Expression of aldehyde dehydrogenase after neoadjuvant chemotherapy is associated with expression of hypoxia-inducible factors 1 and 2 alpha and predicts prognosis in locally advanced breast cancer

Abstract

OBJECTIVE:To analyze the expression of hypoxia-inducible factors (hypoxia-inducible factor 1A and hypoxia-inducible factor 2A) and aldehyde dehydrogenase proteins in patients with locally advanced breast carcinoma who were subjected to neoadjuvant chemotherapy.METHODS:We included 90 patients with histologically confirmed stage II and III breast carcinoma who were treated with neoadjuvant chemotherapy between 2000 and 2005. Immunohistochemistry for aldehyde dehydrogenase, hypoxia-inducible factor 1A, and hypoxia-inducible factor 2A was performed before and after neoadjuvant chemotherapy. We analyzed the influence of clinical and pathological features on clinical and pathological response, disease-free survival, and overall survival.RESULTS:An objective clinical response to neoadjuvant chemotherapy was observed in 80% of patients, with 12% showing a complete pathological response. Among all clinical and pathological parameters, only the expression of hypoxia-inducible factor 1A was associated with a pathological response. A positive association was found between expression of aldehyde dehydrogenase and that of hypoxia-inducible factor 1A before and after chemotherapy. Aldehyde dehydrogenase expression was associated with expression of hypoxia inducible-factor 2A in tumors after neoadjuvant treatment. In a univariate analysis, prognosis was influenced by age, pathological response, metastasis to axillary lymph nodes after neoadjuvant chemotherapy, overexpression of hypoxia-inducible factor 2, and the presence of aldehyde dehydrogenase-positive cells within the primary tumor after neoadjuvant chemotherapy. In a multivariate analysis, only age and the presence of aldehyde dehydrogenase-positive cells after chemotherapy were associated with reduced overall survival.CONCLUSION:The presence of aldehyde dehydrogenase-positive cells within the residual tumor after neoadjuvant chemotherapy is associated with an increase in the expression of hypoxia-inducible factor 2A and with poor prognosis in patients with locally advanced breast cancer.

Hypoxia-inducible factors are required for chemotherapy resistance of breast cancer stem cells

“…The clinical relevance of these results is underscored by studies demonstrating associations between: (i) ALDH expression and ER − /basal subtype breast cancer (51); (ii) HIF-1α and ALDH + cells in breast cancers, both before and after chemotherapy (51); (iii) ALDH + breast cancer cells and resistance to sequential paclitaxel and epirubicin chemotherapy (52); and (iv) increased ALDH + cells after chemotherapy and decreased disease-free survival (51,53). Taken together with these clinical studies, our results provide compelling evidence in support of clinical trials combining HIF inhibitors and cytotoxic chemotherapy in women with TNBC.…”

Implications of Different Cancer Stem Cell Phenotypes in Breast Cancer

“…Increased expression of hypoxia-inducible factors 1 and 2α was also shown to be associated with ALDH1 activity and believed to raise the metastatic propensity of ALDH1 high cells (6,47,48). Furthermore, increased expression of homeobox A1 and mucin 4 were associated with high ALDH1 activity, also contributing to tumor relapse and metastasis.…”

Microbial influences on hormesis, oncogenesis, and therapy: A review of the literature

“…This is because HIF-1α is associated with the host's innate immune functions in order to help the specialized phagocytic cells function in the hypoxic microenvironments of infected tissues (Nizet and Johnson, 2009;Zinkernagel et al, 2007). Thus, bacteria in the microenvironment of the tumor would effectively prepare the neoplasm against hypoxia as well as inflammation, since HIF-1α also has a positive association with the expression of the previously discussed aldehyde dehydrogenase (Tiezzi et al, 2013).…”