Deborah A. Lannigan, PhD
MAP and RSK kinases, estrogen receptor and drug discovery
Signal Transduction in Breast, Prostate and Ovarian Cancer, the Lannigan laboratory is interested in signal-transduction pathways that are involved in breast, prostate and ovarian cancer initiation and progression. Their research can be divided into two areas:
RSK Signal-Transduction Pathway: The family of Ser/Thr protein kinases called p90 ribosomal S6 kinases (RSK) function as downstream effectors of p42/p44 mitogen-activated protein kinase. They have determined that the RSK signal-transduction pathway is able to become the dominant pathway in the regulation of cancer cell proliferation. This statement is partly based on their observations with the RSK-inhibitor, SL0101. They discovered SL0101 during a screen of a natural products library. SL0101 is the first, small-molecule inhibitor for RSK and demonstrates remarkable specificity for RSK in in vitro and in cell-based assays. SL0101 inhibits the proliferation of human breast, prostate and ovarian cancer cell lines, with an efficacy paralleling its ability to inhibit RSK in intact cells. Remarkably, SL0101 does not affect the proliferation of a normal breast line, MCF-10A, and a normal prostate line, RWPE-1, even though SL0101 inhibits RSK in these cells. SL0101 produces a cell cycle block in G1, which indicates that a crucial RSK substrate regulates cell cycle progression in at least some cancer cells. They are currently trying to understand why RSK has become the dominant pathway for regulation of proliferation in some cancer cells.
As part of this effort, in collaboration with Dr. D. Hunt (Dept. Chemistry) they are mapping the phosphorylation sites in RSK2. Additionally, in collaboration with Dr. S. Parsons (Dept. Microbiology) they are evaluating the efficacy of SL0101 to inhibit the formation of mammary tumors in mice. In collaboration with Dr. M. Weber (Dept. Microbiology) they are evaluating the efficacy of SL0101 to inhibit the formation of prostate tumors in mice. They are also collaborating with Dr. H. Frierson, Jr. (Dept. Pathology) to analyze human breast and prostate tumors for expression of RSK.
ERK8 Signal-Transduction Pathway: Tight regulation of the cellular level of estrogen receptor alpha (ER?) is critical to normal breast development and homeostasis. Remarkably, elevating the level of ER? in the mammary gland is in itself sufficient to induce carcinoma. Consistent with this observation, about half of all human breast cancers have abnormally high levels of ER?. The primary mechanism by which ER? levels are increased in breast cancer involves protein turnover rather than transcriptional control. They have found that ER? degradation in breast cells is controlled by the extracellular signal-regulated kinase 8 (ERK8), a unique member of the mitogen-activated protein kinase superfamily. Importantly, loss of ERK8 is associated with human breast cancers. Furthermore, they found that breast cancer tissues with elevated amounts of ER? consistently have undetectably low levels of ERK8. Taken together, these results argue that loss of ERK8 may be involved in the development of ER?-positive tumors. They are currently testing the hypothesis that ERK8 acts as a tumor suppressor and is important in the maintenance of normal breast homeostasis.