Histologically normal human mammary epithelia with silenced p16(INK4a) overexpress COX-2, promoting a premalignant program.
Breast tissue from healthy women contains variant mammary epithelial cells (vHMEC) exhibiting p16INK4a promoter hypermethylation both in vivo and in vitro. When continuously cultured, vHMEC acquire telomeric dysfunction and produce the types of chromosomal abnormalities seen in premalignant lesions of cancer. We find that late passage vHMEC express elevated prostaglandin cyclo-oxygenase 2 (COX-2), which contributes to increased prostaglandin synthesis, angiogenic activity, and invasive ability. These data demonstrate the existence of human mammary epithelial cells with the potential to acquire multiple genomic alterations and phenotypes associated with malignant cells. Moreover, COX-2 overexpression coincides with focal areas of p16INK4a hypermethylation in vivo, creating ideal candidates as precursors to breast cancer. These putative precursors can be selectively eliminated upon exposure to COX-2 inhibitors in vitro.
Crawford
Yongping G
YG
Department of Pathology and Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA 94143, USA.
Gauthier
Mona L
ML
Joubel
Anita
A
Mantei
Kristin
K
Kozakiewicz
Krystyna
K
Afshari
Cynthia A
CA
Tlsty
Thea D
TD
D017209:Apoptosis / Q000502:physiology; D001940:Breast / Q000378:metabolism* / Q000503:physiopathology; D002869:Chromosome Aberrations; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D051546:Cyclooxygenase 2; D004249:DNA Damage / Q000502:physiology; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000378:metabolism*; D008565:Membrane Proteins; D008745:Methylation; D009389:Neovascularization, Pathologic / Q000378:metabolism; D011230:Precancerous Conditions / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011453:Prostaglandins / Q000378:metabolism; D019098:Telomerase / Q000378:metabolism
D019941:Cyclin-Dependent Kinase Inhibitor p16; D007527:Isoenzymes; D008565:Membrane Proteins; D011453:Prostaglandins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D019098:Telomerase