1. Van’t Veer et al, Nature 415:530-536 (2002)
Primary breast carcinomas
Can identify an expression profile that correlates with
incidence of metastases
Suggests bulk primary tumor already has properties that
predispose to metastasis
That is, not (only) rare variant metastatic cells

7. Ramaswamy et al, Nature Genetics 33: 49-54 (2003)
Miscellaneous collection of 12 metastases and 64 primary tumors
of same histological types - all adenocarcinomas
Can identify an expression profile of 128 genes that distinguishes
primaries from metastases
Some primaries show the “metastasis pattern”
Analyzed available data sets and found that the 128 gene set
could split primaries into two sets, one of which
showed the “metastasis pattern” and had poor prognosis
- same result with a 17 gene set
Suggests bulk primary tumors already have properties that
predispose to metastasis
That is, not (only) rare variant metastatic cells

9. 128 gene
signature
17 gene
signature
Clustered
by all genes

10. 17 gene signature

12. Kang/Massague et al Preprint
Breast cancer cell line
Select variants highly metastatic to bone
They “breed true”
They have a characteristic expression profile
Transfection of 2/3 of the overexpressed genes ->
increased metastasis
Random isolation and screening of clones from parent line
identifies clones with the “metastatic signature”
These unselected clones ARE metastatic
Therefore there ARE preexisting variant cells in the
parent population
The “metastatic signature” is overlaid on the “poor
prognosis signature” of van’t Veer
DIFFERENCE - this was done with cell lines

13. In vivo selection of metastatic variants

15. Overexpression
enhancing
metastasis

16. In vitro
isolation of
preexisting
metastatic
variant
clones

18. Conclusion
There IS a global difference between tumors with a
predisposition to metastasize
Within such tumors there ARE preexisting variant
cells that are more metastatic than the bulk population
Can isolate these metastatic variants and they are ‘stably’ different
Poor prognosis
with variants
Good prognosis
Poor prognosis