Cited by 75Protein Kinase Regulation and GTPase SignalingCancer Cells and MetastasisCancer-related Molecular Pathways

Repression of p63 and induction of EMT by mutant Ras in mammary epithelial cells

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Yoh, Kathryn E., Regunath, Kausik, Guzman, Asja, Lee, Seung-Min, Pfister, Neil T., Akanni, Olutosin, Kaufman, Laura J., Prives, Carol +1 more·2016·Proceedings of the National Academy of Sciences

Abstract

Significance: The oncogenes Harvey Rat Sarcoma Virus GTPase ( H-RAS ) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha ( PIK3CA ) are well known for altering cell growth and morphology. We show here that they are also able to modify the differentiation state of mammary epithelial cells by inducing an epithelial-to-mesenchymal transition (EMT). This transition leads to greater invasiveness, a hallmark of the progression of tumors toward metastasis. Expression of p63, a protein required for the development of mammary epithelial cells, is strongly repressed by these oncogenes. In turn, loss of p63, which occurs at the transcriptional level, causes a shift in microRNAs and transcription factors that control EMT. Targeting specific genes within this Ras-to-EMT axis may be useful as a therapy to block breast cancer progression.

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Crossref · 10.1073/pnas.1613417113

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  • p63 and PTEN are tumor suppressors that play a key role in breast and prostate tissue development.

    “we inhibited p63 and PTEN expression, two genes that are described as tumor-suppressors that play a key role in breast and prostate tissue development (32–35).”

    From Direct transfection of clonal organoids in Matrigel microbeads: a promising approach toward organoid-based genetic screens (2018) · cites this paper as [35]

    The paper’s introductory passage (page not provided) says p63 is a master regulator of epithelial cells and that mice lacking it have no mammary glands, supporting a role in breast development. It discusses p63’s cancer role as tissue-dependent and mentions PTEN loss in breast cancer, but does not establish that both genes are tumor suppressors with key roles in breast and prostate tissue development. (LLM, conf=0.86)

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Authors
Yoh, K. E., Regunath, K., Guzman, A., Lee, S.-M., Pfister, N. T., Akanni, O., Kaufman, L. J., Prives, C., & Prywes, R.
Affiliations
  • Columbia University (US)
  • Yonsei University (KR)
Venue
Proceedings of the National Academy of Sciences
Published
2016-09-28
Volume
113
Issue
41
Pages
E6107-E6116
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W2527245570
Cited by
75
References
107
Citations by year
2026: 3 · 2025: 5 · 2024: 6 · 2023: 4 · 2022: 13 · 2021: 15 · 2020: 6 · 2019: 13 · 2018: 7 · 2017: 3
FWCI
3.99
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • HHS | NIH | National Cancer Institute (CA87497)
  • National Science Foundation (ACI-1053575, PESO 1227297)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords
p63, ΔNp63α, epithelial-mesenchymal transition, H-Ras, PIK3CA, mammary epithelial cells, transcriptional regulation, cell invasion, 3D collagen gel, epithelial differentiation
MeSH terms
Base Sequence, Binding Sites, Cell Transformation, Neoplastic, Epithelial Cells, Gene Expression Regulation, Humans, Models, Biological, Mutation, Promoter Regions, Genetic, Protein Binding, Transcription Factors, Signal Transduction, Tumor Suppressor Protein p53, Sequence Deletion, Genes, Reporter, ras Proteins, Phosphatidylinositol 3-Kinases, Tumor Suppressor Proteins, RNA Interference, RNA, Small Interfering, Cell Line, Tumor, Proto-Oncogene Proteins c-akt, Epithelial-Mesenchymal Transition

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