Abstract
Interactions between normal mammary epithelial cells and extracellular matrix (ECM) are important for mammary gland homeostasis. Loss of interactions between ECM and normal mammary epithelial cells are thought to be an early event in mammary carcinogenesis. CREB-binding protein (CBP) is an important regulator of proliferation and apoptosis but the role of CBP in ECM signaling is poorly characterized. CBP was suppressed in basal-cytokeratin-positive HMECs (CK5/6+, CK14+, CK8-, CK18-, CK19-). Suppression of CBP resulted in loss of reconstituted ECM-mediated growth control and apoptosis and loss of laminin-5 alpha3-chain expression. Suppression of CBP in normal human mammary epithelial cells (HMECs) resulted in loss of CBP occupancy of the LAMA3A promoter and decreased LAMA3A promoter activity and laminin-5 alpha-3 chain expression. Exogenous expression of CBP in CBP-negative HMECs that have lost reconstituted ECM-mediated growth regulation and apoptosis resulted in (1) CBP occupancy of the LAMA3A promoter, (2) increased LAMA3A activity and laminin-5 alpha3-chain expression, and (3) enhancement of reconstituted ECM-mediated growth regulation and apoptosis. Similarly, suppression of laminin-5 alpha3-chain expression in HMECs resulted in loss of reconstituted ECM-mediated growth control and apoptosis. These observations suggest that loss of CBP in basal-cytokeratin-positive HMECs results in loss of reconstituted ECM-mediated growth control and apoptosis through loss of LAMA3A activity and laminin-5 alpha3-chain expression. Results in these studies may provide insight into early events in basal-type mammary carcinogenesis.
Highlights
Loss of extracellular matrix (ECM) signaling is thought to be an early event in mammary carcinogenesis and to promote some of the phenotypic changes observed during malignant progression (Petersen et al, 1992; Howlett et al, 1995; Mercurio et al, 2001; Farrelly et al, 1999; Hood and Cheresh, 2002; Stromblad et al, 2002)
We previously performed Spectral karyotypic analyses (SKY)-based cytogenetic analysis on 35 unique late passage human mammary epithelial cells (HMECs)-E6 cells to identify rearrangements that might pinpoint the chromosomal location of potential gene(s) whose loss might promote loss of rECMmediated growth control and apoptosis induction
The most frequent chromosomal losses involved (1) 16p (26/35 cells, 74%), (2) 12p (17/35 cells, 49%), (3) 21p (17/35 cells, 49%), and (4) 17p (14/35 cells, 40%) (Seewaldt et al, 2001a; Seewaldt et al, 2001b). These studies suggested that chromosome 16p harbored a gene(s) whose loss and/or rearrangement might play a role in loss of rECM-mediated growth control and apoptosis induction
Summary
Breast tissue is composed of mammary epithelial cells that rest on extracellular matrix (ECM), and interactions between epithelial cells and ECM regulate normal growth, polarity and apoptosis (Petersen et al, 1992; Strange et al, 1992; Zutter et al, 1995; Ilic et al, 1998; Farrelly et al, 1999; Stupack and Cheresh, 2002). Loss of ECM signaling is thought to be an early event in mammary carcinogenesis and to promote some of the phenotypic changes observed during malignant progression (Petersen et al, 1992; Howlett et al, 1995; Mercurio et al, 2001; Farrelly et al, 1999; Hood and Cheresh, 2002; Stromblad et al, 2002). Loss or mutation of specific tumor suppressor genes such as TP53 promotes mammary carcinogenesis (Fabian et al, 1996; Rohan et al, 1998), not all damaged epithelial cells progress to malignancy and many are thought to be eliminated by apoptosis (Thompson, 1995). Loss of ECM signaling is thought to promote mammary carcinogenesis by preventing the apoptotic elimination of damaged mammary epithelial cells
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