Activated oncogenes and putative tumor suppressor genes involved in human breast cancers

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Abstract

The clinical progression of human breast cancer almost certainly reflects accumulated molecular defects in specific genes that are important in regulating normal breast tissue growth and development. These specific defects may occur in association with gross chromosomal damage and aberrations in total cellular DNA content, once providing the only basis for their genetic detection. Within the past decade, however, new molecular techniques have enabled the detection of an increasing number of genetic abnormalities that are specific to malignant cells but not necessarily unique to breast cancers. Some of these molecular defects found in the earliest stages of human breast cancer (e.g., c-erbB-2 amplification) appear to have clinical significance by their ability to predict tumor relapse and patient survival, suggesting that they produce permanent cellular disturbances contributing to the proliferative or invasive nature of breast cancer. Nonetheless , a unified molecular model explaining breast carcinogenesis and its clinical progression is far from being realized. As this review demonstrates, we have only begun to identify and characterize clinically significant genetic abnormalities as they are found in primary human breast cancers. At present, it is useful to classify these molecular abnormalities into two types: gain-of-function genetic events that activate proto-oncogenes by DNA mutation, rearrangement, or amplification, and loss-of-function defects reflecting putative tumor suppressor genes that have been inactivated by DNA mutation and unmasked by deletion or allelic loss.