title: CREB-binding protein regulates apoptosis and growth of HMECs grown in reconstituted ECM via laminin-5.
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.
authors.affiliation: Division of Medical Oncology, Duke University, Durham, NC 27710, USA.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Dietze
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Bowie
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Mrózek
authors.forename: L Elizabeth
authors.initials: LE
authors.lastname: Caldwell
authors.forename: Cassandra
authors.initials: C
authors.lastname: Neal
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Marjoram
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Troch
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Bean
authors.forename: Kazunari K
authors.initials: KK
authors.lastname: Yokoyama
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Ibarra
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Seewaldt
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D050882:CREB-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016764:Cell Polarity / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D015321:Gene Rearrangement / Q000235:genetics; D006801:Humans; D007797:Laminin / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D042361:Mammary Glands, Human / Q000166:cytology* / Q000473:pathology / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: D007797:Laminin; C095567:laminin alpha 3; D050882:CREB-Binding Protein