Turning cell cycle controller genes into cancer drugs

Mallucci, Livio; Wells, Valerie; Danikas, Antonios; Davies, Derek

doi:10.1016/s0006-2952(03)00512-4

Cited by 10 publications

(1 citation statement)

References 57 publications

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“…We have previously reported that luminal breast cells from cosmetic reduction mammoplasties in short-term culture arrested by βGBP suffer no harm and resume growth. Additionally, we have reported that βGBP has no harmful effect on expanding T cells from healthy subjects nor, importantly, on progenitor cells from bone marrow donors [ 41 - 43 ]. In this study, we find that the naïve MCF10A mammary ductal cells suffered little damage when exposed to βGBP indicating that loss of survival signalling is not harmful in the absence of abnormal mitogenic pressure, thus offering one conceivable explanation for the absence of harmful effect by βGBP in the ex vivo normal cells previously studied [ 41 - 43 ].…”

Section: Discussionmentioning

confidence: 99%

Phosphoinositide 3-kinase targeting by the β galactoside binding protein cytokine negates akt gene expression and leads aggressive breast cancer cells to apoptotic death

Wells

Mallucci

2009

Breast Cancer Res

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IntroductionPhosphoinositide 3-kinase (PI3K)-activated signalling has a critical role in the evolution of aggressive tumourigenesis and is therefore a prime target for anticancer therapy. Previously we have shown that the β galactoside binding protein (βGBP) cytokine, an antiproliferative molecule, induces functional inhibition of class 1A and class 1B PI3K. Here, we have investigated whether, by targeting PI3K, βGBP has therapeutic efficacy in aggressive breast cancer cells where strong mitogenic input is fuelled by overexpression of the ErbB2 (also known as HER/neu, for human epidermal growth factor receptor 2) oncoprotein receptor and have used immortalised ductal cells and non-aggressive mammary cancer cells, which express ErbB2 at low levels, as controls.MethodsAggressive BT474 and SKBR3 cancer cells where ErbB2 is overexpressed, MCF10A immortalised ductal cells and non-invasive MCF-7 cancer cells which express low levels of ErbB2, both in their naive state and when forced to mimic aggressive behaviour, were used. Class IA PI3K was immunoprecipitated and the conversion of phosphatidylinositol (4,5)-biphosphate (PIP2) to phosphatidylinositol (3,4,5)-trisphosphate (PIP3) assessed by ELISA. The consequences of PI3K inhibition by βGBP were analysed at proliferation level, by extracellular signal-regulated kinase (ERK) activation, by akt gene expression and by apoptosis. Apoptosis was documented by changes in mitochondrial membrane potential, alteration of the plasma membrane, caspase 3 activation and DNA fragmentation. Phosphorylated and total ERK were measured by Western blot analysis and akt mRNA levels by Northern blot analysis. The results obtained with the BT474 and SKBR3 cells were validated in the MCF10A ductal cells and in non-invasive MCF-7 breast cancer cells forced into mimicking the in vitro behaviour of the BT474 and SKBR3 cells.ResultsIn aggressive breast cancer cells, where mitogenic signalling is enforced by the ErbB2 oncoprotein receptor, functional inhibition of the catalytic activity of PI3K by the βGBP cytokine and loss of akt mRNA results in apoptotic death. A functional correlation between ERK and the kt gene was also found. The relationship between ERK, akt mRNA, PI3K and cell vulnerability to βGBP challenge was sustained both in mammary ductal cells forced to mimic an aggressive behaviour and in non-aggressive breast cancer cells undergoing an enforced shift into an aggressive phenotype.ConclusionsβGBP, a newly discovered physiological inhibitor of PI3K, is a selective and potent inducer of apoptosis in aggressive breast cancer cells. Due to its physiological nature, which carries no chemotherapeutic disadvantages, βGBP has the potential to be safely tested in clinical trials.

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