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Ectopic expression of mutant forms of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) lacking lipid (G129E) or lipid and protein (C124S) phosphatase activity decreased sensitivity of MCF-7 breast cancer cells, which have wild-type PTEN, to doxorubicin and increased sensitivity to the mammalian target of rapamycin (mTOR) inhibitor rapamycin. Cells transfected with a mutant PTEN gene lacking both lipid and protein phosphatase activities were more resistant to doxorubicin than cells transfected with the PTEN mutant lacking lipid phosphatase activity indicating that the protein phosphatase activity of PTEN was also important in controlling the sensitivity to doxorubicin, while no difference was observed between the lipid (G129E) and lipid and protein (C124S) phosphatase PTEN mutants in terms of sensitivity to rapamycin. A synergistic inhibitory interaction was observed when doxorubicin was combined with rapamycin in the phosphatase-deficient PTENtransfected cells. Interference with the lipid phosphatase activity of PTEN was sufficient to activate Akt/mTOR/ p70S6K signaling. These studies indicate that disruption of the normal activity of the PTEN phosphatase can have dramatic effects on the therapeutic sensitivity of breast cancer cells. Mutations in the key residues which control PTEN lipid and protein phosphatase may act as dominant-negative mutants to suppress endogenous PTEN and alter the sensitivity of breast cancer patients to chemo-and targeted therapies.

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Deregulation of matrix metalloproteinases (MMPs) is an important factor contributing to the development of vascular lesions. Plasma levels and zymographic activities of MMP-2 and MMP-9 were investigated in type II diabetics with (n ϭ 51) or without (n ϭ 42) peripheral artery disease (PAD) and in normal volunteers (n ϭ 23). Plasma MMP-2 levels were higher in type II diabetics with (p Ͻ 0.01) or without (p Ͼ 0.05) PAD in comparison with normal volunteers. Similarly, type II diabetics with (p Ͻ 0.0001) or without (p Ͼ 0.05) PAD had higher plasma MMP-9 levels than normal volunteers. Plasma zymographic activities of both MMP-2 and MMP-9 were positively correlated with their plasma levels. Plasma MMP-2 zymographic activity was higher in type II diabetics with PAD than type II diabetics without PAD (p Ͼ 0.05). Plasma MMP-9 zymographic activity was higher in type II diabetics with (p Ͻ 0.0001) or without (p Ͻ 0.0001) PAD in comparision with normal volunteers. Together, these results indicate that increased plasma levels and zymographic activities of MMP-2 and MMP-9 may contribute to PAD in type II diabetics. In particular, plasma MMP-9 may be a useful marker for the development of vascular disease in type II diabetics.

Mutation of BRAF has been proposed to contribute to melanoma development. However, it remains unclear whether or not BRAF mutation is associated with any particular stage of melanoma progression. Tumor biopsy specimens from patients with melanoma were analyzed to determine whether the frequency of BRAF mutation in metastatic melanoma differed from primary melanoma. BRAF mutation was present in 15 of 23 (61%) patients with primary melanoma and in 7 of 12 (58%) patients with metastatic melanoma. These results suggest that BRAF mutation in melanoma is most likely to occur prior to the development of metastatic disease.

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