Stromal cyclin D1 promotes heterotypic immune signaling and breast cancer growth.

Timothy G Pestell,Sanjay Katiyar,Zhiping Li,Shengqiong Deng,David W Speicher,Xiaoming Ju,Agnese Di Rocco,Hallgeir Rui,Adam Ertel,Xuanmao Jiao,Michael P Lisanti,Kongming Wu,Gabriele Di Sante,Aaron R Goldman,Richard G Pestell,Zuoren Yu,Pooja Jain,Amy R Peck,D Craig Hooper ,Alison B Shupp ,Marco Di Prisco ,Lisa D Laury‐Kleintop ,Matthew C Casimiro ,Mrityunjay Kumar

doi:10.18632/oncotarget.19953

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.

Highlights

The cyclin D1 gene encodes the regulatory subunit of a holoenzyme that phosphorylates and inactivates the retinoblastoma protein, promoting G1/S phase cell cycle entry
Cyclin D1 expression is increased in the stroma of human breast cancer associated with poor prognosis
In view of the finding that the cyclin D1 gene encodes the regulatory subunit of the holoenzyme that phosphorylates pRB, and RB phosphorylation is increased in human breast cancer-associated fibroblasts [34], we determined the abundance of cyclin D1 in the stroma of human breast cancers

Summary

Introduction

The cyclin D1 gene encodes the regulatory subunit of a holoenzyme that phosphorylates and inactivates the retinoblastoma (pRb) protein, promoting G1/S phase cell cycle entry. Cyclin D1 enhances breast cancer cellular proliferation in vivo and endogenous cyclin D1 maintains estradiol-mediated mammary epithelial cell gene expression in vivo [1]. The abundance of cyclin D1 is rate limiting in the growth of tumors in vivo, including ErbB2-induced breast cancer [2, 3] and gastrointestinal tumorigenesis [4]. In addition to canonical signaling governing the G1/S cell-cycle transition, cyclin D1 participates in non canonical cell autonomous functions. Cyclin D1 promotes cellular migration [5] and DNA repair [6], governs the expression of specific miRNAs and determines the processing of miRNA through the induction of Dicer [7]. The ability of cyclin D1 to govern gene transcription correlates with the recruitment of cyclin D1 and cointegrator enzyme complexes into the promoter regulatory region of target genes in the context of chromatin [8, 9]

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Conclusion