RNAseq dataset. Next to other standard techniques, we consider the variably scaled kernel (VSK) setting in the framework of support vector machines. Our results show that mixed schemes obtained via VSKs can outperform standard classification methods in the considered task

    The secreted protease Adamts18 links hormone action to activation of the mammary stem cell niche

    Get PDF
    Estrogens and progesterone control breast development and carcinogenesis via their cognate receptors expressed in a subset of luminal cells in the mammary epithelium. How they control the extracellular matrix, important to breast physiology and tumorigenesis, remains unclear. Here we report that both hormones induce the secreted protease Adamts18 in myoepithelial cells by controlling Wnt4 expression with consequent paracrine canonical Wnt signaling activation. Adamts18 is required for stem cell activation, has multiple binding partners in the basement membrane and interacts genetically with the basal membrane-specific proteoglycan, Col18a1, pointing to the basement membrane as part of the stem cell niche. In vitro, ADAMTS18 cleaves fibronectin; in vivo, Adamts18 deletion causes increased collagen deposition during puberty, which results in impaired Hippo signaling and reduced Fgfr2 expression both of which control stem cell function. Thus, Adamts18 links luminal hormone receptor signaling to basement membrane remodeling and stem cell activation. How hormonal signaling in the mammary epithelium controls the surrounding extracellular matrix is unclear. Here, the authors show that a secreted protease, Adamts18, induced by upstream estrogen-progesterone activated Wnt4 in myoepithelial cells, remodels the basement membrane and contributes to mammary epithelial stemness
    corecore