Inhibition of early 99mTc-MIBI uptake by Bcl-2 anti-apoptotic protein overexpression in untreated breast carcinoma.
Lack of technetium-99m methoxyisobutylisonitrile ((99m)Tc-MIBI) uptake is consistently reported to predict poor response to subsequent chemotherapy in a variety of human malignant tumours. Since (99m)Tc-MIBI accumulates within mitochondria, which also play a central role in apoptosis through the integration of death signals by Bcl-2 family members, we tested whether early (99m)Tc-MIBI uptake is affected by alterations of the apoptotic pathway. Forty-two breast cancer patients were intravenously injected with 740 MBq of (99m)Tc-MIBI and planar images were obtained 10 min post injection with the patients in the prone lateral position. Ten carcinomas failed to accumulate (99m)Tc-MIBI and could not be visualised on scintigraphic images despite being larger than 1.8 cm (MIBI negative). Thirty-two of the 42 breast carcinomas showed focal uptake of (99m)Tc-MIBI (MIBI positive), and 10 min tumour-to-background ratios (T/B) varied between 1.14 and 6.93. The apoptotic index, the rate of proliferation, and the expression of the anti-apoptotic Bcl-2 protein and pro-apoptotic Bax protein were assessed in surgically excised tumours. All MIBI-negative carcinomas showed a dramatic and statistically significant reduction in the apoptotic index as compared with MIBI-positive lesions (mean+/-SD, 0.14+/-0.15 vs 1.28+/-0.83, P<0.0001) independently of rate of proliferation, tumour size and P-glycoprotein expression. Significantly higher levels of Bcl-2 were also found in MIBI-negative as compared with MIBI-positive carcinomas. In MIBI-positive lesions, an inverse significant correlation was found between T/B ratios and Bcl-2 levels ( r=-0.50, P<0.01). Our findings indicate that early uptake of (99m)Tc-MIBI in breast carcinomas is affected by alterations of apoptotic pathway. High levels of Bcl-2, despite the stabilisation of mitochondrial membrane potentials, prevent accumulation of (99m)Tc-MIBI in tumour cells. In conclusion, absent or reduced early (99m)Tc-MIBI uptake in large tumours may indicate a Bcl-2-mediated resistance to chemo- and radiotherapy.
Del Vecchio
Silvana
S
Institute of Biostructures and Bioimages of the National Research Council (CNR), Naples, Italy. delvecc@unina.it
Zannetti
Antonella
A
Aloj
Luigi
L
Caracò
Corradina
C
Ciarmiello
Andrea
A
Salvatore
Marco
M
D000328:Adult; D000368:Aged; D017209:Apoptosis; D001692:Biological Transport; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D044584:Carcinoma, Ductal / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007150:Immunohistochemistry; D008875:Middle Aged; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011877:Radionuclide Imaging; D017256:Technetium Tc 99m Sestamibi / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics*; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D017256:Technetium Tc 99m Sestamibi