Tumor initiating but differentiated luminal-like breast cancer cells are highly invasive in the absence of basal-like activity

Jiyoung Kim; René Villadsen; Therese Sørlie; Louise Fogh; Signe Z. Grønlund; Agla Jael Rubner Fridriksdóttir; Irene Kuhn; Fritz Rank; Vera Timmermans Wielenga; Hiroko Solvang; Paul A.W. Edwards; Anne-Lise Børresen-Dale; Lone Rønnov-Jessen; Mina J. Bissell; Ole William Petersen

doi:10.1073/pnas.1203203109

Tumor initiating but differentiated luminal-like breast cancer cells are highly invasive in the absence of basal-like activity

Jiyoung Kim, René Villadsen, Therese Sørlie, Louise Fogh, Signe Z. Grønlund, Agla Jael Rubner Fridriksdóttir, Irene Kuhn, Fritz Rank, Vera Timmermans Wielenga, Hiroko Solvang, Paul A.W. Edwards, Anne-Lise Børresen-Dale, Lone Rønnov-Jessen, Mina J. Bissell, Ole William Petersen

76 Citations (Scopus)

Abstract

The majority of human breast cancers exhibit luminal epithelial differentiation. However, most aggressive behavior, including invasion and purported cancer stem cell activity, are considered characteristics of basal-like cells. We asked the following questions: Must luminal-like breast cancer cells become basal-like to initiate tumors or to invade? Could luminally differentiated cells within a basally initiated hierarchy also be tumorigenic? To answer these questions, we used rare and mutually exclusive lineage markers to isolate subsets of luminal-like and basal-like cells from human breast tumors. We enriched for populations with or without prominent basal-like traits from individual tumors or single cell cloning from cell lines and recovered cells with a luminal-like phenotype. Tumor cells with basal-like traits mimicked phenotypic and functional behavior associated with stem cells assessed by gene expression, mammosphere formation and lineage markers. Luminal-like cells without basal-like traits, surprisingly, were fully capable of initiating invasive tumors in NOD SCID gamma (NSG) mice. In fact, these phenotypically pure luminal-like cells generated larger and more invasive tumors than their basal-like counterparts. The tumorigenicity and invasive potential of the luminal-like cancer cells relied strongly on the expression of the gene GCNT1, which encodes a key glycosyltransferase controlling O-glycan branching. These findings demonstrate that basal-like cells, as defined currently, are not a requirement for breast tumor aggressiveness, and that within a single tumor there are multiple "stem-like" cells with tumorigenic potential casting some doubt on the hypothesis of hierarchical or differentiative loss of tumorigenicity.

Original language	English
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	109
Issue number	16
Pages (from-to)	6124-6129
Number of pages	6
ISSN	0027-8424
DOIs	https://doi.org/10.1073/pnas.1203203109
Publication status	Published - 17 Apr 2012

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Kim, J., Villadsen, R., Sørlie, T., Fogh, L., Grønlund, S. Z., Fridriksdóttir, A. J. R., Kuhn, I., Rank, F., Wielenga, V. T., Solvang, H., Edwards, P. A. W., Børresen-Dale, A-L., Rønnov-Jessen, L., Bissell, M. J., & Petersen, O. W. (2012). Tumor initiating but differentiated luminal-like breast cancer cells are highly invasive in the absence of basal-like activity. Proceedings of the National Academy of Sciences of the United States of America, 109(16), 6124-6129. https://doi.org/10.1073/pnas.1203203109

Tumor initiating but differentiated luminal-like breast cancer cells are highly invasive in the absence of basal-like activity. / Kim, Jiyoung ; Villadsen, René; Sørlie, Therese et al.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 16, 17.04.2012, p. 6124-6129.

Research output: Contribution to journal › Journal article › Research › peer-review

Kim, J , Villadsen, R, Sørlie, T, Fogh, L, Grønlund, SZ, Fridriksdóttir, AJR, Kuhn, I, Rank, F, Wielenga, VT, Solvang, H, Edwards, PAW, Børresen-Dale, A-L, Rønnov-Jessen, L, Bissell, MJ & Petersen, OW 2012, 'Tumor initiating but differentiated luminal-like breast cancer cells are highly invasive in the absence of basal-like activity', Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 16, pp. 6124-6129. https://doi.org/10.1073/pnas.1203203109

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title = "Tumor initiating but differentiated luminal-like breast cancer cells are highly invasive in the absence of basal-like activity",

abstract = "The majority of human breast cancers exhibit luminal epithelial differentiation. However, most aggressive behavior, including invasion and purported cancer stem cell activity, are considered characteristics of basal-like cells. We asked the following questions: Must luminal-like breast cancer cells become basal-like to initiate tumors or to invade? Could luminally differentiated cells within a basally initiated hierarchy also be tumorigenic? To answer these questions, we used rare and mutually exclusive lineage markers to isolate subsets of luminal-like and basal-like cells from human breast tumors. We enriched for populations with or without prominent basal-like traits from individual tumors or single cell cloning from cell lines and recovered cells with a luminal-like phenotype. Tumor cells with basal-like traits mimicked phenotypic and functional behavior associated with stem cells assessed by gene expression, mammosphere formation and lineage markers. Luminal-like cells without basal-like traits, surprisingly, were fully capable of initiating invasive tumors in NOD SCID gamma (NSG) mice. In fact, these phenotypically pure luminal-like cells generated larger and more invasive tumors than their basal-like counterparts. The tumorigenicity and invasive potential of the luminal-like cancer cells relied strongly on the expression of the gene GCNT1, which encodes a key glycosyltransferase controlling O-glycan branching. These findings demonstrate that basal-like cells, as defined currently, are not a requirement for breast tumor aggressiveness, and that within a single tumor there are multiple {"}stem-like{"} cells with tumorigenic potential casting some doubt on the hypothesis of hierarchical or differentiative loss of tumorigenicity.",

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AU - Kim, Jiyoung

AU - Villadsen, René

AU - Sørlie, Therese

AU - Fogh, Louise

AU - Grønlund, Signe Z.

AU - Fridriksdóttir, Agla Jael Rubner

AU - Kuhn, Irene

AU - Rank, Fritz

AU - Wielenga, Vera Timmermans

AU - Solvang, Hiroko

AU - Edwards, Paul A.W.

AU - Børresen-Dale, Anne-Lise

AU - Rønnov-Jessen, Lone

AU - Bissell, Mina J.

AU - Petersen, Ole William

PY - 2012/4/17

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N2 - The majority of human breast cancers exhibit luminal epithelial differentiation. However, most aggressive behavior, including invasion and purported cancer stem cell activity, are considered characteristics of basal-like cells. We asked the following questions: Must luminal-like breast cancer cells become basal-like to initiate tumors or to invade? Could luminally differentiated cells within a basally initiated hierarchy also be tumorigenic? To answer these questions, we used rare and mutually exclusive lineage markers to isolate subsets of luminal-like and basal-like cells from human breast tumors. We enriched for populations with or without prominent basal-like traits from individual tumors or single cell cloning from cell lines and recovered cells with a luminal-like phenotype. Tumor cells with basal-like traits mimicked phenotypic and functional behavior associated with stem cells assessed by gene expression, mammosphere formation and lineage markers. Luminal-like cells without basal-like traits, surprisingly, were fully capable of initiating invasive tumors in NOD SCID gamma (NSG) mice. In fact, these phenotypically pure luminal-like cells generated larger and more invasive tumors than their basal-like counterparts. The tumorigenicity and invasive potential of the luminal-like cancer cells relied strongly on the expression of the gene GCNT1, which encodes a key glycosyltransferase controlling O-glycan branching. These findings demonstrate that basal-like cells, as defined currently, are not a requirement for breast tumor aggressiveness, and that within a single tumor there are multiple "stem-like" cells with tumorigenic potential casting some doubt on the hypothesis of hierarchical or differentiative loss of tumorigenicity.

AB - The majority of human breast cancers exhibit luminal epithelial differentiation. However, most aggressive behavior, including invasion and purported cancer stem cell activity, are considered characteristics of basal-like cells. We asked the following questions: Must luminal-like breast cancer cells become basal-like to initiate tumors or to invade? Could luminally differentiated cells within a basally initiated hierarchy also be tumorigenic? To answer these questions, we used rare and mutually exclusive lineage markers to isolate subsets of luminal-like and basal-like cells from human breast tumors. We enriched for populations with or without prominent basal-like traits from individual tumors or single cell cloning from cell lines and recovered cells with a luminal-like phenotype. Tumor cells with basal-like traits mimicked phenotypic and functional behavior associated with stem cells assessed by gene expression, mammosphere formation and lineage markers. Luminal-like cells without basal-like traits, surprisingly, were fully capable of initiating invasive tumors in NOD SCID gamma (NSG) mice. In fact, these phenotypically pure luminal-like cells generated larger and more invasive tumors than their basal-like counterparts. The tumorigenicity and invasive potential of the luminal-like cancer cells relied strongly on the expression of the gene GCNT1, which encodes a key glycosyltransferase controlling O-glycan branching. These findings demonstrate that basal-like cells, as defined currently, are not a requirement for breast tumor aggressiveness, and that within a single tumor there are multiple "stem-like" cells with tumorigenic potential casting some doubt on the hypothesis of hierarchical or differentiative loss of tumorigenicity.

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JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 16

ER -

Tumor initiating but differentiated luminal-like breast cancer cells are highly invasive in the absence of basal-like activity

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