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[DOWNLOAD] "Role of Psoriasin (S100a7) in Estrogen Receptor Positive Breast Cancers" by Yadwinder S. Deol ~ Book PDF Kindle ePub Free

Role of Psoriasin (S100a7) in Estrogen Receptor Positive Breast Cancers

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eBook details

  • Title: Role of Psoriasin (S100a7) in Estrogen Receptor Positive Breast Cancers
  • Author : Yadwinder S. Deol
  • Release Date : January 18, 2013
  • Genre: Medical,Books,Professional & Technical,Science & Nature,
  • Pages : * pages
  • Size : 11575 KB

Description

Psoriasin (S100A7) is expressed in several epithelial malignancies including breast cancer. Although S100A7 is associated with the worst prognosis in estrogen receptor α-negative (ERα-) invasive breastcancers, its role in ERα-positive (ERα+) breast cancers is relatively unknown. We investigated the significance of S100A7 in ERα+ breast cancer cells and observed that S100A7-overexpression in ERα+breast cancer cells, MCF7 and T47D, exhibited decreased migration, proliferation, and wound healing. These results were confirmed in vivo in a nude mouse model system. Mice injected with S100A7-overexpressing MCF7 cells showed significant reduction in tumor size compared to mice injected with vector control cells. Mechanistic studies revealed that S100A7 mediates the tumor-suppressive effects by regulating β-catenin/TCF4 and p53 pathways. We observed down-regulation of β-catenin, p-GSK3β, TCF4, cyclin D1, and c-myc in S100A7-overexpressing ERα+ breast cancer cells. In addition, we observed increased expression of GSK3β. Treatment with GSK3β inhibitor CHIR 99021 increased the expression of β-catenin and its downstream target c-myc in S100A7-overexpressing cells. Tumors derived from mice injected with S100A7-overexpressing MCF7 cells also showed reduced activation of the β-catenin/TCF4 pathway. Our results also demonstrated that S100A7-overexpression in MCF7 cells increased the stability of p53 compared to vector control cells. Co-immunoprecipitation studies revealed that S100A7 binds to and co-localize with p53 in the nucleus of S100A7-overexpressing cells. In addition, we found that phosphorylation of p53 at Serine-15 residue was enhanced in S100A7-overexpressing MCF7 cells. Serine-15 is known to stabilize and activate p53 during cellular stresses. Further, real time PCR p53 array and immunoblotting experiments showed that S100A7-overexpression in MCF7 cells up-regulated ATR and its downstream molecules p-Chk1 and p-Chk2 which are known to phosphorylate serine-15 of p53. We further evaluated the role of p53 and S100A7 in vivo by generating a mouse model which was deficient in p53 expression but expressed murine S100A7 (mS100A7A10) in the mammary glands under doxycycline treatment. After 10 weeks of doxycycline treatment, we observed the development of spontaneous tumors in the fourth inguinal mammary gland of the mouse. S100A7-overexpression in MCF7 cells also exhibited decreased actin polymerization as evident from decreased formation of migratory structures. Actin staining revealed F-actin expression on the plasma membrane in vector control cells whereas in S100A7-overexpressing cells, actin staining was intracellular. Both serum and EGF-induced migration were reduced in S100A7-overexpressing cells and upon analysis of the mechanisms that regulate actin polymerization; we observed reduced activation of EGFR, Rac1 and cofilin. In conclusion, our studies reveal for the first time that S100A7-overexpressing ERα+ breast cancer cells exhibit tumor suppressor capabilities by down-modulation of the β-catenin/TCF4 and p53 pathways both in vitro and in vivo. Our results show that S100A7 stabilizes p53 in the nucleus which then activates the stress induced pathway. Moreover, we also show that S100A7 modulates the cytoskeleton by regulating actin polymerization. Since S100A7 has been shown to enhance tumorigenicity in ERα- cells, our studies suggest that S100A7 may possess differential activities in ERα+ compared with ERα- cells.


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