The triple negative breast cancer (TNBC) is an aggressive form of breast cancer frequently seen in African American women and BRCA1 mutation carriers. Although breast cancer risk increases with age, a high proportion of early onset breast cancers (women 40 years old or younger) are TNBC. The TNBC tumors often relapse with distant metastases following standard chemotherapy. Advances in the molecular targets and mechanisms of chemosensitivity may lead to a targeted systemic therapy, and significantly and safely improve the outcome of chemotherapy in a subset of metastatic TNBC. To this end, we have demonstrated that BLID, BH-3 Like motif containing Inducer of cell Death, is a strong prognostic factor in invasive breast cancer. Frequent lack of BLID in breast cancer has been associated with TNBC, African American ethnicity and younger women (median 40 years) (all P values <0.005). Significant correlations exist between BLID negative breast cancer and declines in overall survival, local relapse-free survival and distant metastasis-free survival (all P < 0.03). In a pilot study, the odds of allelic loss of BLID for patients aged 40 years and younger are 3.7 times the odds of loss for patients aged 41-55 years (95% CI, 1.1-13). Despite the fact that members of the Forkhead boxO (FOXO) subfamily of transcriptional regulators have been linked with breast pathogenesis and prognosis, their mechanisms of action in breast cancer are largely unknown. Several FOX proteins are negatively regulated via phosphorylation by AKT, and drug-resistance of breast cancer cells has been correlated with a dysfunctional FOXO3a/AKT axis. Our dose response and time course studies suggest that BLID expression is induced by several chemotherapeutic drugs including doxorubicin (DXR), 5-fluorouracil and cisplatin in hormone-responsive breast cancer cells. In ChIP-PCR and ChIP-qPCR assays, DXR treatment of breast cancer cells resulted in increased binding of FOXO3a, a well known proapoptotic transcription factor, to the BLID gene promoter in a drug-dependent manner. Exogenous expression of BLID cDNA nanocomplex led to significant increase in chemosensitivity in ER-ve and PR-ve (SKBr3) and TNBC cells (MDA-MB231). Consistent with a potential role of BLID in chemosensitivity, BLID knockdown resulted in reversal of DXR-induced cytotoxicity in breast cancer cells. Furthermore, siRNA silencing of FOXO3a was found to be associated with decrease in BLID expression and reversal of drug-induced cytotoxicity. Collectively, it appears that certain chemotherapeutic drugs induce BLID expression via activation of specific FOXO proteins and a functional FOXO/BLID signaling pathway may be an important determinant of breast cancer response to chemotherapy.

Citation Format: Sivaramakrishna Yadavalli, Antonina Rait, Constantinos Broustas, Esther Chang, Usha N. Kasid. BLID is a novel drug-inducible apoptotic molecule: Implications in chemosensitization of breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4393. doi:10.1158/1538-7445.AM2013-4393