Osteocytic connexin hemichannels modulate oxidative bone microenvironment and breast cancer growth

Yi Tian, Manuel A. Riquelme, Chao Tu, Yumeng Quan, Xiaowen Liu, Lu Zhe Sun, Jean X. Jiang

Research output: Contribution to journalArticlepeer-review

Abstract

Osteocytes, the most abundant bone cell types embedded in the mineral matrix, express connexin 43 (Cx43) hemichannels that play important roles in bone remodeling and osteocyte survival. Estrogen deficiency decreases osteocytic Cx43 hemichannel activity and causes a loss in osteocytes’ resistance to oxidative stress (OS). In this study, we showed that OS reduced the growth of both human (MDA-MB-231) and murine (Py8119) breast cancer cells. However, co-culturing these cells with osteocytes reduced the inhibitory effect of OS on breast cancer cells, and this effect was ablated by the inhibition of Cx43 hemichannels. Py8119 cells were intratibially implanted in the bone marrow of ovariectomized (OVX) mice to determine the role of osteocytic Cx43 hemichannels in breast cancer bone metastasis in response to OS. Two transgenic mice overexpressing dominant-negative Cx43 mutants, R76W and ∆130-136, were adopted for this study; the former inhibits gap junctions while the latter inhibits gap junctions and hemichannels. Under normal conditions, ∆130-136 mice had significantly more tumor growth in bone than that in WT and R76W mice. OVX increased tumor growth in R76W but had no significant effect on WT mice. In contrast, OVX reduced tumor growth in ∆130-136 mice. To confirm the role of OS, WT and ∆130-136 mice were administered the antioxidant N-acetyl cysteine (NAC). NAC increased tumor burden and growth in ∆130-136 mice but not in WT mice. Together, the data suggest that osteocytes and Cx43 hemichannels play pivotal roles in modulating the oxidative microenvironment and breast cancer growth in the bone.

Original languageEnglish (US)
Article number6343
JournalCancers
Volume13
Issue number24
DOIs
StatePublished - Dec 1 2021

Keywords

  • Breast cancer bone metastasis
  • Cx43 hemichannels
  • Estrogen deficiency
  • Oxidative stress

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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