Doublecortin-like kinase 1 expression associates with breast cancer with neuroendocrine differentiation

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.

Functional implication of Dclk1 and Dclk1-expressing cells in cancer

“…Thus, O'Connell and colleagues were able to reconcile the apparent contradictory findings of widespread epigenetic silencing of the Dclk1C gene on one hand, and the clear functional importance of the transcript in a broad variety of cancers on the other. 41 Accordingly, Dclk1 expression has been observed in neuroendocrine tumors of the mammary gland and the rectum, 42,43 consistent with the known expression of Dclk1 in neuronal and enteroendocrine cells, but no specific role for Dclk1 in these tumors has been suggested so far. Finally, the relevance of Dclk1 expression in esophageal cancer is presently unclear, 44 but the cells seem to correlate with an increased progression to cancer in a murine model and human patients.…”

Doublecortin-Like Kinase 1 (DCLK1) Regulates B Cell-Specific Moloney Murine Leukemia Virus Insertion Site 1 (Bmi-1) and is Associated with Metastasis and Prognosis in Pancreatic Cancer

“…In addition, IHC results showed that DCLK1 is upregulated in stage II-III tumors compared to normal kidney and stage I tumors [15]. Conversely, DCLK1 was found to be associated with favorable clinicopathologic features and a good prognostic factor in breast cancer, particularly in invasive breast cancers with neuroendocrine differentiation (IBC-NED) [14]. These contrasting results with regard to tumor-promoting roles in gastrointestinal cancers suggest different functional roles for DCLK1 in different type of cancers.…”

“…Accumulating evidence suggests that CSCs are responsible for cancer metastasis, recurrence and radio/chemo-resistance [36][37][38], and previous reports demonstrate that DCLK1 can mark CSCs in gastrointestinal and other cancers [12][13][14]. A recent study revealed that DCLK1 is essential for the invasive and metastatic properties of CSCs in human pancreatic cancer and that it might be a promising therapeutic target [11].…”

“…Moreover, a recent report showed that in preinvasive pancreatic cancer, DCLK1 distinguishes a morphologically distinct and functionally unique population of cancer-initiating cells with stem cell properties [10]. These and several other studies provide strong evidence that DCLK1 can be regarded as a CSC marker in pancreatic cancer [11], colon cancer [12,13], breast cancer [14] and clear renal cell carcinoma [15]. CSCs are now considered to be primarily responsible for tumor relapse and can potentially initiate metastatic growth [16].…”

Prognostic impact of doublecortin‐like kinase 1 expression in locally advanced rectal cancer treated with preoperative chemoradiotherapy

“…Importantly, Nakanishi et al demonstrated that ablation of DCLK1 in murine models resulted in tumor shrinkage without damage to the normal intestine and postulated that DCLK1 was a marker for CSC but not normal intestinal cells (17). In the clinical setting, DCLK1 expression has been reported in tumors of the esophagus, pancreas, kidney, breast, and colon (18)(19)(20)(21)(22)(23)(24). A few studies have demonstrated the association of DCLK1 expression with poor prognosis of colorectal cancer patients treated without preoperative therapy (18,19).…”