Chemotherapeutics

A bacterial protein enhances the release and efficacy of liposomal cancer drugs. Cheong, I. et al. Science 314, 1308–1311 (2006)

Bert Vogelstein and colleagues show that Clostridium novyi-NT, an attenuated anaerobic bacterium, selectively infects hypoxic tumour microenvironments. Once established in the tumour, the bacteria can increase the release of liposome-encapsulated chemotherapy drugs such as doxorubicin or irinotecan. Using a combination of the attenuated bacteria and liposomal doxorubicin or liposomal irinotecan resulted in complete tumour regression and increased the survival of mice with large, established human colorectal cancer xenografts or colon CT26 mouse tumours. Furthermore, Clostridium novyi-NT increased sixfold the concentration of drug that the tumour cells were exposed to. However, treatment with monotherapies or non-liposomal drugs in combination with Clostridium novyi-NT did not increase survival or prolong tumour regression. The secretion of liposomase, the Clostridium novyi-specific lipase, was shown to be the probable cause of the liposome-disrupting ability of the bacteria. Unlike other bacterial lipases, liposomase can alter lipid bilayer structures and disrupt liposomes in vitro. Therefore, the development of Clostridium novyi-NT or liposomase as adjuvant therapies combined with liposomal chemotherapy drugs could substantially improve the specific targeting of tumour cells.

Differentiation

GATA-3 maintains the differentiation of the luminal cell fate in the mammary gland. Kouros-Mehr, H. et al. Cell 127, 1041–1055 (2006)

During puberty, the mammary gland differentiates from multipotent progenitor cells into myoepithelial cells or luminal epithelial cells, the cell type from which breast cancer develops. Zena Werb and colleagues now show that the transcription factor GATA3 is essential to this process. Using an RNA-based genome-wide microarray screen they show that Gata3 is the most highly expressed transcription factor in mouse differentiating and mature mammary epithelium. Furthermore, a conditional Gata3 knockout mouse was used to show that the transcription factor is essential for the pubertal development and maintenance of the mammary gland. Gata3 loss in adult mice resulted in the proliferation of undifferentiated cells and the detachment of existing epithelial cells from the basement membrane. Reduced expression of GATA3 in breast cancers is associated with a poor prognosis. This work suggests that GATA3 loss might have a causal role in breast cancer progression and metastasis.

Prevention

Prevention of Brca1-mediated mammary tumorigenesis in mice by a progesterone antagonist. Poole, A. J. et al. Science 314, 1467–1470 (2006)

How does BRCA1 suppress tumorigenesis in hormone-sensitive tissues? Eva Lee and colleagues show that Brca1;Trp53-deficient mice have a defect in the progesterone receptor (PR)-degradation pathway that results in PR overexpression in mammary epithelial cells. Mammary tumorigenesis was prevented in the Brca1;Trp53-deficient mice by treatment with mifepristone, a progesterone antagonist. Therefore, antiprogesterone treatment might prevent breast cancer in individuals with BRCA1 mutations.