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

Hyeyeon Kim; Kazeera Aliar; Pirashaanthy Tharmapalan; Curtis W McCloskey; Abhijith Kuttanamkuzhi; Barbara T Grünwald; Luis Palomero; Mathepan J Mahendralingam; Matthew Waas; Arvind S Mer; Mitchell J Elliott; Bowen Zhang; Khalid N Al-Zahrani; Ellen R Langille; Michael Parsons; Swami Narala; Stefan Hofer; Paul D Waterhouse; Razqallah Hakem; Benjamin Haibe-Kains; Thomas Kislinger; Daniel Schramek; David W Cescon; Miquel A Pujana; Hal K Berman; Rama Khokha

doi:10.1016/j.celrep.2023.113256

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

Cell Rep. 2023 Oct 31;42(10):113256. doi: 10.1016/j.celrep.2023.113256. Epub 2023 Oct 16.

Authors

Hyeyeon Kim¹, Kazeera Aliar², Pirashaanthy Tharmapalan¹, Curtis W McCloskey², Abhijith Kuttanamkuzhi², Barbara T Grünwald², Luis Palomero³, Mathepan J Mahendralingam¹, Matthew Waas², Arvind S Mer⁴, Mitchell J Elliott², Bowen Zhang¹, Khalid N Al-Zahrani⁵, Ellen R Langille⁶, Michael Parsons⁴, Swami Narala², Stefan Hofer², Paul D Waterhouse⁷, Razqallah Hakem⁸, Benjamin Haibe-Kains¹, Thomas Kislinger¹, Daniel Schramek⁶, David W Cescon², Miquel A Pujana³, Hal K Berman², Rama Khokha⁹

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: rama.khokha@uhn.ca.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents* / pharmacology
DNA Damage
DNA Repair
Homologous Recombination
Humans
Mice
Poly(ADP-ribose) Polymerase Inhibitors* / pharmacology

Substances

Poly(ADP-ribose) Polymerase Inhibitors
Antineoplastic Agents

Grants and funding

CIHR/Canada