BECN1 and BRCA1 Deficiency Sensitizes Ovarian Cancer to Platinum Therapy and Confers Better Prognosis

Abstract

Background: BRCA1, BECN1 and TP53 are three tumor suppressor genes located on chromosome 17 and frequently found deleted, silenced, or mutated in many cancers. These genes are involved in autophagy, apoptosis, and drug resistance in ovarian cancer. Haploinsufficiency or loss-of-function of either TP53, BRCA1 or BECN1 correlates with enhanced predisposition to cancer development and progression, and chemoresistance. Expectedly, the combined altered expression of these three tumor suppressor genes worsens the prognosis of ovarian cancer patients. However, whether such a genotypic pattern indeed affects the chemo-responsiveness to standard chemotherapy thus worsening patients’ survival has not been validated in a large cohort of ovarian cancer patients. Aim: We interrogated datasets from the TCGA database to analyze how the expression of these three tumor suppressor genes impacts on the clinical response to platinum-based chemotherapy thus affecting the survival of ovarian cancer patients. Results and conclusion: Compared to EOC with homozygous expression of BECN1 and BRCA1, tumors expressing low mRNA expression of these two tumor suppressor genes (either because of shallow (monoallelic) co-deletion or of promoter hypermethylation), showed higher sensitivity to platinum-based therapies and were associated with a better prognosis of ovarian cancer-bearing patients. This outcome was independent of TP53 status, though it was statistically more significant in the cohort of patients with mutated TP53. Thus, sensitivity to platinum therapy (and probably to other chemotherapeutics) correlates with low expression of a combination of critical tumor suppressor genes. Our study highlights the importance of thoroughly assessing the genetic lesions of the most frequently mutated genes to stratify the patients in view of a personalized therapy. More importantly, the present findings suggest that targeting the function of both BECN1 and BRCA1 could be a strategy to restore chemosensitivity in refractory tumors.

Resveratrol Contrasts LPA-Induced Ovarian Cancer Cell Migration and Platinum Resistance by Rescuing Hedgehog-Mediated Autophagy

“…The stratification of ovarian cancer patients as poor and good responders to the platinum-based first-line therapy based on the oncogenic and tumor suppressor genetic background is crucial for implementation of personalized therapy [58]. Here we investigated whether the LPA-induced activation of the Hh pathway and of its downstream effectors (including GLI1, BMI-1, SNAIL-1, TWIST1) and the associated autophagy signature could have a translational relevance for therapeutic intervention.…”

Isolation, Characterization, and Autophagy Function of BECN1-Splicing Isoforms in Cancer Cells

“…Therefore, mutated p53 that cannot bind to BECN1 or a wild-type p53 in combination with BECN1 isoforms lacking the BH3D may result in upregulation of autophagy. Indeed, mutated p53 along with low BECN1 mRNA expressions significantly correlate with a better prognosis associated with upregulated autophagy and sensitization to cis-platinum in ovarian cancer patients [ 9 ]. In conclusion, it is important to consider that different BECN1 variants can compete with the wild-type for binding with the interactors depending on both the microenvironmental stimuli and the genetic context leading to different effects on autophagy and cancer patient prognosis.…”

“…Moreover, data from patients with ovarian cancer and lymphomas indicate that higher levels of BECN1 are associated with a better prognosis and higher survival rate [ 7 , 8 ]. Interestingly, patients with ovarian cancer presenting co-deletions of BECN1 and BRCA1 were found to benefit from platinum-based therapy and show improved chances of survival [ 9 ]. Overall, these studies highlight the importance of BECN1 as both tumor prognostic marker and potential molecular target for the therapeutic treatment of cancer.…”

Glycosylation-Related Genes Predict the Prognosis and Immune Fraction of Ovarian Cancer Patients Based on Weighted Gene Coexpression Network Analysis (WGCNA) and Machine Learning

“…Approximately 70% of OC individuals will develop a recurrence after surgery, and about 75% of high-grade serous ovarian cancer (HGSOC) patients will experience chemoresistance against cisplatin, oxaliplatin, carboplatin, etc. [9,10]. Identifying novel risk factors that regulate tumorigenesis, migration, and proliferation will contribute to early diagnosis and personalized interventions for OC treatment.…”