Introduction: Luminal breast cancers are estrogen receptor positive (ER+) malignancies, where Luminal B tumors are associated with poor prognosis, and resistance to endocrine therapy. In the clinic, Luminal B tumors are very difficult to distinguish from the more treatable Luminal A subtype. Importantly, the cancer genome project has recently illuminated an amplification and overexpression, exclusive to Luminal B tumors in Chromosome 11. This genomic amplification contains a novel and yet unexplored target, C11orf67. C11orf67 has also been shown to be one of the proteins regulating NFkB activation by a genome wide siRNA screen.
Aims: (1) Confirm the overexpression of C11orf67 in luminal B breast cancer cell lines (2) Study whether the expression of C11orf67 is regulated by estrogen, and anti-estrogen stimulation (3) Investigate the role of C11orf67 in modulating NFkB activity and resistance to endocrine therapy.
Methods: A panel of ER+ and ER- breast cancer cell lines was tested for C11orf67 mRNA expression. The effect of target gene knock-down by RNA interference on estrogen receptor expression was addressed. Lastly, functional assays were performed in the breast cell lines upon modulation of C11orf67 expression.
Outcomes: We clearly demonstrated the overexpression of C11orf67 in the ER+ but not in the ER- cell lines. Transient knockdown of the gene did not affect the ER expression. Importantly, estrogen stimulation of ER+ cells led to a remarked down-regulation of C11orf67 mRNA levels, whilst anti-estrogen treatment resulted in up-regulation of C11orf67.
Conclusions: The overexpression of C11orf67 in the ER+ cell lines suggests that C11orf67 is potentially a novel biomarker of Luminal B disease. Our results point to C11orf67 as a novel estrogen response gene downstream the ER signalling. We propose that C11orf67 is one of the targets that link the hormone response pathway with NFkB signalling, resulting in resistance to anti-estrogen treatment.