Background: The Cancer Genome Atlas (TCGA) consortium reported that most dominant feature of Luminal/ER-positive breast cancers is increased mRNA and protein levels of ESR1, GATA3, FOXA1, XBP1 and MYB. Most notably ESR1 and XBP1 were highly expressed and infrequently mutated. XBP1 is a multitasking transcription factor and a key component of the unfolded protein response (UPR). Despite the wealth of knowledge about the role of XBP1-S in luminal/ER-positive breast cancer not much is known about the molecular effectors of XBP1-S in context of estrogen signalling. Nuclear receptor coactivator 3 (NCOA3/SRC-3/AIB1/ACTR/pCIP/RAC3) is a member of p160 family of coactivators. NCOA3 not only functions to promote breast cancer development, it also participates in resistance to anti-hormonal therapy. NCOA3 was found to be overexpressed in >60% of primary breast tumours. Nonetheless, how NCOA3 becomes overexpressed in breast cancers is not well understood. In this study we demonstrate that expression of NCOA3 is regulated by XBP1-S during the conditions of UPR, as well as estrogen stimulation in human breast cancer cells. Materials and Methods: We have used ER-positive human breast cancer cell lines and tumour samples from breast cancer patients to study the regulation of NCOA3 expression during conditions of ER stress and estrogen signalling. We have used combination of qRT-PCR, western blotting, promoter reporter assays cell proliferation and cell death assays for this work. Results: We observed increased expression of NCOA3 during conditions of UPR and estrogen (E2) stimulation. Further investigations revealed that XBP1-S regulates the expression of NCOA3 via the XBP1-binding sites in the promoter of NCOA3 during UPR and estrogen signalling. We identify a novel role for NCOA3 in activation of PERK-ATF4 axis during UPR where knockdown of NCOA3 compromised the optimal activation of PERK-ATF4 pathway. Further we show that NCOA3 is required for induction of XBP1S upon E2-stimulation but not during the conditions of ER stress. Furthermore upregulated NCOA3 was required for XBP1-mediated resistance to anti-hormonal agents. Increased expression of NCOA3 was associated with poor prognosis and higher levels of XBP1S in breast cancer tissues. Conclusions: Our results showing the increased expression of NCOA3 during UPR provides a mechanism for overexpression of NCOA3 in human cancers. Our results uncover a novel steroid hormone independent role for NCOA3 in UPR signalling. Further we identify a positive feedback regulatory loop consisting of XBP1 and NCOA3 that maintains high levels of NCOA3 and XBP1 expression in breast cancer tissues. Taken together our data identify XBP1-NCOA3 axis that regulates cell fate decisions in ER-positive breast cancer cells.