Chromosomal radiosensitivity of triple negative breast cancer patients

Abstract

Purpose: Based on clinical and molecular data, breast cancer is a heterogeneous disease. Breast cancers that have no expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) are defined as triple negative breast cancers (TNBCs); luminal cancers have different expressions of ER, PR and/or HER2. TNBCs are frequently linked with advanced disease, poor prognosis and occurrence in young African women, and about 15% of the cases are associated with germline BRCA1/2 mutations. Since radiotherapy is utilized as a principle treatment in the management of TNBC, we aimed to investigate the chromosomal instability and radiosensitivity of lymphocytes in TNBC patients compared to luminal breast cancer patients and healthy controls using the micronucleus (MN) assay. The effect of mutations in breast cancer susceptibility genes on chromosomal radiosensitivity was also evaluated.

Methods: Chromosomal radiosensitivity was evaluated in the G0 (83 patients and 90 controls) and S/G2 (34 patients and 17 controls) phase of the cell cycle by exposing blood samples from all patients and controls to 2 and 4 Gy ionizing radiation (IR).

Results: In the G0 MN assay, the combined cohort of all breast cancer, TNBC and luminal patients’ exhibit significantly elevated spontaneous MN values compared to controls indicating chromosomal instability. Chromosomal radiosensitivity is also significantly elevated in the combined cohort of all breast cancer patients compared to controls. The TNBC patients, however, do not exhibit enhanced chromosomal radiosensitivity. Similarly, in the S/G2 phase, 76% of TNBC patients do not show enhanced chromosomal radiosensitivity compared to the controls. In both the G0 and S/G2 phase, luminal breast cancer patients demonstrate a shift toward chromosomal radiosensitivity compared to TNBC patients and controls.

Conclusions: The observations of the MN assay suggest increased chromosomal instability and chromosomal radiosensitivity in South African breast cancer patients. However, in TNBC patients, the irradiated MN values are not elevated. Our results suggest that the healthy lymphocytes in TNBC patients could handle higher doses of IR.

Keywords:

• Triple negative breast cancer
• luminal breast cancer
• DNA repair
• chromosomal radiosensitivity
• micronucleus assay

Acknowledgments

The authors wish to thank Suretha Erasmus and Noelene Kinsley for providing genetic counseling to the patients in this study. Additionally, the lab staffs at the Center for Medical Genetics, Ghent University Hospital, Belgium are acknowledged for their assistance. We would like to thank all the patients and volunteers who participated in this study.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This research was supported by a grant under the Nuclear Technologies in Medicine and the Biosciences Initiative (NTeMBI), a national technology platform developed and managed by the SA Nuclear Energy Corporation and supported by the Department of Science and Technology, SA, a grant from CANSA (Cancer Association of South Africa) and the BOF-DOS (Special Research Fund) scholarship [Scholarship code: 01W04115], Ghent University.

Notes on contributors

Flavia Zita Francies

Flavia Zita Francies, PhD, is a Postdoctoral Researcher at the Department of Radiation Sciences, Radiobiology, University of the Witwatersrand, Johannesburg, South Africa.

Olivia Herd

Olivia Herd, PhD, was a Postdoctoral Researcher at the Department of Radiation Sciences, Radiobiology, University of the Witwatersrand, Johannesburg, South Africa.

Alan Cairns

Alan Cairns, MBBCh, FCS (SA), is a Specialist Surgeon in the Department of Surgery at Donald Gordon Medical Centre, Johannesburg, South Africa.

Sarah Nietz

Sarah Nietz, MD, MMed Surg, FCS (SA), is a Specialist Surgeon in the Department of Surgery at Charlotte Maxeke Johannesburg Academic Hospital and Donald Gordon Medical Centre, Johannesburg, South Africa.

Marshall Murdoch

Marshall Murdoch, MBBCh, FC PlastSurg (SA), is a Plastic & Reconstructive Surgeon in the Department of Surgery at Donald Gordon Medical Centre, Johannesburg, South Africa.

Jacobus Slabbert

Jacobus Slabbert, PhD, was the Head of Biomedical Physics at iThemba LABS (NRF), Somerset West, South Africa.

Kathleen B. M. Claes

Kathleen B. M. Claes, PhD, is an Associate Professor, Laboratory Head at Center for Medical Genetics, Ghent University Hospital and Group Leader at Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium.

Anne Vral

Anne Vral, PhD, is an Associate Professor at the Department of Human Structure and Repair, Radiobiology, Ghent University, Ghent, Belgium.

Ans Baeyens

Ans Baeyens, PhD, is a Senior Clinical Lecturer and Radiobiology Head at the Department of Radiation Sciences, Radiobiology, University of the Witwatersrand, Johannesburg, South Africa. She also serves as a Group Leader at Cancer Research Institute Ghent (CRIG), Ghent University and an Associate Professor at the Department of Human Structure and Repair, Radiobiology, Ghent University, Ghent, Belgium.