Journal article

Synergistic targeting of BRCA1 mutated breast cancers with PARP and CDK2 inhibition

Diar Aziz, Neil Portman, Kristine J Fernandez, Christine Lee, Sarah Alexandrou, Alba Llop-Guevara, Zoe Phan, Aliza Yong, Ashleigh Wilkinson, C Marcelo Sergio, Danielle Ferraro, Dariush Etemadmoghadam, David D Bowtell, Violeta Serra, Paul Waring, Elgene Lim, C Elizabeth Caldon



Basal-like breast cancers (BLBC) are aggressive breast cancers that respond poorly to targeted therapies and chemotherapies. In order to define therapeutically targetable subsets of BLBC we examined two markers: cyclin E1 and BRCA1 loss. In high grade serous ovarian cancer (HGSOC) these markers are mutually exclusive, and define therapeutic subsets. We tested the same hypothesis for BLBC. Using a BLBC cohort enriched for BRCA1 loss, we identified convergence between BRCA1 loss and high cyclin E1 protein expression, in contrast to HGSOC in which CCNE1 amplification drives increased cyclin E1. In cell lines, BRCA1 loss was associated with stabilized cyclin E1 during the cell cycle, and BRCA1 s..

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Awarded by European Regional Development FEDER Funds

Awarded by Asociacion Espanola Contra el Cancer (AECC)

Awarded by National Breast Cancer Foundation Career Development Fellowship

Awarded by Cancer Institute NSW Fellowship

Funding Acknowledgements

D.A. was a recipient of the Higher Committee of Education of Iraq Scholarship. V.S. is supported by Instituto de Salud Carlos III (ISCIII) funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds [CP19/00033] and A.L.-G. by the Asociacion Espanola Contra el Cancer (AECC) [INVES20095LLOP]. E.L. is a National Breast Cancer Foundation Endowed Chair and supported by Love Your Sister. C.E.C. is supported by a National Breast Cancer Foundation Career Development Fellowship (ECF17-002) and Cancer Institute NSW Fellowship (2020/CDF1071), and is grateful for the support of the Dr. Lee MacCormick Edwards Charitable Foundation. We wish to thank Heather Thorne, Eveline Niedermayr, Sharon Guo, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the National Institute of Health (USA)) for their contributions to this resource, and the many families who contribute to kConFab. kConFab is supported by a grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. We also thank and acknowledge A/Prof Alex Swarbrick and the Tumour Progression Lab at the Garvan Institute for expanding the HCI-002 model, and the BReast Origin CAncer tissue DonatEd after death (BROCADE) program, funded by the National Breast Cancer Foundation of Australia. The authors additionally thank the Experimental Therapeutics and the Breast Cancer Groups from VHIO for providing study materials.