Abstract
Estrogen is believed to be pre-initiator in the risk of breast cancer. The BRCA1 is a tumor suppressor gene associated with breast and ovarian cancer risk. This report describes functional analysis of two BRCA1 missense mutations (Asp67Glu and Thr1051Ser) observed in the familial breast/ovarian cancer patients in Thailand. Levels of luciferase activity of the two mutations were relatively lower than in the wild-type BRCA1. It is indicated that mutants may fail to promote the estrogen receptor dependent functions. It is presumed that estrogen and insulin/IGF-1 regulate c-Myc and cyclin D1 during breast cancer cell proliferation. It is also likely to affect ubiquitination mechanism. Since three affected cancer families carry the Asp67Glu mutation, it is believed that this type of mutation could have some effect on breast/ovarian cancer progression.
Highlights
Breast cancer is the most common form cancer of women worldwide
We studied the role of these two missense mutations in estrogen receptor signaling pathway for promote the breast/ovarian carcinogenesis
For the patient ID34 in family F17, the age of onset was low (27 years) and she had infiltrative adenocarcinoma of right breast. Both breast and ovarian cancer were found among the F17 members (Figure 1)
Summary
Breast cancer is the most common form cancer of women worldwide. In many developing countries, including in Asia, which were formerly believed to have low risk of breast cancer, the incidence is presently increasing. Human ER α comprises of 595 amino acids and has molecular weight of 66-70 kD It contains six functional domains (A to F). Region C is DNA binding domain (DBD) and contains two zinc finger motif and responsible for the binding of the receptor to estrogen response elements as well as contribute to dimerization and transactivation. Region E contains the ligand binding domain (LBD) and activation function 2 (AF-2). The transformed ER dimer binds to its specific estrogen response element (ERE) located in the promoter region of estrogen responsive genes, regulating their transcriptional activity. Asp67Glu and Thr1051Ser are the two BRCA1 missense mutations which occurred in Thai familial breast/ovarian cancer patients [16]. We studied the role of these two missense mutations in estrogen receptor signaling pathway for promote the breast/ovarian carcinogenesis
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