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The tumor suppressing gene pRb2/p130 may play a significant role in determining the effectiveness of drug therapies against breast cancer in women, according to a study by researchers at Temple University's Sbarro Institute for Cancer Research and Molecular Medicine.
The study, "pRb2/p130-E2F4/5-HDAC1-SUV39H1-p300 and pRb2/p130-E2F4/5-HDAC1-SUV39H1-DNMT1 Multimolecular Complexes Mediate the Transcription of Estrogen Receptor-a in Breast Cancer," will be presented at an international scientific lecture on Thursday, June 5, by Antonio Giordano, M.D., Ph.D., director of the Sbarro Institute. It will also be published in the June 5 issue of Oncogene (http://www.nature.com/onc/).
In the study, led by Giordano, researchers at the Sbarro Institute looked at the estrogen receptor gene alpha, which plays a crucial role in normal breast development in women and has been linked to the development and progression of mammary carcinoma, or breast cancer.
The study found that in estrogen receptor-positive and estrogen receptor-negative mammary cell lines of women who have been affected with breast cancer, pRb2/p130 binds with the estrogen receptor gene alpha and sends out signals to engage or recruit a number of molecules.
"These key molecules together are recruited by pRb2/p130 onto the receptor gene alpha, which when expressed on mammary cell lines makes the breast tumors more responsive to treatment," says Giordano, who discovered the Rb2 gene while working at Temple's Fels Cancer Institute in the early 1990s.
The researchers discovered that in estrogen receptor-negative cell lines, pRb2/p130's signal is damaged or mutated and it recruits a different sequence of molecules which cause Rb2 to silence the expression of the estrogen receptor and block drug therapies from being successful against the cancer cells.
"There is a lack of success in therapies because the drug does not recognize the tumor cells anymore," says Giordano. "It cannot distinguish between the good cells and the bad cells.
"One gene on its own doesn't mean anything," he adds. "It's the dialogue among the genes that are writing the sentences, and this finding really writes a very important sentence in the book that we are authoring on uncovering the understanding of how a normal cell functions and why some therapies work or some therapies don't work.
"It also clearly shows that cancer is not the event of one gene, but an army of genes and it looks like pRb2/p130 is one of the generals."
"During the development of cancer, many genes that suppress the transformation of normal cells to a malignant cell are inactivated or shut off. In this regard, Dr. Giordano's group has made a very important discovery on how the estrogen receptor alpha gene is shut off in breast cancer cells," says Dr. Richard L. Momparler, professor of pharmacology at the University of Montreal and Research Center, Hôpital Sainte-Justine. "This gene plays a key role in dictating the response to therapy in women with breast cancer. A better understanding of how gene inactivation occurs in tumor cells can lead to the design of more effective therapy and early diagnosis of breast cancer."
Giordano, who was joined in this study by lead author Dr. Marcella Macaluso, a research associate at the Sbarro Institute and a member of the Center for the Biomolecular Characterization of Neoplasms and Genetic Screening of Hereditary Tumors at the University of Palermo, says the next step for researchers is to figure out how they can restore pRb2/p130's correct communication or dialogue with the molecules in order to have the estrogen receptor alpha correctly express on the tumor cells. By understanding this mechanism of how Rb2 recruits molecules, he says, researchers will be able to eventually design drugs that are very precise in the target they recognize.
The study was carried out at Temple's Sbarro Institute in collaboration with the universities of Palermo and Siena in Italy. It was funded by the Sbarro Health Research Organization and the National Institutes of Health.
Journal
Oncogene