C-terminally phosphorylated p27 activates self-renewal driver genes to program cancer stem cell expansion, mammary hyperplasia and cancer

Sep 21, 2026

Uploaded by Hazel

Study examines how cancer stem cell abundance is transcriptionally regulated by C-terminally phosphorylated p27 (p27pT157pT198). Mechanistic findings show p27 co-recruits with STAT3/CBP to CSC self-renewal gene regulators including MYC, JAG1, and ANGPTL4, while p27pT/STAT3 brings in SIN3A/HDAC1 to co-repress Pyk2 inhibitor PTPN12, enabling a feed-forward STAT3 activation loop. Results link the p27-activated gene profile to STAT3-driven breast cancers and demonstrate that phosphomimetic p27 in mammary tissue increases duct branching, hyperplasia, and microinvasive, metastasis-capable cancers.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages18

Reading Time45 min

AccessFree to download

Background and rationale

Cancer stem cells and stem-like properties in breast cancer

STAT3 signaling in CSC maintenance and TNBC

p27 dual roles and phosphorylation biology

Mechanistic model and evidence

p27pT157pT198 co-recruitment with STAT3/CBP

SIN3A/HDAC1 recruitment and Pyk2 inhibitor repression

Feed-forward loop and functional consequences

In vivo and clinical relevance

Phosphomimetic p27 in mammary transgenic models

Gene-profile overlap with STAT3-activated human breast cancers

Article [https://doi.org/10.1038/s41467-024-48742-y](https://doi.org/10.1038/s41467-024-48742-y) C-terminally phosphorylated p27 activates self-renewal driver genes to program cancer stem cell expansion, mammary hyperplasia and cancer Received: 14 July 2023 | Accepted: 14 May 2024 | | --- | | | | Check for updates | Seyedeh Fatemeh Razavipour 1,2, Hyunho Yoon2,3, Kibeom Jang2, Minsoon Kim2, Hend M. Nawara 1, Amir Bagheri1, Wei-Chi Huang1, Miyoung Shin 2,4, Dekuang Zhao2, Zhiqun Zhou2, Derek Van Boven5, Karoline Briegel 2,6, Lluis Morey 2,5, Tan A. Ince7, Michael Johnson1 & Joyce M. Slingerland 1,2 In many cancers, a stem-like cell subpopulation mediates tumor initiation, dissemination and drug resistance. Here, we report that cancer stem cell (CSC) abundance is transcriptionally regulated by C-terminally phosphorylated p27 (p27pT157pT198). Mechanistically, this arises through p27 co-recruitment with STAT3/CBP to gene regulators of CSC self-renewal including MYC, the Notch ligand JAG1, and ANGPTL4. p27pTpT/STAT3 also recruits a SIN3A/HDAC1 complex to co-repress the Pyk2 inhibitor, PTPN12. Pyk2, in turn, activates STAT3, creating a feed-forward loop increasing stem-like properties in vitro and tumor-initiating stem cells in vivo. The p27-activated gene proﬁle is overrepresented in STAT3 activated human breast cancers. Furthermore, mammary transgenic expression of phosphomimetic, cyclin-CDK-binding defective p27 (p27CK-DD) increases mammary duct branching morphogenesis, yielding hyperplasia and microinvasive cancers that can metastasize to liver, further supporting a role for p27pTpT in CSC expansion. Thus, p27pTpT interacts with STAT3, driving transcriptional programs governing stem cell expansion or maintenance in normal and cancer tissues. As in normal development, cancers are maintained by stem-like cell populations termed cancer stem cells (CSC), that seed new growth1. CSCs are deﬁned by their tumor-initiating ability and can self-renew, generate more differentiated progeny, and mediate therapy resistance and metastasis1. In breast cancer, populations with CD44+CD24-/low surface markers and high ALDH1 activity are enriched for cells with stem cell properties1–3. These cells rely on expression of stem cell transcription factor genes including SOX2, MYC, and NANOG to generate tumor spheres in vitro and tumors in vivo with high frequency1–3. While normal epithelial cells undergo programmed cell death oranoikis upon loss of adhesion to their basement membrane, CSC form spheroids in suspension4. During metastasis, cancer cells undergo epithelial–mesenchymal transition (EMT)5. CSC enriched populations show a shift to EMT, overexpress drivers of EMT and metastasis, and 1Cancer Host Interactions Program, Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington DC, USA. 2Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Fl, USA. 3Department of Medical and Biological Sciences, The Catholic University of Korea, Bucheon-si, South Korea. 4Department of Pathology, Yale School of Medicine, New Haven, CT, USA. 5John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL, USA. 6Department of Surgery, University of Miami, Miller School of Medicine, Miami, Fl, USA. 7Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA. [e-mail:](e-mail: js4915@georgetown.edu)[ js4915@georgetown.edu](e-mail: js4915@georgetown.edu) are thought to seed metastasis6–8. Triple-negative breast cancers (TNBC) lack expression of hormone receptors and HER2 ampliﬁcation. While they account for only15%ofbreast cancers, they have avery high mortality, affecting younger women, with early recurrences leading to early patient demise9. The aggressiveness ofTNBC has been attributed to an enrichm

FAQs

How does C-terminally phosphorylated p27 influence cancer stem cell gene programs?

It is transcriptionally linked to CSC self-renewal regulators by co-recruiting with STAT3/CBP to genes such as MYC, JAG1, and ANGPTL4, supporting expanded stem-like properties.

What is the proposed STAT3-related feed-forward mechanism involving p27?

p27pT/STAT3 recruits a SIN3A/HDAC1 complex to co-repress the Pyk2 inhibitor PTPN12, allowing Pyk2 to activate STAT3 and strengthen the self-renewal loop.

What do mammary transgenic findings suggest about p27pTpT in tumor progression?

Phosphomimetic cyclin-CDK binding defective p27 (p27CK-DD) increases mammary duct branching, producing hyperplasia and microinvasive cancers that can metastasize to the liver.

Sep 21, 2026

Uploaded by Hazel