TβRIII Expression in Human Breast Cancer Stroma and the Role of Soluble TβRIII in Breast Cancer Associated Fibroblasts.
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 inTGFBR3mRNA in tumor stroma in comparison to control tissue. We investigated publicly available databases, and have identified thatTGFBR3mRNA 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.
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. bojana_jovanovic@dfci.harvard.edu.
Bojana
B
Jovanović
Department of Bioengineering, University of California San Francisco, San Francisco, CA 94117, USA. michael.pickup@ucsfmedctr.org.
Michael W
MW
Pickup
Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA. anna.chytil@vanderbilt.edu.
Anna
A
Chytil
Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA. agnes.gorska@vanderbilt.edu.
Agnieszka E
AE
Gorska
Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA. kimberly.n.johnson@vanderbilt.edu.
Kimberly C
KC
Johnson
Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA. hal.moses@vanderbilt.edu.
Harold L
HL
Moses
Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA. Philip.owens@vanderbilt.edu.|Research Medicine, Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37232, USA. Philip.owens@vanderbilt.edu.
Philip
P
Owens
Betaglycan; Cancer-Associated-Fibroblasts (CAFs); TGFBR3; TβRIII; cancer stroma; tumor microenvironment