Abstract

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. 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. 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). 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.

Highlights

  • Breast cancer is the commonest malignancy in women and the second leading cause of cancer deaths

  • This study aims to analyse the expression of apoptosis proteins Bax, Bcl-2 and survivin after treatment with rapamycin, Platelet factor 4 (PF4) and rapamycin+PF4 in MNU-induced murine breast cancer model

  • Our study demonstrates that Bax expression was higher in all breast cancer specimens treated with rapamycin, PF4 and combined groups when compared against a control group (p value=0.001, 0.007 and 0.001, respectively)

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Summary

Introduction

Breast cancer is the commonest malignancy in women and the second leading cause of cancer deaths. The latest report from Ma et al, in 2012, an expected 226,870 new cases of invasive breast cancer and 39,510 breast cancer deaths are predictable to arise among U.S women (Hassan et al, 2013). 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. Results: The histopathological pattern of the untreated control cohort showed that the severity of the malignancy augments with mammary tumor growth. Conclusions: In our rat model, it could be clearly shown that rapamycin 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

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