Post as: Bowers et al.: Obesity enhances nongenomic estrogen receptor crosstalk together with the PI3KAkt and MAPK pathways to promote in vitro measures of breast cancer progression. Breast Cancer Research 2013 15:R59.Submit your subsequent manuscript to BioMed Central and take complete advantage of:Easy on the web submission Thorough peer assessment No space constraints or colour figure charges Quick publication on acceptance Inclusion in PubMed, CAS, Scopus and Google Scholar Analysis that is freely accessible for redistributionSubmit your manuscript at www.biomedcentral.comsubmit
Nam et al. Breast Cancer Research 2013, 15:R60 http:breastcancerresearch.comcontent154RRESEARCH ARTICLEOpen Accessb1integrin through NFB signaling is essential for acquisition of invasiveness in a model of radiation treated in situ breast cancerJinMin Nam1, Kazi M Ahmed2, Sylvain Costes2, Hui Zhang2, Yasuhito Onodera3, Adam B Olshen4, Kanako C Hatanaka5, Rumiko Kinoshita1, Masayori Ishikawa6, Hisataka Sabe3, Hiroki Shirato1 and Catherine C Park2,7AbstractIntroduction: Ductal carcinoma in situ (DCIS) is characterized by noninvasive cancerous cell development within the breast ducts. Though radiotherapy is generally utilized inside the therapy of DCIS, the impact and molecular mechanism of ionizing radiation (IR) on DCIS usually are not properly understood, and invasive recurrence following radiotherapy remains a considerable clinical problem. This study investigated the effects of IR on a clinically relevant model of Aktdriven DCIS and identified attainable molecular mechanisms underlying invasive progression in surviving cells. Methods: We measured the level of phosphorylatedAkt (pAkt) in a cohort of human DCIS specimens by immunohistochemistry (IHC) and correlated it with recurrence risk. To model human DCIS, we employed Akt overexpressing human mammary epithelial cells (MCF10AAkt) which, in threedimensional lamininrich extracellular matrix (lrECM) and in vivo, type organotypic DCISlike lesions with lumina expanded by pleiomorphic cells contained within an intact basement membrane. In a population of cells that survived substantial IR doses in threedimensional lrECM, a malignant phenotype emerged producing a model for invasive recurrence. Outcomes: PAkt was upregulated in clinical DCIS specimens and was linked with recurrent disease. MCF10AAkt cells that formed DCISlike structures in threedimensional lrECM showed considerable apoptosis just after IR, preferentially within the luminal compartment. Strikingly, when cells that survived IR were repropagated in threedimensional lrECM, a malignant phenotype emerged, characterized by invasive activity, upregulation of 3PO Inhibitor fibronectin, a5b1integrin, matrix metalloproteinase9 (MMP9) and loss of Ecadherin. In addition, IR induced nuclear translocation and binding of nuclear factorkappa B (NFB) towards the b1integrin promoter area, linked with upregulation of a5b1integrins. Inhibition of NFB or b1integrin signaling abrogated emergence with the invasive activity. Conclusions: PAkt is upregulated in some human DCIS lesions and is possibly linked with recurrence. MCF10AAkt cells type organotypic DCISlike lesions in threedimensional lrECM and in vivo, and are a plausible model for some forms of human DCIS. A population of Aktdriven DCISlike Dimaprit manufacturer spheroids that survive IR progresses to an invasive phenotype in threedimensional lrECM mediated by b1integrin and NFB signaling. Search phrases: ductal carcinoma in situ, DCIS, integrin, ionizing radiationIntroduction Ductal carcinoma in situ (DCI.