Authors

Timothy G. Pestell, Thomas Jefferson UniversityFollow
Xuanmao Jiao, Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute
Mukesh Kumar, Thomas Jefferson UniversityFollow
Amy R. Peck, Medical College of Wisconsin
Marco Prisco, Thomas Jefferson UniversityFollow
Shengqiong Deng, Thomas Jefferson University; Tongji University School of Medicine
Zhiping Li, Thomas Jefferson UniversityFollow
Adam Ertel, Thomas Jefferson UniversityFollow
Matthew C. Casimiro, Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute
Xiaoming Ju, Thomas Jefferson UniversityFollow
Agnese Di Rocco, Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute
Gabriele Di Sante, Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute
Sanjay Katiyar, Thomas Jefferson University
Alison Shupp, Thomas Jefferson UniversityFollow
Michael P. Lisanti, University of Salford
Pooja Jain, Drexel University College of Medicine
Kongming Wu, Tongji Hospital of Tongji Medical College
Hallgeir Rui, Medical College of Wisconsin
Douglas Craig Hooper, Thomas Jefferson UniversityFollow
Zuoren Yu, Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute
Aaron R. Goldman, The Wistar Institute
David W. Speicher, The Wistar Institute
Lisa Laury-Kleintop, Lankenau Institute for Medical Research
Richard G. Pestell, Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute; Nanyang Technological University

Document Type

Article

Publication Date

8-4-2017

Comments

This article has been peer reviewed. It is the author’s final published version in Oncotarget

Volume 8, Issue 47, August 2017, Pages 81754-81775.

The published version is available at DOI: 10.18632/oncotarget.19953. Copyright © Pestell et al.

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. © Pestell et al.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 3.0 License.

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