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Stromal cyclin D1 promotes heterotypic immune signaling and breast cancer growth
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Abstract
Timothy G. Pestell2,*, Xuanmao Jiao1,*, Mukesh Kumar2, Amy R. Peck3, Marco Prisco2, Shengqiong Deng2,8, Zhiping Li2, Adam Ertel2, Mathew C. Casimiro1, Xiaoming Ju2, Agnese Di Rocco1, Gabriele Di Sante1, Sanjay Katiyar2, Alison Shupp2, Michael P. Lisanti4, Pooja Jain5, Kongming Wu6, Hallgeir Rui3, Douglas C. Hooper7, Zuoren Yu1,8, Aaron R. Goldman9, David W. Speicher9, Lisa Laury-Kleintop10, Richard G. Pestell1,11
1 Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Pennsylvania Biotechnology Center, Wynnewood, PA, USA
2 Departments of Cancer Biology, Thomas Jefferson University, Bluemle Life Sciences Building, Philadelphia, PA, USA
3 Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
4 Translational Medicine, School of Environment and Life Sciences, Biomedical Research Centre, University of Salford, Salford, Greater Manchester, England, UK
5 Department of Microbiology and Immunology, Institute for Molecular Medicine & Infectious Disease, Drexel University College of Medicine, Philadelphia, PA, USA
6 Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
7 Department of Microbiology, Thomas Jefferson University, Bluemle Life Sciences Building, Philadelphia, PA, USA
8 Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai, China
9 Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA
10 Lankenau Institute for Medical Research, Wynnewood, PA, USA
11 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
* These authors have contributed equally to this work
Correspondence to:
Richard G. Pestell, email:
Keywords: cyclin D1, OPN, CAFs, stem cell, breast cancer
Abbreviations: CAFs, cancer-associated fibroblasts; hTERT, human telomerase reverse transcriptase
Received: April 28, 2017 Accepted: July 09, 2017 Published: August 04, 2017
Abstract
The cyclin D1 gene encodes the regulatory subunit of a holoenzyme that drives cell autonomous cell cycle progression and proliferation. Herein we show cyclin D1 abundance is increased >30-fold in the stromal fibroblasts of patients with invasive breast cancer, associated with poor outcome. Cyclin D1 transformed hTERT human fibroblast to a cancer-associated fibroblast phenotype. Stromal fibroblast expression of cyclin D1 (cyclin D1Stroma) in vivo, enhanced breast epithelial cancer tumor growth, restrained apoptosis, and increased autophagy. Cyclin D1Stroma had profound effects on the breast tumor microenvironment increasing the recruitment of F4/80+ and CD11b+ macrophages and increasing angiogenesis. Cyclin D1Stroma induced secretion of factors that promoted expansion of stem cells (breast stem-like cells, embryonic stem cells and bone marrow derived stem cells). Cyclin D1Stroma resulted in increased secretion of proinflammatory cytokines (CCL2, CCL7, CCL11, CXCL1, CXCL5, CXCL9, CXCL12), CSF (CSF1, GM-CSF1) and osteopontin (OPN) (30-fold). OPN was induced by cyclin D1 in fibroblasts, breast epithelial cells and in the murine transgenic mammary gland and OPN was sufficient to induce stem cell expansion. These results demonstrate that cyclin D1Stroma drives tumor microenvironment heterocellular signaling, promoting several key hallmarks of cancer.
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