Differential DNA damage repair and PARP inhibitor vulnerability of the mammary epithelial lineages

  • Cell Rep. 2023 Oct 16;42(10):113256. doi: 10.1016/j.celrep.2023.113256.
Hyeyeon Kim  1 ,  Kazeera Aliar  2 ,  Pirashaanthy Tharmapalan  1 ,  Curtis W McCloskey  2 ,  Abhijith Kuttanamkuzhi  2 ,  Barbara T Grünwald  2 ,  Luis Palomero  3 ,  Mathepan J Mahendralingam  1 ,  Matthew Waas  2 ,  Arvind S Mer  4 ,  Mitchell J Elliott  2 ,  Bowen Zhang  1 ,  Khalid N Al-Zahrani  5 ,  Ellen R Langille  6 ,  Michael Parsons  4 ,  Swami Narala  2 ,  Stefan Hofer  2 ,  Paul D Waterhouse  7 ,  Razqallah Hakem  8 ,  Benjamin Haibe-Kains  1 ,  Thomas Kislinger  1 ,  Daniel Schramek  6 ,  David W Cescon  2 ,  Miquel A Pujana  3 ,  Hal K Berman  2 ,  Rama Khokha  9
Affiliations
  • 1. Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
  • 2. Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
  • 3. ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908 Barcelona, Catalonia, Spain.
  • 4. Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
  • 5. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
  • 6. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • 7. Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
  • 8. Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5G 2N2, Canada.
  • 9. Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5G 2N2, Canada. Electronic address: [email protected].
PMID: 37847590 DOI: 10.1016/j.celrep.2023.113256
Abstract

It is widely assumed that all normal somatic cells can equally perform homologous recombination (HR) and non-homologous end joining in the DNA damage response (DDR). Here, we show that the DDR in normal mammary gland inherently depends on the epithelial cell lineage identity. Bioinformatics, post-irradiation DNA damage repair kinetics, and clonogenic assays demonstrated luminal lineage exhibiting a more pronounced DDR and HR repair compared to the basal lineage. Consequently, basal progenitors were far more sensitive to poly(ADP-ribose) polymerase inhibitors (PARPis) in both mouse and human mammary epithelium. Furthermore, PARPi sensitivity of murine and human breast Cancer cell lines as well as patient-derived xenografts correlated with their molecular resemblance to the mammary progenitor lineages. Thus, mammary epithelial cells are intrinsically divergent in their DNA damage repair capacity and PARPi vulnerability, potentially influencing the clinical utility of this targeted therapy.

Keywords
CP: Cancer; CP: Cell biology; DNA damage response; PARP inhibitors; breast cancer; homologous recombination repair; mammary lineages; mammary stem/progenitors; γ-irradiation.
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