Rapamycin and PF4 Induce Apoptosis by Upregulating Bax and Down-Regulating Survivin in MNU-Induced Breast Cancer

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 invasivebreast carcinoma model. Materials and
Methods: Thirty five female Sprague Dawley rats at age 21-day old weredivided 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 70mg/kg body weight. The rats weretreated when the tumors reached the size of 14.5±0.5mm and subsequently sacrificed after 5 days. Rapamycinand PF4 were administered as focal intralesional injections at the dose of 20 μg/lesion. The tumor tissue was thensubjected to histopathological examinations for morphological appraisal and immunohistochemical assessmentof the pro-apoptotic marker, Bax and anti-apoptotic markers, Bcl-2 and survivin.
Results: The histopathologicalpattern of the untreated control cohort showed that the severity of the malignancy augments with mammary tumorgrowth. Tumors developing in untreated groups were more aggressive whilst those in treated groups demonstrateda transformation to a less aggressive subtype. Combined treatment resulted in a significant reduction of tumorsize without phenotypic changes. Bax, the pro-apoptotic marker, was significantly expressed at higher levels in therapamycin-treated and rapamycin+PF4-treated groups compared to controls (p<0.05). Consequently, survivinwas also significantly downregulated in the rapamycin-treated and rapamycin+PF4-treated group and this wassignificantly different when compared to controls (p).
Conclusions: In our rat model, it could be clearly shownthat rapamycin specifically affects Bax and survivin signaling pathways in activation of apoptosis. We concludethat rapamycin plays a critical role in the induction of apoptosis in MNU-induced mammary carcinoma.