Is HET/SAFB a Tumor Suppressor Gene in Breast Cancer. Generation of a Mouse Model

摘要

The scaffold attachment factor HET/SAFB 1 maps to a chromosomal locus that displays extremely high loss of heterozygozity (78%) in estrogen depend of the breast cancers. My mentors lab has shown that HET/SAFB I functions as a co-repressor of estrogen receptor transcriptional activation. We hypothesize that HET/SAFB 1 is a tumor suppressor gene. To test this hypothesis we created a mouse knockout model. During the first year of my grant we established 2 independent lines of HET/SAFBl knockout mice. During the second year of my grant we found that loss of HET/SAFBl function resulted in multiple phenotypes including prenatal and postnatal lethality, growth retardation, male infertility, female sub-fertility and hyperplasia of the mammary gland. During the third year we found that low levels of Estradiol and IGF-1 repress early development of mammary gland in knockout females. The hormone stimulation (E2) increased branching and lobulo-alveolar development, increased proliferation (BrdU) and co-localization of ER+ and proliferation. These studies show that HET/SAFB-l is involved in the hormonal regulation of development and maturation of the reproductive system and the mammary gland. Tumorogenesis studies are ongoing.