New Insight into cervical cancer development: turning it up a notch

August 31, 2002

A collaboration of scientists from Harvard Medical School and Brigham and Women's Hospital have uncovered a key genetic event in the progression of malignant cervical cancer -- and a potential new therapeutic target.

Dr. G. Paolo Dotto and colleagues have found that the decreased expression of a single gene, called Notch1, is instrumental in the late stages of human papilloma virus-induced cervical cancer. The report is published in the September 1 issue of Genes & Development.

Human papilloma virus (HPV) is the most prevalent sexually transmitted infection in the world, and HPV infection is associated with the majority of the 400,000 new cervical cancer cases reported annually. Previous genetic studies have, to some degree, elucidated the molecular mechanism of HPV-induced cervical carcinogenesis: The HPV genome encodes two viral proteins, E6 and E7, which interfere with two of the infected cell's primary tumor suppressor pathways (p53 and Rb). However, it is thought that while basal levels of E6/7 expression are necessary for HPV-induced cervical tumorigenesis, other genetic changes are needed to fully transform a normal cervical cell into a malignant one.

Dr. Dotto and colleagues have identified one such change.

Dr. Dotto and colleagues have discovered that the down-regulation of a cell signaling molecule, called Notch1, in HPV-infected cervical cells allows for the increased expression of E6 and E7, which, in turn, promote malignant cervical cell transformation. The researchers found that in low-grade HPV-positive cervical lesions, Notch1 is expressed at an adequate level to suppress E6 and E7, and thereby protects the cell against HPV-induced transformation. However, in high-grade HPV-positive cervical lesions, Notch1 expression is markedly decreased, relieving the suppression of E6 and E7 activity, and creating the correct genetic milieu for malignant cell transformation.

The researchers conclude that the reduced expression of Notch1 in HPV-infected cervical cells is an important step in malignant cervical cancer development. This finding sheds new light on the role of Notch signaling in tumorigenesis, as previous research found that the activation of Notch promotes tumor development. Dr. Dotto explains that "The main conclusion that can be drawn from our findings is that the positive or negative role of the Notch pathway in tumor development is likely to be highly context-dependent. Therefore, the potential therapeutic applications of agents that suppress Notch signaling need to be carefully evaluated, as they could have the opposite effect of what was actually intended."

Cold Spring Harbor Laboratory

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