Year-end Sale % OFF 
Abstract
Here, we used a data-mining and informatics approach to discover new biomarkers of resistance to hormonal therapy in breast cancer. More specifically, we investigated whether nuclear-encoded genes associated with mitochondrial biogenesis can be used to predict tumor recurrence, distant metastasis and treatment failure in high-risk breast cancer patients. Overall, this strategy allowed us to directly provide in silico validation of the prognostic value of these mitochondrial components in large and clinically relevant patient populations, with >15 years of follow-up data. For this purpose, we employed a group of 145 ER(+) luminal A breast cancer patients, with lymph-node (LN) metastasis at diagnosis, that were treated with tamoxifen, but not any chemotherapy agents. Using this approach, we identified >60 new individual mitochondrial biomarkers that predicted treatment failure and tumor recurrence, with hazard-ratios (HR) of up to 4.17 (p=2.2e-07). These include mitochondrial chaperones (HSPD1, HSPA9), membrane proteins (VDAC2, TOMM70A) and anti-oxidants (SOD2), as well as 18 different mitochondrial ribosomal proteins (MRPs) and >20 distinct components of the OXPHOS complexes. In addition, we combined 4 mitochondrial proteins (HSPD1, UQCRB, MRPL15, COX17), to generate a compact mitochondrial gene signature, associated with a HR of 5.34 (p=1e-09). This signature also successfully predicted distant metastasis and was effective in larger groups of ER(+) (N=2,447), basal (N=540) and HER2(+) (N=193) breast cancers. It was also effective in all breast cancers (N=3,180), if considered together as a single group. Based on this analysis, we conclude that mitochondrial biogenesis should be considered as a new therapeutic target for overcoming tumor recurrence, distant metastasis and treatment failure in patients with breast cancer. In summary, we identified individual mitochondrial biomarkers and 2 compact mitochondrial gene signatures that can be used to predict tamoxifen-resistance and tumor recurrence, at their initial diagnosis, in patients with advanced breast cancer. In the long-term, these mitochondrial biomarkers could provide a new companion diagnostics platform to help clinicians to accurately predict the response to hormonal therapy in ER(+) breast cancer patients, facilitating more personalized and effective treatment. Similarly, these mitochondrial markers could be used as companion diagnostics, to determine which breast cancer patients would benefit most from clinical treatments with mitochondrially-targeted anti-cancer therapeutics. Finally, we also showed that these mitochondrial markers are superior when directly compared with conventional biomarkers, such as Ki67 and PCNA.
Highlights
Treatment failure, due to drug resistance, still remains a major obstacle for more effective anti-cancer therapy and personalized medicine [1,2,3,4,5,6,7,8,9]
Establishing the prognostic value of conventional markers in the patient population To identify new potential biomarkers of tamoxifen-resistance, here we used publically available transcriptional profiling data from the tumors of breast cancer patients that were treated with tamoxifen, but did not receive any chemotherapy
We selected high-risk patients that were lymph-node positive at diagnosis, and we focused on the luminal A subtype, which represents the most common form of estrogen receptor alpha (ER)(+) breast cancers (N = 145 patients) (Figure 1)
Summary
Due to drug resistance, still remains a major obstacle for more effective anti-cancer therapy and personalized medicine [1,2,3,4,5,6,7,8,9]. We set out to test the hypothesis that individual markers of mitochondrial biogenesis and OXPHOS may have prognostic value in the early identification of tamoxifen-resistant patients at diagnosis, up to 15 years before the onset of tumor recurrence and distant metastasis. For this purpose, we performed outcome analysis on > 400 nuclear mitochondrial gene transcripts. We discuss the possibility that mitochondria should be therapeutically targeted, to overcome resistance to hormonal therapy, and to prevent tumor recurrence and distant metastasis. Mitochondrial markers showed prognostic value in different sub-groups of ER(-) breast cancer patients [12]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
