Abstract
BackgroundThe specific mechanism underlying the contribution of the Aldehyde dehydrogenase 1 (ALDH1) phenotype to metastatic behavior and early tumor relapse in breast cancer is currently unclear.Methods147 randomly selected invasive ductal carcinoma samples were assayed for expression of ALDH1A1, NOTCH1, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2), and association of the ALDH1A1 phenotype with clinic pathological features was further evaluated.ResultsALDH1A1-positive cells were detected in 63.3% (93 of 147) of tumors. 80.0% (32 of 40) of tumors with strong ALDH1A1 staining displayed early recurrence, compared with 20.0% (8 of 40) of tumors negative for ALDH1A1 expression (P = 0.027). ALDH1A1 status was significantly correlated with strong malignant proliferative marker Ki67 staining (P = 0.001), and no significantly different expression of ALDH1A1 across the subtypes of ER, PR, and HER2 expression and triple negative features of tumor tissue. Multivariate regression analysis demonstrated that elevated ALDH1A1 expression is an independent predictor of recurrence-free survival and distant metastasis-free survival. Notably, breast cancer tissue strong for ALDH1A1 expression displayed weak NOTCH1 staining compared to ALDH1A1 weak tumor tissue (P = 0.002), and the relationship between ALDH1A1 and NOTCH1 mRNA positivity was significant (Pearson correlation - 0.337, P = 0.014; Spearman’s rho - 0.376, P = 0.006). Elevated NOTCH1 mRNA level (using a cut-off value based on the median ALDH1A1 2-△△CT value) was associated with reduction of ALDH1A1 mRNA level (P = 0.001).ConclusionsThe ALDH1A1 phenotype is an independent predictor of early tumor relapse characteristic (specifically, incidence of early local recurrence and distant metastasis) of invasive ductal carcinoma. The NOTCH1 signaling pathway is possibly involved in the negative association of the ALDH1A1 phenotype with early malignant relapse in invasive ductal carcinoma.
Highlights
Breast invasive ductal carcinoma is a common breast malignancy and a major cause of cancer-related death in women worldwide [1]
Several studies have suggested that Aldehyde dehydrogenase 1 (ALDH1) contributes to normal and tumor stem cell differentiation, and invasion and metastasis in breast cancer are mediated by a cellular subcomponent with stem cell characteristics expressing ALDH1 [11,12]
Given the association between high ALDH1 expression and elevated staining for the proliferating cell marker, we focused on whether ALDH1 is linked to the cell proliferation pathway
Summary
Breast invasive ductal carcinoma is a common breast malignancy and a major cause of cancer-related death in women worldwide [1]. Several cellular subcomponent changes have been described in breast cancer, including aldehyde dehydrogenase 1 (ALDH1) positivity, CD44 positivity, CD24 negativity, RHOC overexpression, hypomethylation of caveolin promoters, and deletion of some tumor suppressors [5,6,7,8,9]. Populations of normal mammary epithelial cells with increased ALDH1 activity have the ability to form mammospheres and self-renew, and breast carcinoma cells with high ALDH1 activity display tumor-generating potential. Emerging evidence suggests that ALDH1 plays important functional roles related to self-protection [14] Another previous report describing the association of ALDH1 expression with early metastasis and decreased survival in inflammatory breast cancer has further demonstrated a critical role of ALDH1-positive cancer cells in mediating the clinically aggressive behavior of breast cancer [15]. The specific mechanism underlying the contribution of the Aldehyde dehydrogenase 1 (ALDH1) phenotype to metastatic behavior and early tumor relapse in breast cancer is currently unclear
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