Lani
01-30-2011, 01:31 AM
and it can't come fast enough!
Cancer Res. 2011 Jan 25. [Epub ahead of print]
MicroRNA-1258 Suppresses Breast Cancer Brain Metastasis by Targeting Heparanase.
Zhang L, Sullivan PS, Goodman JC, Gunaratne PH, Marchetti D.
Authors' Affiliations: Departments of Pathology and Immunology and Molecular and Cellular Biology, Human Genome Sequencing Center, and Dan L. Duncan Cancer Center, Baylor College of Medicine; and Department of Biology and Biochemistry, University of Houston, Houston, Texas; and Department of Pathology and Laboratory Medicine, University of California-Los Angeles, Los Angeles, California.
Abstract
Heparanase (HPSE) is a potent protumorigenic, proangiogenic, and prometastatic enzyme that is overexpressed in brain metastatic breast cancer (BMBC). However, little is known about the regulation of this potential therapeutic target in BMBC, which remains very poorly managed in the clinic. We hypothesized that HPSE gene expression might be regulated by micro RNA that might be exploited therapeutically. Using miRanda and RNAhybrid, we identified miR-1258 as a candidate micro RNA that may directly target HPSE and suppress BMBC. In support of our hypothesis, we found that miR-1258 levels inversely correlated with heparanase expression, enzymatic activity, and cancer cell metastatic propensities, being lowest in highly aggressive BMBC cell variants compared with either nontumorigenic or nonmetastatic human mammary epithelial cells. These findings were validated by analyses of miR-1258 and heparanase content in paired clinical specimens of normal mammary gland versus invasive ductal carcinoma, and primary breast cancer versus BMBC. In regulatory experiments, miR-1258 inhibited the expression and activity of heparanase in BMBC cells, whereas modulating heparanase blocked the phenotypic effects of miR-1258. In functional experiments, stable expression of miR-1258 in BMBC cells inhibited heparanase in vitro cell invasion and experimental brain metastasis. Together, our findings illustrate how micro RNA mechanisms are linked to brain metastatic breast cancer through heparanase control, and they offer a strong rationale to develop heparanase-based therapeutics for treatment of cancer patients with brain metastases, BMBC in particular. Cancer Res; 71(3); 645-54. ©2011 AACR.
PMID: 21266359
Cancer Res. 2011 Jan 25. [Epub ahead of print]
MicroRNA-1258 Suppresses Breast Cancer Brain Metastasis by Targeting Heparanase.
Zhang L, Sullivan PS, Goodman JC, Gunaratne PH, Marchetti D.
Authors' Affiliations: Departments of Pathology and Immunology and Molecular and Cellular Biology, Human Genome Sequencing Center, and Dan L. Duncan Cancer Center, Baylor College of Medicine; and Department of Biology and Biochemistry, University of Houston, Houston, Texas; and Department of Pathology and Laboratory Medicine, University of California-Los Angeles, Los Angeles, California.
Abstract
Heparanase (HPSE) is a potent protumorigenic, proangiogenic, and prometastatic enzyme that is overexpressed in brain metastatic breast cancer (BMBC). However, little is known about the regulation of this potential therapeutic target in BMBC, which remains very poorly managed in the clinic. We hypothesized that HPSE gene expression might be regulated by micro RNA that might be exploited therapeutically. Using miRanda and RNAhybrid, we identified miR-1258 as a candidate micro RNA that may directly target HPSE and suppress BMBC. In support of our hypothesis, we found that miR-1258 levels inversely correlated with heparanase expression, enzymatic activity, and cancer cell metastatic propensities, being lowest in highly aggressive BMBC cell variants compared with either nontumorigenic or nonmetastatic human mammary epithelial cells. These findings were validated by analyses of miR-1258 and heparanase content in paired clinical specimens of normal mammary gland versus invasive ductal carcinoma, and primary breast cancer versus BMBC. In regulatory experiments, miR-1258 inhibited the expression and activity of heparanase in BMBC cells, whereas modulating heparanase blocked the phenotypic effects of miR-1258. In functional experiments, stable expression of miR-1258 in BMBC cells inhibited heparanase in vitro cell invasion and experimental brain metastasis. Together, our findings illustrate how micro RNA mechanisms are linked to brain metastatic breast cancer through heparanase control, and they offer a strong rationale to develop heparanase-based therapeutics for treatment of cancer patients with brain metastases, BMBC in particular. Cancer Res; 71(3); 645-54. ©2011 AACR.
PMID: 21266359