Pten regulates collagen fibrillogenesis by fibroblasts through SPARC.

Caitlin E Jones,Joe T Sharick,Joshua M Zent,Michael C Ostrowski,Jennifer L Leight,Steven T Sizemore,Sheila E Colbert,Samir N Ghadiali,Vasudha C Shukla,Donald Gullberg

doi:10.1371/journal.pone.0245653

Abstract

Collagen deposition contributes to both high mammographic density and breast cancer progression. Low stromal PTEN expression has been observed in as many as half of breast tumors and is associated with increases in collagen deposition, however the mechanism connecting PTEN loss to increased collagen deposition remains unclear. Here, we demonstrate that Pten knockout in fibroblasts using an Fsp-Cre;PtenloxP/loxP mouse model increases collagen fiber number and fiber size within the mammary gland. Pten knockout additionally upregulated Sparc transcription in fibroblasts and promoted collagen shuttling out of the cell. Interestingly, SPARC mRNA expression was observed to be significantly elevated in the tumor stroma as compared to the normal breast in several patient cohorts. While SPARC knockdown via shRNA did not affect collagen shuttling, it notably decreased assembly of exogenous collagen. In addition, SPARC knockdown decreased fibronectin assembly and alignment of the extracellular matrix in an in vitro fibroblast-derived matrix model. Overall, these data indicate upregulation of SPARC is a mechanism by which PTEN regulates collagen deposition in the mammary gland stroma.

Highlights

Collagen deposition within the mammary gland impacts both cancer development and progression
Shown that low stromal PTEN expression is associated with increases in mammographic density [10] and stromal Pten knockout increased collagen deposition in the mammary gland in a mouse model [9]
We show that Pten loss contributes to collagen shuttling out of the cell as well as collagen fiber formation, and that the increases in collagen fiber formation are dependent on increased expression of SPARC

Summary

Introduction

Collagen deposition within the mammary gland impacts both cancer development and progression. It is one of the primary tissue properties contributing to high mammographic density [1], which is one of the greatest risk factors for breast cancer development [2,3,4]. Images presented in this report were generated using the instruments and services at the Campus Microscopy and Imaging Facility, The Ohio State University. This facility is supported in part by NIH cancer center grant P30 CA016058 to The Ohio State University, National Cancer Institute, Bethesda, MD. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

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