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Interaction of the Tumor Metastasis Suppressor Nonmetastatic Protein 23 Homologue H1 and Estrogen Receptor Alters Estrogen-Responsive Gene Expression

Departments of ¹ Molecular and Integrative Physiology and ² Biochemistry, University of Illinois, Urbana, Illinois; and ³ Department of Cell Biology, The Scripps Research Institute, La Jolla, California

Requests for reprints: Ann M. Nardulli, Department of Molecular and Integrative Physiology, University of Illinois at Urbana–Champaign, 524 Burrill Hall, 407 South Goodwin Avenue, Urbana, IL 61801. Phone: 217-244-5679; Fax: 217-333-1133; E-mail: anardull{at}life.uiuc.edu.

Metastasis of cancer cells from the primary tumor is associated with poor prognosis and decreased overall survival. One protein implicated in inhibiting metastasis is the tumor metastasis suppressor nonmetastatic protein 23 homologue 1 (NM23-H1). NM23-H1 is a multifunctional protein, which, in addition to limiting metastasis, has DNase and histidine protein kinase activities. We have identified new functions for NM23-H1 in influencing estrogen receptor (ER)–mediated gene expression. Using a battery of molecular and biochemical techniques, we show that NM23-H1 interacts with ER and increases the ER–estrogen response element (ERE) interaction. When NM23-H1 expression is increased in U2 osteosarcoma and MDA-MB-231 breast cancer cells, transcription of a transiently transfected, estrogen-responsive reporter plasmid is decreased. More importantly, when endogenous NM23-H1 expression is knocked down in MCF-7 human breast cancer cells using small interfering RNA, estrogen responsiveness of the progesterone receptor (PR), Bcl-2, cathepsin D, and cyclin D1 genes, but not the pS2 gene, is enhanced. Furthermore, NM23-H1 associates with the region of the PR gene containing the +90 activator protein 1 site, but not with the ERE-containing region of the pS2 gene, indicating that NM23-H1 mediates gene-specific effects by association with endogenous chromatin. Our studies suggest that the capacity of NM23-H1 to limit the expression of estrogen-responsive genes such as cathepsin D and Bcl-2, which are involved in cell migration, apoptosis, and angiogenesis, may help to explain the metastasis-suppressive effects of this protein. The complementary abilities of ER and NM23-H1 together to influence gene expression, cell migration, and apoptosis could be key factors in helping to determine tumor cell fate. [Cancer Res 2007;67(21):10600–7]

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