A human breast cell model of preinvasive to invasive transition.
A crucial step in human breast cancer progression is the acquisition of invasiveness. There is a distinct lack of human cell culture models to study the transition from preinvasive to invasive phenotype as it may occur "spontaneously" in vivo. To delineate molecular alterations important for this transition, we isolated human breast epithelial cell lines that showed partial loss of tissue polarity in three-dimensional reconstituted basement membrane cultures. These cells remained noninvasive; however, unlike their nonmalignant counterparts, they exhibited a high propensity to acquire invasiveness through basement membrane in culture. The genomic aberrations and gene expression profiles of the cells in this model showed a high degree of similarity to primary breast tumor profiles. The xenograft tumors formed by the cell lines in three different microenvironments in nude mice displayed metaplastic phenotypes, including squamous and basal characteristics, with invasive cells exhibiting features of higher-grade tumors. To find functionally significant changes in transition from preinvasive to invasive phenotype, we performed attribute profile clustering analysis on the list of genes differentially expressed between preinvasive and invasive cells. We found integral membrane proteins, transcription factors, kinases, transport molecules, and chemokines to be highly represented. In addition, expression of matrix metalloproteinases MMP9, MMP13, MMP15, and MMP17 was up-regulated in the invasive cells. Using small interfering RNA-based approaches, we found these MMPs to be required for the invasive phenotype. This model provides a new tool for dissection of mechanisms by which preinvasive breast cells could acquire invasiveness in a metaplastic context.
Rizki
Aylin
A
Life Sciences Division, Ernest Orlando Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. ARizki@vcu.edu
Weaver
Valerie M
VM
Lee
Sun-Young
SY
Rozenberg
Gabriela I
GI
Chin
Koei
K
Myers
Connie A
CA
Bascom
Jamie L
JL
Mott
Joni D
JD
Semeiks
Jeremy R
JR
Grate
Leslie R
LR
Mian
I Saira
IS
Borowsky
Alexander D
AD
Jensen
Roy A
RA
Idowu
Michael O
MO
Chen
Fanqing
F
Chen
David J
DJ
Petersen
Ole W
OW
Gray
Joe W
JW
Bissell
Mina J
MJ
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008679:Metaplasia / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis