Abstract
The adult mouse mammary epithelium contains self-sustained cell lineages that form the inner luminal and outer basal cell layers, with stem and progenitor cells contributing to its proliferative and regenerative potential. A key issue in breast cancer biology is the effect of genomic lesions in specific mammary cell lineages on tumour heterogeneity and progression. The impact of transforming events on fate conversion in cancer cells of origin and thus their contribution to tumour heterogeneity remains largely elusive. Using in situ genetic lineage tracing and limiting dilution transplantation, we have unravelled the potential of PIK3CAH1047R, one of the most frequent mutations occurring in human breast cancer, to induce multipotency during tumorigenesis in the mammary gland. Here we show that expression of PIK3CAH1047R in lineage-committed basal Lgr5-positive and luminal keratin-8-positive cells of the adult mouse mammary gland evokes cell dedifferentiation into a multipotent stem-like state, suggesting this to be a mechanism involved in the formation of heterogeneous, multi-lineage mammary tumours. Moreover, we show that the tumour cell of origin influences the frequency of malignant mammary tumours. Our results define a key effect of PIK3CAH1047R on mammary cell fate in the pre-neoplastic mammary gland and show that the cell of origin of PIK3CAH1047R tumours dictates their malignancy, thus revealing a mechanism underlying tumour heterogeneity and aggressiveness.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 114-118 |
| Number of pages | 5 |
| Journal | Nature |
| Volume | 525 |
| Issue number | 7567 |
| DOIs | |
| State | Published - Sep 3 2015 |
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Cite this
PIK3CAH1047R induces multipotency and multi-lineage mammary tumours. / Koren, Shany; Reavie, Linsey; Couto, Joana Pinto; De Silva, Duvini; Stadler, Michael B.; Roloff, Tim; Britschgi, Adrian; Eichlisberger, Tobias; Kohler, Hubertus; Aina, Olulanu; Cardiff, Robert; Bentires-Alj, Mohamed.
In: Nature, Vol. 525, No. 7567, 03.09.2015, p. 114-118.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - PIK3CAH1047R induces multipotency and multi-lineage mammary tumours
AU - Koren, Shany
AU - Reavie, Linsey
AU - Couto, Joana Pinto
AU - De Silva, Duvini
AU - Stadler, Michael B.
AU - Roloff, Tim
AU - Britschgi, Adrian
AU - Eichlisberger, Tobias
AU - Kohler, Hubertus
AU - Aina, Olulanu
AU - Cardiff, Robert
AU - Bentires-Alj, Mohamed
PY - 2015/9/3
Y1 - 2015/9/3
N2 - The adult mouse mammary epithelium contains self-sustained cell lineages that form the inner luminal and outer basal cell layers, with stem and progenitor cells contributing to its proliferative and regenerative potential. A key issue in breast cancer biology is the effect of genomic lesions in specific mammary cell lineages on tumour heterogeneity and progression. The impact of transforming events on fate conversion in cancer cells of origin and thus their contribution to tumour heterogeneity remains largely elusive. Using in situ genetic lineage tracing and limiting dilution transplantation, we have unravelled the potential of PIK3CAH1047R, one of the most frequent mutations occurring in human breast cancer, to induce multipotency during tumorigenesis in the mammary gland. Here we show that expression of PIK3CAH1047R in lineage-committed basal Lgr5-positive and luminal keratin-8-positive cells of the adult mouse mammary gland evokes cell dedifferentiation into a multipotent stem-like state, suggesting this to be a mechanism involved in the formation of heterogeneous, multi-lineage mammary tumours. Moreover, we show that the tumour cell of origin influences the frequency of malignant mammary tumours. Our results define a key effect of PIK3CAH1047R on mammary cell fate in the pre-neoplastic mammary gland and show that the cell of origin of PIK3CAH1047R tumours dictates their malignancy, thus revealing a mechanism underlying tumour heterogeneity and aggressiveness.
AB - The adult mouse mammary epithelium contains self-sustained cell lineages that form the inner luminal and outer basal cell layers, with stem and progenitor cells contributing to its proliferative and regenerative potential. A key issue in breast cancer biology is the effect of genomic lesions in specific mammary cell lineages on tumour heterogeneity and progression. The impact of transforming events on fate conversion in cancer cells of origin and thus their contribution to tumour heterogeneity remains largely elusive. Using in situ genetic lineage tracing and limiting dilution transplantation, we have unravelled the potential of PIK3CAH1047R, one of the most frequent mutations occurring in human breast cancer, to induce multipotency during tumorigenesis in the mammary gland. Here we show that expression of PIK3CAH1047R in lineage-committed basal Lgr5-positive and luminal keratin-8-positive cells of the adult mouse mammary gland evokes cell dedifferentiation into a multipotent stem-like state, suggesting this to be a mechanism involved in the formation of heterogeneous, multi-lineage mammary tumours. Moreover, we show that the tumour cell of origin influences the frequency of malignant mammary tumours. Our results define a key effect of PIK3CAH1047R on mammary cell fate in the pre-neoplastic mammary gland and show that the cell of origin of PIK3CAH1047R tumours dictates their malignancy, thus revealing a mechanism underlying tumour heterogeneity and aggressiveness.
UR - http://www.scopus.com/inward/record.url?scp=84940937183&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84940937183&partnerID=8YFLogxK
U2 - 10.1038/nature14669
DO - 10.1038/nature14669
M3 - Article
C2 - 26266975
AN - SCOPUS:84940937183
VL - 525
SP - 114
EP - 118
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7567
ER -