PT  - JOURNAL ARTICLE
AU  - Nathaniel J Robinson
AU  - Chevaun D Morrison-Smith
AU  - Alex J Gooding
AU  - Barbara J Schiemann
AU  - Mark W Jackson
AU  - Derek J Taylor
AU  - William P Schiemann
TI  - SLX4IP and telomere dynamics dictate breast cancer metastasis and therapeutic responsiveness
AID  - 10.26508/lsa.201900427
DP  - 2020 Apr 01
TA  - Life Science Alliance
PG  - e201900427
VI  - 3
IP  - 4
4099  - https://www.life-science-alliance.org/content/3/4/e201900427.short
4100  - https://www.life-science-alliance.org/content/3/4/e201900427.full
SO  - Life Sci. Alliance2020 Apr 01; 3
AB  - Metastasis is the leading cause of breast cancer-related death and poses a substantial clinical burden owing to a paucity of targeted treatment options. The clinical manifestations of metastasis occur years-to-decades after initial diagnosis and treatment because disseminated tumor cells readily evade detection and resist therapy, ultimately giving rise to recurrent disease. Using an unbiased genetic screen, we identified SLX4-interacting protein (SLX4IP) as a regulator of metastatic recurrence and established its relationship in governing telomere maintenance mechanisms (TMMs). Inactivation of SLX4IP suppressed alternative lengthening of telomeres (ALT), coinciding with activation of telomerase. Importantly, TMM selection dramatically influenced metastatic progression and survival of patients with genetically distinct breast cancer subtypes. Notably, pharmacologic and genetic modulation of TMMs elicited telomere-dependent cell death and prevented disease recurrence by disseminated tumor cells. This study illuminates SLX4IP as a potential predictive biomarker for breast cancer progression and metastatic relapse. SLX4IP expression correlates with TMM identity, which also carries prognostic value and informs treatment selection, thereby revealing new inroads into combating metastatic breast cancers.