RT Journal Article
SR Electronic
T1 SLX4IP and telomere dynamics dictate breast cancer metastasis and therapeutic responsiveness
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e201900427
DO 10.26508/lsa.201900427
VO 3
IS 4
A1 Nathaniel J Robinson
A1 Chevaun D Morrison-Smith
A1 Alex J Gooding
A1 Barbara J Schiemann
A1 Mark W Jackson
A1 Derek J Taylor
A1 William P Schiemann
YR 2020
UL https://www.life-science-alliance.org/content/3/4/e201900427.abstract
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.