Our Science – Steeg Website
Patricia S. Steeg, Ph.D.
Molecular Characterization of Breast Cancer Progression
The Women's Cancers Section performs basic and translational research on the molecular biology of breast cancer. Three major projects are under investigation: (1) What is the role of the nm23 metastasis suppressor gene in breast cancer progression? (2) What molecular events are involved in breast cancer metastasis to the brain? (3) What molecular events are responsible for early neoplastic progression in the breast?
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. Eleven transfection studies have documented that overexpression of nm23 cDNA in metastastic cell lines results in a significant decrease in metastatic potential in vivo, without an effect on tumorigenicity, establishing nm23 as a metastasis suppressor gene. Increased Nm23 expression induced morphological and functional differentiation in transfection studies involving breast and neuroendocrine cells. Reduced Nm23 expression has been correlated with poor patient survival and the presence of metastases or other histopathological indicators of aggressive clinical course in breast and other cohort studies, although it does not represent an independent prognostic factor
We have investigated the biochemical mechanism of action of Nm23-H1 in suppressing metastasis. Site directed mutation experiments showed a correlation between the histidine protein kinase activity of Nm23-H1 and its ability to suppress motility in vitro. We have recently identified a physiologic substrate for Nm23-H1 as a histidine protein kinase, the kinase suppressor of ras (Ksr). Ksr is a putative scaffold protein for the Erk arm of the Map kinase pathway. Using MDA-MB-435 breast carcinoma cells, we showed that Nm23-H1 overexpression altered Ksr binding of Hsp90, Ksr degradation and tumor cell sensitivity to geldanamycin inhibition of colonization. The data indicate that common signaling pathways may be affected by the expression and activity of metastasis suppressor genes.
Translational projects are under way in the section based on the hypothesis that elevation of Nm23 expression in micrometastatic breast and possibly other tumor cells may impact their colonization, motility, and differentiation with a clinical benefit. Analysis of the nm23-H1 promoter revealed its regulation by a set of mammary specific transcription factors, controlled in the MMTV-LTR by glucocorticoids. While traditional glucocorticoids were ineffective at elevating the Nm23-H1 expression of metastatic breast carcinoma cell lines, medroxyprogesterone acetate (MPA), through an unusual post-translational, glucocorticoid receptor based interaction, elevated cell line Nm23-H1 expression and inhibited colonization in vitro. In vivo analysis of MPA is underway.
Brain metastases occur in at least 15% of breast cancer metastatic patients and confer a dismal prognosis. We have undertaken a microarray analysis of surgically resected brain metastases of breast cancer, and compared these data to a cohort of independent primary breast tumors matched for hormone receptor status, patient age and TNM stage. Our preliminary data indicate that brain metastases are distinct from primary tumors and that translationally important targets are apparent.
The development of preventive strategies for women at high risk for breast cancer will require a 'molecular map' of the cancer progress. A new initiative is to identify proteins differentially expressed among human premalignant breast lesions using proteomics and mass spectroscopy sequencing. Fifty-seven proteins were identified in a proteomic comparison of normal ductal/lobular units and DCIS, many of which were new to the breast cancer literature. These proteins suggest that breast cancer exhibits massive alterations in subcellular trafficking of lipids, proteins, putative prevention compounds, ions, etc. Functional analysis of Rab 11 expression is underway and indicates a functional impact on the EGF receptor pathway.
This page was last updated on 6/7/2013.