The combinatorial activation of the PI3K and Ras/MAPK pathways is sufficient for aggressive tumor formation, while individual pathway activation supports cell persistence.
A high proportion of human tumors maintain activation of both the PI3K and Ras/MAPK pathways. In basal-like breast cancer (BBC), PTEN expression is decreased/lost in over 50% of cases, leading to aberrant activation of the PI3K pathway. Additionally, BBC cell lines and tumor models have been shown to exhibit an oncogenic Ras-like gene transcriptional signature, indicating activation of the Ras/MAPK pathway. To directly test how the PI3K and Ras/MAPK pathways contribute to tumorigenesis, we deleted PTEN and activated KRas within non-tumorigenic MCF-10A breast cells. Neither individual mutation was sufficient to promote tumorigenesis, but the combination promoted robust tumor growth in mice. However, in vivo bioluminescence reveals that each mutation has the ability to promote a persistent phenotype. Inherent in the concept of tumor cell dormancy, a stage in which residual disease is present but remains asymptomatic, viable cells with each individual mutation can persist in vivo during a period of latency. The persistent cells were excised from the mice and showed increased levels of the cell cycle arrest proteins p21 and p27 compared to the aggressively growing PTEN-/-KRAS(G12V) cells. Additionally, when these persistent cells were placed into growth-promoting conditions, they were able to re-enter the cell cycle and proliferate. These results highlight the potential for either PTEN loss or KRAS activation to promote cell survival in vivo, and the unique ability of the combined mutations to yield rapid tumor growth. This could have important implications in determining recurrence risk and disease progression in tumor subtypes where these mutations are common.
University of Maryland School of Medicine, Marlene and Stewart Greenebaum National Cancer Institute Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
Keyata N
KN
Thompson
University of Maryland School of Medicine, Marlene and Stewart Greenebaum National Cancer Institute Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
Rebecca A
RA
Whipple
University of Maryland School of Medicine, Marlene and Stewart Greenebaum National Cancer Institute Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
Jennifer R
JR
Yoon
Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA.
Michael
M
Lipsky
University of Maryland School of Medicine, Marlene and Stewart Greenebaum National Cancer Institute Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.|Graduate Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
Monica S
MS
Charpentier
University of Maryland School of Medicine, Marlene and Stewart Greenebaum National Cancer Institute Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.|Graduate Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.|Department of Pathology and Laboratory Medicine, Perelman School of Medicine, Univesity of Pennsylvainia, Philadelphia, PA, USA.
Amanda E
AE
Boggs
University of Maryland School of Medicine, Marlene and Stewart Greenebaum National Cancer Institute Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.|Graduate Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
Kristi R
KR
Chakrabarti
University of Maryland School of Medicine, Marlene and Stewart Greenebaum National Cancer Institute Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.|Graduate Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
Lekhana
L
Bhandary
University of Maryland School of Medicine, Marlene and Stewart Greenebaum National Cancer Institute Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
Lindsay K
LK
Hessler
University of Maryland School of Medicine, Marlene and Stewart Greenebaum National Cancer Institute Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.|Graduate Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.|Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA.
Stuart S
SS
Martin
University of Maryland School of Medicine, Marlene and Stewart Greenebaum National Cancer Institute Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.|Graduate Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.|Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA.
Michele I
MI
Vitolo
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins
MAPK; PI3K; PTEN; breast cancer; dormancy