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Abstract
The Hsp70-binding protein 1 (HspBP1) belongs to a family of co-chaperones that regulate Hsp70 activity and whose biological significance is not well understood. In the present study, we show that when HspBP1 is either knocked down or overexpressed in BRCA1-proficient breast cancer cells, there were profound changes in tumorigenesis, including anchorage-independent cell growth in vitro and in tumor formation in xenograft models. However, HspBP1 did not affect tumorigenic properties in BRCA1-deficient breast cancer cells. The mechanisms underlying HspBP1-induced tumor suppression were found to include interactions with BRCA1 and promotion of BRCA1-mediated homologous recombination DNA repair, suggesting that HspBP1 contributes to the suppression of breast cancer by regulating BRCA1 function and thereby maintaining genomic stability. Interestingly, independent of BRCA1 status, HspBP1 facilitates cell survival in response to ionizing radiation (IR) by interfering with the association of Hsp70 and apoptotic protease-activating factor-1. These findings suggest that decreased HspBP1 expression, a common occurrence in high-grade and metastatic breast cancers, leads to genomic instability and enables resistance to IR treatment.

Affiliations

Cha Kyung Youn #  1   2 , Jung-Hee Lee #  1   3 , Gurusamy Hariharasudhan  1 , Hong Beum Kim  1   4 , Jeeho Kim  1 , Sumi Lee  1 , Sung-Chul Lim  1   5 , Sang-Pil Yoon  6 , Sang-Gon Park  7 , In-Youb Chang  8 , Ho Jin You  9   10
1 DNA Damage Response Network Center, Chosun University School of Medicine, 375 Seosuk-dong, Gwangju, Republic of Korea.
2 Department of Meridian & AcupointᆞDiagnosis, College of Korean Medicine, Dongshin University, 67, Dongsindae-gil, Naju-si, Jeollanam-do, Republic of Korea.
3 Department of Cellular and Molecular Medicine, Chosun University School of Medicine, 375 Seosuk-dong, Gwangju, Republic of Korea.
4 Division of Natural Medical Sciences, Chosun University School of Medicine, 375 Seosuk-dong, Gwangju, Republic of Korea.
5 Department of Pathology, Chosun University School of Medicine, 375 Seosuk-dong, Gwangju, Republic of Korea.
6 Department of Anatomy, School of Medicine, Jeju National University, Jeju-Do, Republic of Korea.
7 Department of Hemato-oncology, Chosun University Hospital Internal Medicine, Gwangju, Republic of Korea. sgpark@chosun.ac.kr.
8 Department of Anatomy, Chosun University School of Medicine, 375 Seosuk-dong, Gwangju, Republic of Korea. iyjang@chosun.ac.kr.
9 DNA Damage Response Network Center, Chosun University School of Medicine, 375 Seosuk-dong, Gwangju, Republic of Korea. hjyou@chosun.ac.kr.
10 Department of Pharmacology, Chosun University School of Medicine, 375 Seosuk-dong, Gwangju, Republic of Korea. hjyou@chosun.ac.kr.
# Contributed equally.