Ionizing radiation-mediated premature senescence and paracrine interactions with cancer cells enhance the expression of syndecan 1 in human breast stromal fibroblasts: the role of TGF-β

Aging (Albany NY). 2016 Aug;8(8):1650-69. doi: 10.18632/aging.100989.

Abstract

The cell surface proteoglycan syndecan 1 (SDC1) is overexpressed in the malignant breast stromal fibroblasts, creating a favorable milieu for tumor cell growth. In the present study, we found that ionizing radiation, a well-established treatment in human breast cancer, provokes premature senescence of human breast stromal fibroblasts in vitro, as well as in the breast tissue in vivo. These senescent cells were found to overexpress SDC1 both in vitro and in vivo. By using a series of specific inhibitors and siRNA approaches, we showed that this SDC1 overexpression in senescent cells is the result of an autocrine action of Transforming Growth Factor-β (TGF-β) through the Smad pathway and the transcription factor Sp1, while the classical senescence pathways of p53 or p38 MAPK - NF-kB are not involved. In addition, the highly invasive human breast cancer cells MDA-MB-231 (in contrast to the low-invasive MCF-7) can also enhance SDC1 expression, both in early-passage and senescent fibroblasts via a paracrine action of TGF-β. The above suggest that radiation-mediated premature senescence and invasive tumor cells, alone or in combination, enhance SDC1 expression in breast stromal fibroblasts, a poor prognostic factor for cancer growth, and that TGF-β plays a crucial role in this process.

Keywords: TGF-β; breast stroma; cancer; ionizing radiation; senescence; syndecan 1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cellular Senescence / physiology*
  • Cellular Senescence / radiation effects
  • Female
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Fibroblasts / radiation effects
  • Humans
  • Mammary Glands, Human / metabolism*
  • Mammary Glands, Human / radiation effects
  • NF-kappa B / metabolism
  • Paracrine Communication / physiology*
  • Radiation, Ionizing
  • Signal Transduction / physiology
  • Smad Proteins / metabolism
  • Syndecan-1 / genetics
  • Syndecan-1 / metabolism*
  • Transforming Growth Factor beta / metabolism*

Substances

  • NF-kappa B
  • SDC1 protein, human
  • Smad Proteins
  • Syndecan-1
  • Transforming Growth Factor beta