|
Deborah A. Lannigan, Ph.D.
Associate Professor of Microbiology
Kinases, Drugs & Cancer
 Overview: The laboratory focuses on signaling pathways that are involved in mammary gland homeostasis and breast cancer. Cancer cells frequently hijack pathways used during development. Therefore, by studying normal organogenesis it is possible to identify novel therapeutic opportunities for the treatment of breast cancer. To facilitate these studies we are currently developing a novel model system for the study of human mammary development.
Drug Discovery & Development:
Recently, we discovered the first specific small molecule inhibitor for the Ser/Thr protein kinase, RSK. This inhibitor, which we call SL0101, was discovered from a high throughput screen of a collection of botanical extracts. SL0101 was isolated from a plant found only in the S. American rainforest, Forsteronia refracta. Interestingly, SL0101 inhibits the proliferation of numerous transformed cell lines but does not effect the proliferation of untransformed cell lines. We have found that RSK regulates several key breast cancer-associated proteins. For example, we have found that RSK2, a member of the RSK family, stimulates the transcriptional activity of estrogen receptor alpha, which is known to be important in the etiology of many breast cancers. Additionally, we have found that RSK2 regulates expression of the oncogene, cyclin D1, which is over-expressed in ~50% of human breast tumors. RSK1 and RSK2 are over-expressed in ~50% of human breast tissue compared to normal tissues. Signaling molecules involved in the transformation process are frequently found to have elevated levels in the tumor. Taken together, these observations suggest that RSK is an important chemotherapeutic target for breast cancer. Currently, we are collaborating with several groups to develop additional RSK inhibitors with the intention of being able to transition these inhibitors into the clinic. In ongoing studies we are determining which patients would benefit from treatment with a RSK inhibitor. Additionally, it is likely that RSK inhibitors will be administered to a patient as part of a cocktail tailored to the individual’s cancer. Therefore, we are also investigating which additional agents should be combined with RSK inhibitors to maximize the therapeutic response and minimize the development of resistance.
Mammary Gland Homeostasis:
The discovery of SL0101 is helping us elucidate the physiological functions of RSK. Excitingly, we recently made a novel, unanticipated link between stress granules and RSK2. Stress granules aid cell survival in response to environmental stressors by acting as sites of translational repression. Stress granules represent an ancient mechanism in eukaryotes for the posttranslational regulation of mRNA during stress insult. In stressed breast cells, endogenous RSK2 associates with and colocalizes with the essential stress granule proteins, TIA-1 and PABP. RSK2 controls TIA-1 recruitment into stress granules and this regulation is physiologically important, because loss of RSK2 decreases cell survival in response to stress. RSK2 has not previously been implicated as a regulatory component in the stress response. Stress granules are found in vivo in response to ischemia, inflammation, viral infection and radiation treatment of tumors. Our discovery of a linkage between RSK2 and stress granules will increase our mechanistic understanding of the function of RSK2 and stress granules in promoting disease.
We have other ongoing projects in the laboratory related to mammary gland organogenesis and we are preparing these for publication soon!!
Techniques:
We use a variety of techniques to address our biological questions, including high throughput screening for small molecule inhibitors, proteomics, medicinal chemistry, biochemistry, molecular biology, human tissue analysis, immunofluorescence and live-cell 6D imaging (x, y, z, time, wavelength and multiwell).
|
