Biological Function of BRCA1 and Its Regulation by the Extracellular Matrix and PTEN in Breast Cancer

摘要

A high incidence of familial breast and ovarian cancer is associated with inactivation of BRCAl. We demonstrated previously that HRG induced the phosphorylation of BRCAl, which was mediated by the phosphatidylinositol-3 kinase (PI3K)/Akt pathway. Since both extracellular matrix (ECM) and PTEN can modulate P13K/Akt pathway we hypothesized that ECM and PTEN may affect the expression and phosphorylation of BRCAl. To test this we wanted: (1) To determine the effect of ECM/integrins on BRCA1 expression, phosphorylation and nuclear translocation. (2) To characterize biological functions of BRCAl in breast cancer cells. (3) To determine the effect of PTEN on BRCAl phosphorylation. Both cell proliferation and BRCAl phosphorylation were enhanced in T47D cells seeded on laminin after treatment with heregulin (HRG). The enhanced BRCAl phosphorylation on laminin was mediated through alpha(6)beta(4) integrins. Overexpression of BRCAl inhibited HRG-dependent DNA synthesis in breast cancer cells. HRG suppressed BRCAl expression through protein degradation, which required both calpain and proteosome. ECM suppressed BRCAl mRNA expression through its C-terminus, while forced expression of PTEN inhibited HRG-dependent activation of Akt. Taken together these findings show that while BRCAl suppresses HRG-dependent DNA synthesis, ECM and/or HRG can regulate BRCAl expression and phosphorylation. Experiments with PTEN indicated that this phosphatase could affect phosphorylation of BRCA1.