Abstract
Doublecortin-like kinase 1 (DCLK1), a microtubule associated kinase, has recently been proposed to be a putative marker for stemness and adverse prognosis in gastrointestinal cancers. However, it is not clear whether the protein also plays similar roles in breast cancer. Here, the expression of DCLK1 was analyzed in a large cohort of invasive breast cancers (IBC) by immunohistochemistry. DCKL1 was associated with favorable clinico-pathologic features, namely lower histologic grade, absence of lymphovascular invasion, fibrotic focus, necrosis and lower pN stage (p≤0.045). Additionally, independent significant correlations were found with estrogen receptor and neuroendocrine markers (p ≤0.019), implicating its relationship with IBC with neuroendocrine differentiation (IBC-NED). In the current cohort, IBC-NED showed worse outcome than luminal cancers without NED (hazard ratio=1.756, p=0.041). Interestingly, within the IBC-NED group, DCLK1 was found to be a good prognostic factor (hazard ratio =0.288, p=0.011). These findings were in contrast to those in gastrointestinal cancers, suggesting different functional roles of DCLK1 in different types of cancers. In clinical practice, NED is not routinely assessed; thus IBC-NED are not well studied. Its poor outcome and significant heterogeneity warrants more attention. DCLK1 expression could aid in the prognostication and management of this special cancer subtype.
Highlights
Doublecortin-like kinase 1 (DCLK1) is a microtubule associated kinase, containing two doublecortin domains in the N-terminus for regulation of microtubule polymerization and a serine/threonine protein kinase domain in the C-terminus
DCLK1 was more frequently found in luminal cancers than basal-like and HER2 over-expressed (HER2-OE) subtypes [15, 20, 21], associated with invasive breast cancers (IBC)-neuroendocrine differentiation (NED) and potentially an independent favorable prognostic factor in these cancers
Classic neuroendocrine morphology is comparatively rare in breast cancer, its significance has been debatable for some time
Summary
Doublecortin-like kinase 1 (DCLK1) is a microtubule associated kinase, containing two doublecortin domains in the N-terminus for regulation of microtubule polymerization and a serine/threonine protein kinase domain in the C-terminus. DCLK1 has been proposed as a cancer stem cell marker for gastrointestinal cancers. DCLK1 marked cancer stem cells (CSC) that self-renew and generate tumor progeny in ApcMin/+ mice [8]. DCLK1 positive differentiated tuft cells can be activated by tissue injury and initiate colon cancer [9]. DCLK1 positive cells displayed increased sphere forming and tumor initiating capacity [10], and enhanced epithelialwww.impactjournals.com/oncotarget mesenchymal transition (EMT), a process closely linked to the acquisition of stem cell properties, via regulation of microRNA biogenesis [4, 6, 11]. Colorectal cancer with high DCLK1 expression had increased cancer specific mortality [5]. Upregulation of DCLK1 expression in blood circulation was found in chemoradiotherapytreated colorectal cancer patients [12]
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