Bfl-1 Gene Expression in Breast Cancer: Its Relationship with other Prognostic Factors

Yoon, Ho-Sung; Hong, Sunghee; Kang, Hee-Jun; Ko, Byung Kyun; Ahn, Sei-Hyun; Huh, Jooryung

doi:10.3346/jkms.2003.18.2.225

Cited by 22 publications

(13 citation statements)

References 20 publications

(12 reference statements)

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“…It has also been seen to protect against growth factor withdrawal-induced apoptosis in myeloid precursor cells, and surprisingly to allow differentiation of these cells, whereas Bcl-2 had an anti-proliferative function 388 . Bfl-1 is also seen overexpressed in solid tumours, such as stomach cancer 369 , breast cancer 389 , and metastatic melanoma 368 . It also appears to regulate hypoxia-induced apoptosis and oxidant-induced necrosis of epithelial cells in culture 390 , presenting an opportunity for drug studies targeting Bfl-1 in hyperoxic acute lung injury (HALI) in addition to haematological malignancies and solid tumours.…”

Section: The Role Of Bfl-1 In Cancermentioning

confidence: 99%

Role of the pro-survival molecule Bfl-1 in melanoma

Hind

Carter

Harris

et al. 2015

The International Journal of Biochemistry & Cell Biology

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Melanoma, the cancer derived from the melanocytes of the skin, is becoming an ever more common cancer in the ageing population of the developed world and displays an intrinsic resistance to current therapies. This chemo resistance makes metastatic melanoma an extremely difficult cancer to treat leading to a 5 year survival rate of just 20%. As such, it is important to unearth new potential drug targets to increase the prospects for melanoma patients.Bfl-1 is a pro-survival protein of the Bcl-2 family of apoptosis regulating proteins. It has been found to be over-expressed in a small subset of chemo resistant tumours, including melanoma. Accordingly, I characterised the molecule in melanoma cells and determined its role in protecting these cells from chemotherapy-induced apoptosis. I elucidated the expression profile and half-lives of the protein and mRNA across a panel of melanoma cell-lines and healthy melanocytes. I also confirmed, using pathway specific inhibitors, that Bfl-1 was transcriptionally regulated by the NFB pathway and concluded through pulsechase experiments that Bfl-1 protein was degraded, at least in part, by the proteasome. Subcellular fractionation and indirect immunofluorescence techniques elucidated that Bfl-1 was located mostly at the mitochondria in both resting and apoptotic cells, with a diffuse level present throughout the cytoplasm. As well as characterising the protein in both melanoma cells and healthy primary melanocytes, I determined its role in the resistance of these cells to apoptosis. Over-expressed Bfl-1 was found to protect melanoma cells from apoptosis caused by a range of chemotherapeutic agents in A375 melanoma cells, which naturally expressed very low levels of Bfl-1. Further, knock down of Bfl-1 using siRNA technology in melanoma cells revealed the dependence of these cells on Bfl-1 for their resistance to certain chemotherapeutic agents currently used in melanoma treatment, including the MEK inhibitor PD901. All together, this research contributes to our understanding of Bfl-1 and highlights it as a potentially important therapeutic target in metastatic melanoma.

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Section: The Role Of Bfl-1 In Cancermentioning

confidence: 99%

Role of the pro-survival molecule Bfl-1 in melanoma

Hind

Carter

Harris

et al. 2015

The International Journal of Biochemistry & Cell Biology

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“…Amongst a panel of different solid tumour tissues, the highest expression of BCL2A1 mRNA was detected in breast cancer samples [ 62 ]. Interestingly, in advanced breast cancer a higher expression of BCL2A1 mRNA was found when compared to less advanced tumours [ 63 ], suggesting an association of BCL2A1 expression with later and more severe disease stages. Furthermore, BCL2A1 expression was associated with metastatic disease in melanoma [ 64 ] and hepatocellular carcinoma [ 65 ].…”

Section: Expression Of Antiapoptotic Bcl2-proteins In Solid Tumourmentioning

confidence: 99%

Targeting BCL2-Proteins for the Treatment of Solid Tumours

Vogler

2014

Advances in Medicine

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Due to their central role in the regulation of apoptosis, the antiapoptotic BCL2-proteins are highly promising targets for the development of novel anticancer treatments. To this end, several strategies have been developed to inhibit BCL2, BCL-XL, BCL-w, and MCL1. While early clinical trials in haematological malignancies demonstrated exciting single-agent activity of BCL2-inhibitors, the response in solid tumours was limited, indicating that, in solid tumours, different strategies have to be developed in order to successfully treat patients with BCL2-inhibitors. In this review, the function of the different antiapoptotic BCL2-proteins and their role in solid tumours will be discussed. In addition, a comprehensive analysis of current small molecules targeting these antiapoptotic BCL2-proteins (e.g., ABT-737, ABT-263, ABT-199, TW-37, sabutoclax, obatoclax, and MIM1) will be provided including a discussion of the results of any clinical trials. This analysis will summarise the potential of BCL2-inhibitors for the treatment of solid tumours and will unravel novel approaches to utilise these inhibitors in clinical applications.

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“…77 Among a panel of solid tumor tissues of different origins, including breast, colon, lung, ovarian and prostate, the highest expression of BCL2A1 mRNA was detected in breast cancer samples. 78 Interestingly, in advanced breast cancer a higher expression of BCL2A1 mRNA was found when compared with less advanced tumors, 79 suggesting an association of BCL2A1 expression with later and more severe disease stages. Furthermore, BCL2A1 expression was associated with metastatic disease in melanoma 80 and hepatocellular carcinoma.…”

Section: Expression Of Bcl2a1 In Cancermentioning

confidence: 99%