Dietze Eric C, Bowie Michelle L, Mrózek Krzysztof, Caldwell L Elizabeth, Neal Cassandra, Marjoram Robin J, Troch Michelle M, Bean Gregory R, Yokoyama Kazunari K, Ibarra Catherine A, Seewaldt Victoria L
Division of Medical Oncology, Duke University, Durham, NC 27710, USA.
J Cell Sci. 2005 Nov 1;118(Pt 21):5005-22. doi: 10.1242/jcs.02616. Epub 2005 Oct 11.
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.
正常乳腺上皮细胞与细胞外基质（ECM）之间的相互作用对于乳腺稳态至关重要。ECM与正常乳腺上皮细胞之间相互作用的丧失被认为是乳腺癌发生的早期事件。CREB结合蛋白（CBP）是增殖和凋亡的重要调节因子，但CBP在ECM信号传导中的作用尚不清楚。在基底细胞角蛋白阳性的人乳腺上皮细胞（CK5/6+、CK14+、CK8-、CK18-、CK19-）中CBP受到抑制。CBP的抑制导致重组ECM介导的生长控制和凋亡丧失以及层粘连蛋白-5α3链表达丧失。在正常人乳腺上皮细胞（HMECs）中抑制CBP导致CBP对LAMA3A启动子的占据丧失，LAMA3A启动子活性降低以及层粘连蛋白-5α-3链表达减少。在已丧失重组ECM介导的生长调节和凋亡的CBP阴性HMECs中外源表达CBP导致（1）CBP对LAMA3A启动子的占据，（2）LAMA3A活性增加和层粘连蛋白-5α3链表达增加，以及（3）重组ECM介导的生长调节和凋亡增强。同样，在HMECs中抑制层粘连蛋白-5α3链表达导致重组ECM介导的生长控制和凋亡丧失。这些观察结果表明，基底细胞角蛋白阳性HMECs中CBP的丧失通过LAMA3A活性和层粘连蛋白-5α3链表达的丧失导致重组ECM介导的生长控制和凋亡丧失。这些研究结果可能为基底型乳腺癌发生的早期事件提供见解。
