Mapping the cellular and molecular heterogeneity of normal and malignant breast tissues and cultured cell lines.
BACKGROUND
Normal and neoplastic breast tissues are comprised of heterogeneous populations of epithelial cells involving various degrees of maturation and differentiation. While cultured cell lines have been derived from both normal and malignant tissues, it remains unclear whether they retain a similar cellular heterogeneity as to that found within breast tissues.


METHODS
We used 12 reduction mammoplasty tissues, 15 primary breast cancer tissues, and 20 human breast epithelial cell lines (16 cancer lines, 4 normal lines) to perform flow cytometry for CD44, CD24, epithelial cell adhesion molecule (EpCAM), and CD49f expression as well as immunohistochemistry, and in vivo tumor xenograft formation studies to extensively analyze the molecular and cellular characteristics of breast epithelial cell lineages.


RESULTS
Human breast tissues contain four distinguishable epithelial differentiation states (two luminal phenotypes and two basal phenotypes) that differ on the basis of CD24, EpCAM and CD49f expression. Primary human breast cancer tissues also contain these four cellular states, but in altered proportions compared to normal tissues. In contrast, cultured cancer cell lines are enriched for rare basal and mesenchymal phenotypes, which are normally present in small numbers within human tissues. Similarly, cultured normal human mammary epithelial cell lines were enriched for rare basal and mesenchymal phenotypes that represent a minor fraction of cells within reduction mammoplasty tissues. Although normal human mammary epithelial cell lines exhibited features of bi-potent progenitor cells they were unable to differentiate into mature luminal breast epithelial cells.


CONCLUSIONS
As a group breast cancer cell lines represent the heterogeneity of human breast tumors, but individually they exhibit increased lineage-restricted profiles that fall short of truly representing the intratumoral heterogeneity of individual breast tumors. Additionally, normal human mammary epithelial cell lines fail to retain much of the cellular diversity found in human breast tissues and are enriched for differentiation states that are a minority in breast tissues, although they do exhibit features of bi-potent basal progenitor cells. These findings suggest that collections of cell lines representing multiple cell types can be used to model the cellular heterogeneity of tissues.
Department of Anatomy & Cellular Biology, Sackler School, Tufts University School of Medicine, Boston, MA 02111, USA.
Patrica J
PJ
Keller
Amy F
AF
Lin
Lisa M
LM
Arendt
Ina
I
Klebba
Ainsely D
AD
Jones
Jenny A
JA
Rudnick
Theresa A
TA
DiMeo
Hannah
H
Gilmore
Douglas M
DM
Jefferson
Roger A
RA
Graham
Stephen P
SP
Naber
Stuart
S
Schnitt
Charlotte
C
Kuperwasser
D000818:Animals; D000951:Antigens, Neoplasm / Q000032:analysis; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D001940:Breast / Q000166:cytology* / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D051927:CD24 Antigen / Q000032:analysis; D015815:Cell Adhesion Molecules / Q000032:analysis; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D000071858:Epithelial Cell Adhesion Molecule; D004847:Epithelial Cells / Q000166:cytology* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis; D039503:Integrin alpha6 / Q000032:analysis; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D051927:CD24 Antigen; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D018960:Hyaluronan Receptors; D039503:Integrin alpha6