Tumor metastasis is the major cause of death for cancer patients including breast cancer patients. The previous work have demonstrated that activated c-erbB-2/neu (also known as HER-2) oncogene can lead to higher metastatic potential in mouse 3T3 cells. This result supports the clinical observation that overexpression of the c-erbB-2-encoded p185 receptor is correlated with the number of lymph node metastasis in breast cancer patients. The ligand of c-erbB-2 receptor (named heregulin) contains an immunoglobulin-like domain that may function in cell-cell homing and adhesion, which are important events in cancer metastasis. Therefore, studies on the role and interaction of c-erbB-2 receptor and its ligand in human breast cancer metastasis would give new insights for understanding the molecular mechanisms and cellular processes of cancer metastasis. The long term goal of this proposal is to understand how c-erbB-2-encoded p185 receptor and its cognate ligands contribute to human breast cancer metastasis, hence provide a more rational basis for designing future approaches for the prevention and treatment of breast cancer metastasis.
The Specific Aims of this proposal are: 1) To elucidate the role of c-erbB-2 receptor in breast cancer cell metastasis. The breast cancer cell lines MDA-MB-231 and MCF-7 are metastatic in nude mice after injection into the mammary fatpad. Both cell lines contain only one copy of the c-erbB-2 gene and express low levels of p185 protein. However, the MDA-MB-231 cells secrete the ligands for the c-erbB-2 receptor but the MCF-7 cells do not. They will transfect c-erbB-2 expression plasmids into both cell lines, develop c-erbB-2-overexpressing stable transfectants and then assay their metastatic potential. 2) To determine the role of the heregulin in breast cancer metastasis. The investigators will introduce the heregulin expression plasmid into the MCF-7 cells that do not express ligand, and examine whether the ligand-expressing MCF-7 stable transfectants exhibit higher metastatic potential than the parental MCF-7 cells. An alternative approach is to use an antisense construct of heregulin to block the ligand expression in MDA-MB-231 cells and then examine whether this will lead to reduce metastatic potential in these cells. 3) To examine autocrine interactions of c-erbB-2 receptor and is ligand in breast cancer cell metastasis. They will generate MCF-7 double transfectants that express both high levels of c-erbB-2 receptor and heregulin and then investigate whether the receptor+ligand double transfectants exhibit higher metastatic potential than the receptor only or ligand only transfectants. Alternatively, they can use antisense c-erbB-2 to block the p185 expression in MDA-MB-231 breast cancer cells and examine whether blocking of the autocrine loop will lead to reduced metastatic potential. 4) To study the possible mechanisms of breast cancer metastasis induced by c-erbB-2 and its ligand. They will (1) examine whether heregulin can function as cell-adhesion molecule (CAM) in localizing c-erbB-2 expression breast cancer cells to extracellular matrix (ECM); (2) determine whether autocrine activations or adhesion properties of heregulin or both may contribute to breast cancer metastasis by introducing into MCF-7 breast cancer cells two p185 mutants that are defective in kinase activity and defective in autocrine signaling; (3) examine the breast cancer cell transfectants generated in Aims 1, 2 and 3 for metastasis-related properties to see which steps of the metastatic cascade (adhesion, migration and basement membrane-degradative enzyme secretion etc.) can be induced by growth signals associated with c-erbB-2 receptor and its ligand.
|Tan, Ming; Yu, Dihua (2007) Molecular mechanisms of erbB2-mediated breast cancer chemoresistance. Adv Exp Med Biol 608:119-29|
|Tan, M; Li, P; Sun, M et al. (2006) Upregulation and activation of PKC alpha by ErbB2 through Src promotes breast cancer cell invasion that can be blocked by combined treatment with PKC alpha and Src inhibitors. Oncogene 25:3286-95|
|Tan, Ming; Li, Ping; Klos, Kristine S et al. (2005) ErbB2 promotes Src synthesis and stability: novel mechanisms of Src activation that confer breast cancer metastasis. Cancer Res 65:1858-67|
|Sellappan, Shankar; Grijalva, Rebecca; Zhou, Xiaoyan et al. (2004) Lineage infidelity of MDA-MB-435 cells: expression of melanocyte proteins in a breast cancer cell line. Cancer Res 64:3479-85|
|Nagata, Yoichi; Lan, Keng-Hsueh; Zhou, Xiaoyan et al. (2004) PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6:117-27|
|Zhou, Xiaoyan; Tan, Ming; Stone Hawthorne, Valerie et al. (2004) Activation of the Akt/mammalian target of rapamycin/4E-BP1 pathway by ErbB2 overexpression predicts tumor progression in breast cancers. Clin Cancer Res 10:6779-88|
|Tan, Ming; Jing, Tong; Lan, Keng-Hsueh et al. (2002) Phosphorylation on tyrosine-15 of p34(Cdc2) by ErbB2 inhibits p34(Cdc2) activation and is involved in resistance to taxol-induced apoptosis. Mol Cell 9:993-1004|
|Lee, Sangkyou; Yang, Wentao; Lan, Keng-Hsueh et al. (2002) Enhanced sensitization to taxol-induced apoptosis by herceptin pretreatment in ErbB2-overexpressing breast cancer cells. Cancer Res 62:5703-10|
|Yu, D; Hung, M C (2000) Overexpression of ErbB2 in cancer and ErbB2-targeting strategies. Oncogene 19:6115-21|