Patricia S. Steeg, Ph.D.
Women's Malignancies Branch
Building 37, Room 1-126
Bethesda, MD 20892
Molecular Characterization of Breast Cancer Progression
The Women's Cancers Section performs basic and translational research on the molecular biology of breast cancer. The vast majority of breast cancer patients succumb to metastatic disease, or complications of its treatment. The Section focuses on two aspects of breast cancer metastasis:(1) What is the role of the nm23 metastasis suppressor gene (NME) in breast cancer progression? (2) What molecular events are involved in breast cancer metastasis to the brain? The nm23 family of genes was discovered by Dr. Steeg on the basis of its reduced expression in highly metastatic murine melanoma cell lines, as compared to related, poorly metastatic cell lines. Multiple transfection studies have documented that overexpression of Nm23 in metastastic cell lines resulted in a significant decrease in metastatic potential in vivo, without an effect on tumorigenicity, establishing Nm23 as a metastasis suppressor gene. Our research on the Nm23 family of genes spans its basic biochemical mechanisms to translational development. Nm23 likely suppresses metastasis by complex mechanisms involving its histidine kinase activity and protein:protein associations. We have found that the Lysophosphatidic acid receptor 1 (LPAR1 or LPA1) is inversely expressed with regard to Nm23 in breast cancer. Overexpression of LPA1 overcame Nm23 suppression of tumor metastasis.
Recently, we have reported that a preclinical LPA1 inhibitor, Debio 0719, had no effect on primary tumor formation in two model systems but significantly suppressed metastasis development, inducing metastatic dormancy. Our lab is working to bring this new lead to the clinic. Brain metastases historically occurred in at least 15% of metastatic breast cancer patients and conferred a dismal prognosis. Brain metastases are now being diagnosed in at least one-third of metastatic patients with triple-negative or HER2-positive tumors, and are increasingly a cause of death. Both the lesions and their treatments can cause neurocognitive damage.
My group has (a) developed experimental models for brain metastasis of breast cancer; (b)profiled resected brain metastases for gene expression patterns to discover functional pathways. Genes demonstrated to influence brain metastatic capacity include HER2, PEDF, RAD51 and BARD1; (c) collaboratively determined the influence of the blood-tumor barrier on drug penetration into experimental brain metastases; (d) tested multiple compounds for the prevention or treatment of brain metastases preclinically. A few compounds have been demonstrated to partially prevent brain metastasis formation including lapatinib, vorinostat and pazopanib; none were effective in a treatment (shrinkage of established lesions) setting. New clinical trial designs will be needed to advance brain metastasis prevention.
Lyle LT, Lockman PR, Adkins CE, Mohammad AS, Sechrest E, Hua E, Palmieri D, Liewehr DJ, Steinberg SM, Kloc W, Izycka-Swieszewska E, Duchnowska R, Nayyar N, Brastianos PK, Steeg PS, Gril B. Alterations in Pericyte Subpopulations Are Associated with Elevated Blood-Tumor Barrier Permeability in Experimental Brain Metastasis of Breast Cancer. Clin Cancer Res. 2016;22(21):5287-5299.
Steeg PS. Targeting metastasis. Nat Rev Cancer. 2016;16(4):201-18.
Palmieri D, Duchnowska R, Woditschka S, Hua E, Qian Y, Biernat W, Sosińska-Mielcarek K, Gril B, Stark AM, Hewitt SM, Liewehr DJ, Steinberg SM, Jassem J, Steeg PS. Profound prevention of experimental brain metastases of breast cancer by temozolomide in an MGMT-dependent manner. Clin Cancer Res. 2014;20(10):2727-39.
Marshall JC, Collins JW, Nakayama J, Horak CE, Liewehr DJ, Steinberg SM, Albaugh M, Vidal-Vanaclocha F, Palmieri D, Barbier M, Murone M, Steeg PS. Effect of inhibition of the lysophosphatidic acid receptor 1 on metastasis and metastatic dormancy in breast cancer. J Natl Cancer Inst. 2012;104(17):1306-19.
Steeg PS, Camphausen KA, Smith QR. Brain metastases as preventive and therapeutic targets. Nat Rev Cancer. 2011;11(5):352-63.
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This page was last updated on September 11th, 2017