Combined Inhibition of PI3K, mTOR and Bcl-2 Significantly Radiosensitises Progesterone and Oestrogen Receptor Negative Breast Cancer Cells

Roswita Hamunyela,Mogammad Hamid,Antonio Serafín ,John Akudugu

doi:10.18314/gjct.v2i1.138

Abstract

Patients with triple-negative breast cancers (TNBC) constitute about one-fifth of all breast cancer patients. TNBC is an aggressive and heterogeneous disease entity in comparison with other types of breast cancer and, therefore, tends to be resistant to existing treatment regimens, such as, targeted and hormone therapies. There is evidence to suggest that proliferative and survival pathways of triple-negative tumours are still poorly understood, which could be the reason for the observed treatment resistance. Novel treatment approaches are, therefore, needed to overcome the challenges in the treatment of triple-negative breast cancers. Three human breast cell lines (MDAMB- 231, MCF-7 and MCF-12A) were pre-treated ith inhibitors of phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), and the pro-survival gene (Bcl-2), and their radiosensitivities were evaluated using the clonogenic cell survival assay. Inhibition of PI3K, mTOR, and Bcl-2 with a cocktail of small molecule inhibitors NVP-BEZ235 and ABT-263 resulted in a 4- to 14-fold radiosensitisation of human breast cell lines with features similar to those of triple-negative cancers. These findings suggest that inhibition of I3K, mTOR, and Bcl-2 can significantly enhance the sensitivity of breast cells devoid of progesterone and oestrogen receptor expression. This approach may have therapeutic potential for breast cancer management.

Highlights

Triple-negative breast cancers (TNBC) are devoid of expression of progesterone receptor (PR) and oestrogen receptor (ER), and do not overexpress the human epidermal growth factor receptor 2 (HER2)
Pre-treatment of radioresistant MDAMB-231 cells with Bcl-2 inhibitor, ABT-263, alone or a cocktail of ABT-263 and NVP-BEZ235 resulted in significant radiosensitisation, with the latter yielding the highest effect (Figure 1)
Patients with triple-negative breast cancer may not benefit from existing targeted therapies, as the malignancies do not present with target antigens of relevance to these treatment approaches

Summary

Introduction

Triple-negative breast cancers (TNBC) are devoid of expression of progesterone receptor (PR) and oestrogen receptor (ER), and do not overexpress the human epidermal growth factor receptor 2 (HER2). J Cancer Biol Therap, 1(2): 101-108 (2016) doi: subtype constitutes about 20% of women with breast cancer [1], the majority of whom are young Black and Hispanic women [2] Inadequate expression of these antigens that could potentially be therapeutic targets may be responsible for the apparent resistance of triple-negative breast cancer to existing treatment regimens like radiotherapy. It was hypothesised that concomitant inhibition of phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), and the pro-survival gene (Bcl-2) may sensitise TNBC to radiotherapy to a larger extent To test this hypothesis, the effect of concurrently inhibiting PI3K, mTOR and Bcl-2 on the radiosensitivity of three human breast cell lines with a wide range of HER2, ER and PR expression was assessed. The potential of this combined modality as an effective therapeutic approach for TNBC is discussed

Methods

Results

Conclusion