1 Ocak 2015 Dergi makalesi Açık Erişim

Erin, Nuray; Nizam, Esra; Tanriover, Gamze; Koksoy, Sadi

Citation Style Language JSON

{
  "DOI": "10.1007/s10549-015-3297-3", 
  "abstract": "CXCR2 interacts with a wide range of chemokines and CXCR2 antagonists may have therapeutic value for treatment-resistant metastatic carcinomas. We aimed to explore regulation of activity of CXCR2 and its ligand, MIP-2, in metastatic breast carcinoma. We used mouse breast carcinoma cells metastasize to brain (4TBM), liver (4TLM), and heart (4THM) and explored the extra- and intracellular mechanisms effecting MIP-2 secretion using CXCR2 antagonist and inhibitors of downstream signaling molecules. 4TBM, 4TLM, and 4THM cells include cancer stem cell features and metastasize extensively. We also determined kinetics of MIP-2 secretion in 4T1 and non-metastatic 67NR mouse breast carcinoma cells. We found that there is an autocrine-inhibition of MIP-2 secretion. Specifically, metastatic cells selectively express CXCR2 only, and not CXCR1 and attenuating CXCR2 activity with SB225002 increased MIP-2 secretion. This may be due to the inhibition of protein kinase C (PKC) activity since RO318220; a specific inhibitor of PKC also increased MIP-2 secretion. Attenuating CXCR2 activity with SB225002, otherwise suppressed proliferation of 4THM and 4TBM cells. Tumor explants and cancer-associated fibroblasts obtained from 4TLM, 4THM, and 4TBM primary tumors secreted high levels of MIP-2. Surprisingly, CXCR2 expression was low in 4TLM cells demonstrating that liver metastatic cells might be resistant to the anti-tumoral effects of CXCR2 antagonists. Our results demonstrated that resistance to anti-proliferative effects of CXCR2 may also arise from feedback increases in MIP-2 secretion. Activation of PI3 K pathway augments MIP-2 secretion, hence possible resistance to the antitumor effects of CXCR2 antagonists might be prevented with inhibitors of PI3 K.", 
  "author": [
    {
      "family": "Erin", 
      "given": " Nuray"
    }, 
    {
      "family": "Nizam", 
      "given": " Esra"
    }, 
    {
      "family": "Tanriover", 
      "given": " Gamze"
    }, 
    {
      "family": "Koksoy", 
      "given": " Sadi"
    }
  ], 
  "container_title": "BREAST CANCER RESEARCH AND TREATMENT", 
  "id": "76477", 
  "issue": "1", 
  "issued": {
    "date-parts": [
      [
        2015, 
        1, 
        1
      ]
    ]
  }, 
  "page": "57-69", 
  "title": "Autocrine control of MIP-2 secretion from metastatic breast cancer cells is mediated by CXCR2: a mechanism for possible resistance to CXCR2 antagonists", 
  "type": "article-journal", 
  "volume": "150"
}