Reactivation of multipotency by oncogenic PIK3CA induces breast tumour heterogeneity.
Breast cancer is the most frequent cancer in women and consists of heterogeneous types of tumours that are classified into different histological and molecular subtypes. PIK3CA and P53 (also known as TP53) are the two most frequently mutated genes and are associated with different types of human breast cancers. The cellular origin and the mechanisms leading to PIK3CA-induced tumour heterogeneity remain unknown. Here we used a genetic approach in mice to define the cellular origin of Pik3ca-derived tumours and the impact of mutations in this gene on tumour heterogeneity. Surprisingly, oncogenic Pik3ca(H1047R) mutant expression at physiological levels in basal cells using keratin (K)5-CreER(T2) mice induced the formation of luminal oestrogen receptor (ER)-positive/progesterone receptor (PR)-positive tumours, while its expression in luminal cells using K8-CReER(T2) mice gave rise to luminal ER(+)PR(+) tumours or basal-like ER(-)PR(-) tumours. Concomitant deletion of p53 and expression of Pik3ca(H1047R) accelerated tumour development and induced more aggressive mammary tumours. Interestingly, expression of Pik3ca(H1047R) in unipotent basal cells gave rise to luminal-like cells, while its expression in unipotent luminal cells gave rise to basal-like cells before progressing into invasive tumours. Transcriptional profiling of cells that underwent cell fate transition upon Pik3ca(H1047R) expression in unipotent progenitors demonstrated a profound oncogene-induced reprogramming of these newly formed cells and identified gene signatures characteristic of the different cell fate switches that occur upon Pik3ca(H1047R) expression in basal and luminal cells, which correlated with the cell of origin, tumour type and different clinical outcomes. Altogether our study identifies the cellular origin of Pik3ca-induced tumours and reveals that oncogenic Pik3ca(H1047R) activates a multipotent genetic program in normally lineage-restricted populations at the early stage of tumour initiation, setting the stage for future intratumoural heterogeneity. These results have important implications for our understanding of the mechanisms controlling tumour heterogeneity and the development of new strategies to block PIK3CA breast cancer initiation.
Université Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium.
Alexandra
A
Van Keymeulen
Université Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium.
May Yin
MY
Lee
Université Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium.
Marielle
M
Ousset
Institut Jules Bordet, Université Libre de Bruxelles, Brussels B-1000, Belgium.
Sylvain
S
Brohée
Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, Brussels B-1070, Belgium.|DIAPATH - Center for Microscopy and Molecular Imaging (CMMI), Gosselies B-6041, Belgium.
Sandrine
S
Rorive
Université Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium.
Rajshekhar R
RR
Giraddi
Université Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium.
Aline
A
Wuidart
Université Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium.
Gaëlle
G
Bouvencourt
Université Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium.
Christine
C
Dubois
Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, Brussels B-1070, Belgium.|DIAPATH - Center for Microscopy and Molecular Imaging (CMMI), Gosselies B-6041, Belgium.
Isabelle
I
Salmon
Institut Jules Bordet, Université Libre de Bruxelles, Brussels B-1000, Belgium.
Christos
C
Sotiriou
Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, Melbourne 3002, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville 3002, Australia.
Wayne A
WA
Phillips
Université Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium.|WELBIO, Université Libre de Bruxelles, Brussels B-1070, Belgium.
Cédric
C
Blanpain
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000235:genetics; D002455:Cell Division; D019070:Cell Lineage; D002471:Cell Transformation, Neoplastic; D058534:Class I Phosphatidylinositol 3-Kinases; D005260:Female; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009154:Mutation / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism
D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C546639:Pik3ca protein, mouse