Molecular Mechanisms of ErbB2-Driven Three-Dimensional Breast Tumor Growth

The cells lining milk-producing ducts of the breast (epithelial cells) grow in two layers. Cells of the top layer are attached to those of the bottom layer. If cells of the top layer detach they die. Breast tumors are usually derived from cells of the top layer. Breast cancer cells need to survive without attachment to the bottom layer to spread throughout the body. Cellular protein ErbB2/Her2 is normally activated by signals coming from outside of the cell and causes events changing cellular levels of many proteins. Genetic alterations in cancer cells often make ErbB2 abnormally active. One property of ErbB2 that makes it a major factor in breast cancer is its ability to drive growth of tumor cells outside of their original location. The mechanisms by which ErbB2 exerts this effect are not well understood. Our goal is tounderstand them. We found recently that ErbB2 reduces levels of a cell death-promoting protein Perp in breast cancer cells. Perp has never been To establish whether ErbB2-induced downregulation of Perp is required for the ability of breast epithelial cells to survive after detachment from a substratum.Our preliminary data indicate that his is the case. We will expand these findings in the proposed study.To identify the mechanism of ErbB2-induced downregulation of Perp.According to our preliminary observations, ErbB2 downregulates Perp by activating protein kinase Mek1, a well established ErbB2 target. We will expand these findings and examine in detail the mechanisms by which ErbB2 downregulates Perp.To establish whether ErbB2-induced downregulation of Perp is required for the ability of breast epithelial cells to form metastasis in mice.The ability of tumor cells to survive anchorage-independently is thought to be required for their metastatic potential, and we will test whether ErbB2-induced Perp downregulation contributes to this potential.To establish whether Perp is downregulated in human primary breast carcinoma.We found that ErbB2 downregulates Perp in breast epithelial cells. As ErbB2 is often overexpressed in human breast cancer we will use tissue microarrays of primary human breast carcinomas and adjacent normal breast tissues to test if Perp is downregulated in human breast cancer.