title: Rapamycin and PF4 induce apoptosis by upregulating Bax and down-regulating survivin in MNU-induced breast cancer.
abstract: BACKGROUND
  To elucidate the role of rapamycin and PF4 on apoptosis regulation via Bax (pro-apoptosis), Bcl-2 (anti-apoptosis) and survivin activation on the growth in the 1-methyl-1-nitrosourea -induced invasive breast carcinoma model.
  
  
  METHODS
  Thirty five female Sprague Dawley rats at age 21-day old were divided into 4 groups; Group 1 (control, n=10), Group 2 (PF4, n=5), Group 3 (rapamycin, n=10) and Group 4 (rapamycin+PF4, n=10). MNU was administered intraperitionally, dosed at 70 mg/kg body weight. The rats were treated when the tumors reached the size of 14.5 ± 0.5 mm and subsequently sacrificed after 5 days. Rapamycin and PF4 were administered as focal intralesional injections at the dose of 20 μg/lesion. The tumor tissue was then subjected to histopathological examinations for morphological appraisal and immunohistochemical assessment of the pro-apoptotic marker, Bax and anti-apoptotic markers, Bcl-2 and survivin.
  
  
  RESULTS
  The histopathological pattern of the untreated control cohort showed that the severity of the malignancy augments with mammary tumor growth. Tumors developing in untreated groups were more aggressive whilst those in treated groups demonstrated a transformation to a less aggressive subtype. Combined treatment resulted in a significant reduction of tumor size without phenotypic changes. Bax, the pro-apoptotic marker, was significantly expressed at higher levels in the rapamycin-treated and rapamycin+PF4-treated groups compared to controls (p<0.05). Consequently, survivin was also significantly downregulated in the rapamycin-treated and rapamycin+PF4-treated group and this was significantly different when compared to controls (p).
  
  
  CONCLUSIONS
  In our rat model, it could be clearly shown that rapamycin specifically affects Bax and survivin signaling pathways in activation of apoptosis. We conclude that rapamycin plays a critical role in the induction of apoptosis in MNU-induced mammary carcinoma.
authors.affiliation: Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia E-mail : saintispath@gmail.com.
authors.forename: Tengku Ahmad Damitri
authors.initials: TA
authors.lastname: Al-Astani Tengku Din
authors.forename: Shazana Hilda
authors.initials: SH
authors.lastname: Shamsuddin
authors.forename: Fauziah Mohamad
authors.initials: FM
authors.lastname: Idris
authors.forename: Wan Nor
authors.initials: WN
authors.lastname: Ariffin Wan Mansor
authors.forename: Muhammad Irfan
authors.initials: MI
authors.lastname: Abdul Jalal
authors.forename: Hasnan
authors.initials: H
authors.lastname: Jaafar
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic; D015536:Down-Regulation; D005260:Female; D008321:Mammary Glands, Animal / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy*; D008770:Methylnitrosourea; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis*; D010978:Platelet Factor 4 / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D000077022:Survivin; D015533:Transcriptional Activation; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis*
chemical_list: C516989:Birc5 protein, rat; D008869:Microtubule-Associated Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D000077022:Survivin; D051028:bcl-2-Associated X Protein; D010978:Platelet Factor 4; D008770:Methylnitrosourea; D020123:Sirolimus