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Cancers 2016, 8(11), 100;

TβRIII Expression in Human Breast Cancer Stroma and the Role of Soluble TβRIII in Breast Cancer Associated Fibroblasts

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
Department of Bioengineering, University of California San Francisco, San Francisco, CA 94117, USA
Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA
Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA
Research Medicine, Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37232, USA
Author to whom correspondence should be addressed.
Academic Editor: Huey-Jen Lin
Received: 30 August 2016 / Revised: 4 October 2016 / Accepted: 20 October 2016 / Published: 4 November 2016
(This article belongs to the Special Issue Cancer-Associated Fibroblasts)
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The TGF-β pathway plays a major role in tumor progression through regulation of epithelial and stromal cell signaling. Dysfunction of the pathway can lead to carcinoma progression and metastasis. To gain insight into the stromal role of the TGF-β pathway in breast cancer, we performed laser capture microdissection (LCM) from breast cancer patients and reduction mammoplasty patients. Microdissected tumor stroma and normal breast stroma were examined for gene expression. Expression of the TGF-β type III receptor (TGFBR3) was greatly decreased in the tumor stroma compared to control healthy breast tissue. These results demonstrated a 44-fold decrease in TGFBR3 mRNA in tumor stroma in comparison to control tissue. We investigated publicly available databases, and have identified that TGFBR3 mRNA levels are decreased in tumor stroma. We next investigated fibroblast cell lines derived from cancerous and normal breast tissue and found that in addition to mRNA levels, TβRIII protein levels were significantly reduced. Having previously identified that cancer-associated fibroblasts secrete greater levels of tumor promoting cytokines, we investigated the consequences of soluble-TβRIII (sTβRIII) on fibroblasts. Fibroblast conditioned medium was analyzed for 102 human secreted cytokines and distinct changes in response to sTβRIII were observed. Next, we used the fibroblast-conditioned medium to stimulate human monocyte cell line THP-1. These results indicate a distinct transcriptional response depending on sTβRIII treatment and whether it was derived from normal or cancerous breast tissue. We conclude that the effect of TβRIII has distinct roles not only in cancer-associated fibroblasts but that sTβRIII has distinct paracrine functions in the tumor microenvironment. View Full-Text
Keywords: TGFBR3; TβRIII; Cancer-Associated-Fibroblasts (CAFs); tumor microenvironment; cancer stroma; Betaglycan TGFBR3; TβRIII; Cancer-Associated-Fibroblasts (CAFs); tumor microenvironment; cancer stroma; Betaglycan

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Jovanović, B.; Pickup, M.W.; Chytil, A.; Gorska, A.E.; Johnson, K.C.; Moses, H.L.; Owens, P. TβRIII Expression in Human Breast Cancer Stroma and the Role of Soluble TβRIII in Breast Cancer Associated Fibroblasts. Cancers 2016, 8, 100.

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