The role of cavin-1 and caveolin-1 in breast cancer
MetadataShow full item record
Caveolae are small invaginations on the plasma membrane of a variety of tissue types and are formed by the caveolin (1 and 2) and cavin (1-3) proteins families. Physiological roles implicated for caveolae include vesicular trafficking, signal transduction, cell adhesion, and mechanosensation. Over 20 years ago, caveolin-1, a small integral membrane protein, was observed to be the major tyrosine phosphorylation target in cells transformed by the Src oncogene. Subsequently its expression has been widely studied in a variety of cancers where it has been shown, confusingly, to have both oncogenic and tumor suppressive capabilities in vitro and in vivo. However, the role of cavin family of proteins in caveolae has been only recently described and minimally studied in this context. Thus to understand possible roles of caveolae in cancer biology, I investigated the roles of caveolin-1 and cavin-1 in breast cancer cell line behavior in vitro. Caveolin-1, and cavin-1 and -2 are expressed to a significant degree in aggressive estrogen receptor (ER) negative cell lines but not in ER positive cell lines. Forced ER expression, however, does not abrogate the expression of caveolar proteins. Knock-down of caveolin-1 and/or cavin-1 in the ER negative cell lines results in increased proliferation, migration, matrigel invasion, and matrix metalloproteinase activity. Consistent with this result, a highly metastatic variant of one of these cell lines shows a decrease in caveolar protein expression consistent with a role for caveolae in aggressive cell behavior. Since cell migration and matrix invasion require cytoskeletal rearrangements, I measured the activity of the cytoskeletal-associated Rho family GTPase, Cdc42, after caveolin-1and cavin-1 knockdown, and observed it to be enhanced, whereas treatment with the Cdc42 inhibitor reduced the migratory capability of the cells to wild type levels. Taken together, my data supports a tumor suppressive role for the caveolae proteins caveolin-1 and cavin-1 in ER negative breast cancer through the regulation of Cdc42. Data also suggest that both caveolin-1 and cavin-1 are required for proper caveolae formation and function. Furthermore, it stresses that cavin-1 needs to be examined in the context of caveolae and cancer.
Thesis (Ph.D.)--Boston University