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PreprintCC BY-NC-NDbioRxiv

Risk-Window Palbociclib Exposure Delays ErbB2-Driven Mammary Tumorigenesis and Suppresses Mammary Epithelial Cell Stemness

  • Y. Liu
  • A. B. Parris
  • Z. Ma
  • L. Wei
  • Y. Qi
  • X. Yang1
  1. 1North Carolina Central University
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Abstract

ErbB2 overexpression occurs in 15-20% of invasive breast cancer (BC) and inactivation of Cyclin D1-CDK4/6 axis reduce mammary stem/progenitor cells in ErbB2-driven tumorigenesis. Here, we explored the preventive role of short-term palbociclib intervention in MMTV-ErbB2 mice. Palbociclib significantly inhibited the proliferation and stemness of ErbB2-overexpressed BC cells in vitro and in vivo. Furthermore, short-term palbociclib exposure during the early premalignant risk window significantly delayed mammary tumor development and reduced tumor multiplicity, accompanied by the suppression of epithelial proliferation and ductal/alveolar morphogenesis in premalignant tissues, as well as prolonged tumor-free survival compared with controls. Importantly, palbociclib reduced the luminal epithelial (CD24high/CD49flow), mammary reconstitution unit-enriched (CD24high/CD49fhigh) subpopulations, and luminal progenitor/TIC-enriched (CD61high/CD49fmid) subpopulations. These changes were accompanied by diminished mammary epithelial cell stemness functions, including colony-forming, mammosphere-forming, and 3D growth activities of mammary epithelial cells. Mechanistically, palbociclib-treated tissues showed inhibition of the Cyclin D1-CDK4/6-RB-E2F axis and coordinated attenuation of ER-, ErbB2- and Wnt/{beta}-catenin-associated signaling. Together, we demonstrate that short-term CDK4/6 inhibition during a premalignant risk window produces a sustained delay in ErbB2-driven mammary tumorigenesis, associated with remodeling of the mammary epithelial hierarchy and suppression of proliferative and stem/progenitor-associated activity, suggesting CDK4/6 inhibition as a strategy for ErbB2-positive BC prevention.

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Cite

BibTeXRIS
BibTeX
@misc{liu2026riskwindow,
  title = {{Risk-Window Palbociclib Exposure Delays ErbB2-Driven Mammary Tumorigenesis and Suppresses Mammary Epithelial Cell Stemness}},
  author = {Y. Liu and A. B. Parris and Z. Ma and L. Wei and Y. Qi and X. Yang},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.14.751306},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.14.751306v1},
  note = {CC BY-NC-ND},
}
RIS
TY  - UNPB
TI  - Risk-Window Palbociclib Exposure Delays ErbB2-Driven Mammary Tumorigenesis and Suppresses Mammary Epithelial Cell Stemness
AU  - Y. Liu
AU  - A. B. Parris
AU  - Z. Ma
AU  - L. Wei
AU  - Y. Qi
AU  - X. Yang
PY  - 2026
DA  - 2026/09/14
PB  - bioRxiv
DO  - 10.64898/2026.09.14.751306
UR  - https://www.biorxiv.org/content/10.64898/2026.09.14.751306v1
AB  - ErbB2 overexpression occurs in 15-20% of invasive breast cancer (BC) and inactivation of Cyclin D1-CDK4/6 axis reduce mammary stem/progenitor cells in ErbB2-driven tumorigenesis. Here, we explored the preventive role of short-term palbociclib intervention in MMTV-ErbB2 mice. Palbociclib significantly inhibited the proliferation and stemness of ErbB2-overexpressed BC cells in vitro and in vivo. Furthermore, short-term palbociclib exposure during the early premalignant risk window significantly delayed mammary tumor development and reduced tumor multiplicity, accompanied by the suppression of epithelial proliferation and ductal/alveolar morphogenesis in premalignant tissues, as well as prolonged tumor-free survival compared with controls. Importantly, palbociclib reduced the luminal epithelial (CD24high/CD49flow), mammary reconstitution unit-enriched (CD24high/CD49fhigh) subpopulations, and luminal progenitor/TIC-enriched (CD61high/CD49fmid) subpopulations. These changes were accompanied by diminished mammary epithelial cell stemness functions, including colony-forming, mammosphere-forming, and 3D growth activities of mammary epithelial cells. Mechanistically, palbociclib-treated tissues showed inhibition of the Cyclin D1-CDK4/6-RB-E2F axis and coordinated attenuation of ER-, ErbB2- and Wnt/{beta}-catenin-associated signaling. Together, we demonstrate that short-term CDK4/6 inhibition during a premalignant risk window produces a sustained delay in ErbB2-driven mammary tumorigenesis, associated with remodeling of the mammary epithelial hierarchy and suppression of proliferative and stem/progenitor-associated activity, suggesting CDK4/6 inhibition as a strategy for ErbB2-positive BC prevention.
ER  -