Genes involved in tumor invasion and metastasis are differentially modulated by estradiol and progestin in human breast-cancer cells.
Invasion of basement membranes by cancer cells is a critical step in metastasis, which requires the coordinated expression of specific genes such as laminin receptors and metalloproteinases. Estradiol and progesterone modulate the clinical progression of steroid-sensitive breast cancers; however, little is known about the molecular regulation of the invasive phenotype by these hormones. We therefore examined the effects of 10 nM estradiol and/or 10 nM progestin R5020 on the expression of 2 non-integrin laminin binding proteins, the 67-kDa laminin receptor (67LR) and HLBP31 as well as the 72-kDa type-IV collagenase (MMP-2) and its inhibitor, TIMP-2, in steroid-receptor-positive (T47D and MCF-7) and -negative (MDA-MB 231) human breast-cancer cells. The relative steady-state level of 67LR mRNA was increased 2- to 3-fold by estradiol in both MCF-7 (p < 0.001) and T47D (p < 0.001) cells, also by R5020, alone or in combination with estradiol, in T47D cells (p < 0.001) and to a much less extent in MCF-7 cells. HLBP31 mRNA and protein levels were increased 2- to 3-fold (p < 0.001) by R5020 alone or in combination with estradiol, but not by estradiol alone. None of the steroid treatments affected the expression or activity of MMP-2. Interestingly, however, TIMP-2 mRNA levels and protein expression in MCF-7 and T47D cells were 50% down-regulated (p < 0.001) by treatment with R5020 or R5020 plus estradiol, but not by treatment with estradiol alone. None of these genes were modulated in steroid-independent MDA-MB231 cells. The data suggest that estradiol and progesterone might act as coordinators regulating specific genes in the steroid-sensitive breast-cancer cell, leading to the acquisition of the metastatic phenotype.
van den Brûle
F A
FA
Tumor Invasion and Metastasis Section, National Cancer Institute, Bethesda, MD 20892.
Engel
J
J
Stetler-Stevenson
W G
WG
Liu
F T
FT
Sobel
M E
ME
Castronovo
V
V
D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D017364:Collagenases / Q000032:analysis / Q000235:genetics; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D020780:Matrix Metalloproteinase 9; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000032:analysis / Q000235:genetics; D011397:Promegestone / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D017474:Receptors, Laminin / Q000032:analysis / Q000235:genetics; D019716:Tissue Inhibitor of Metalloproteinase-2; D014407:Tumor Cells, Cultured
D009363:Neoplasm Proteins; D012333:RNA, Messenger; D017474:Receptors, Laminin; D019716:Tissue Inhibitor of Metalloproteinase-2; D004958:Estradiol; D011397:Promegestone; D017364:Collagenases; D020780:Matrix Metalloproteinase 9