The glycomic profile of invasive ductal carcinoma of the breast is altered in patients with hypoxic regions: implications for tumor behavior

Abstract

Hypoxic areas in solid tumors are often associated with poor prognosis and resistance to chemotherapy. The aim of the study was to analyze the expression of galectin-1 (Gal-1), galectin-3 (Gal-3), sialic acid and b1-6 branched glycan structures in hypoxic environment of invasive ductal carcinoma (IDC) of the breast. We performed lectin histochemistry with phytohemagglutinin-L (L-PHA) and Sambucus nigra lectin (SNA); and immunohistochemistry for Gal-1, Gal-3, carbonic anhydrase IX, hypoxia-inducible factor, estrogen receptor (ER), progesterone receptor and human epidermal growth factor receptor type-2 for 86 IDC samples. Patients with markers positive for hypoxia were mostly ER-negative (p = 0.003) and presented with more nodal invasion than the non-hypoxic group (p = 0.0439). Concerning the glycobiological aspects, the hypoxic group expressed more of Gal-3 (p = 0.0021) and SNA ligands (p = 0.0498), however, there was no association between lectin-and galectin-staining and clinical and histopathological data. Our results suggest a change in the glycomic profile of patients within hypoxic regions of IDC. However, further studies are needed to evaluate the role of lectin-and galectin-ligands in tumor's hypoxic environment, as well as their potential to be used as therapeutic targets. (Folia Histochemica et Cytobiologica 2014, Vol. 52, No. 2, 96-103) Key words: breast cancer; IDC; hypoxia; glycomic profile; galectins; lectin ligands; IHC; histochemistry Ĩ ntroduction Breast cancer is the most common cancer among women, accounting for 22% of new cases every year, and the second most common cancer world wide [1]. Moreover, as with most solid tumors, breast cancers often have central regions of hypoxia which are usually peri-necrotic [2]. Cells that survive in this adverse environment are typically resistant to radiotherapy and chemotherapy and differ from cells in areas with adequate blood supply [3,4]. Hypoxia-inducible factor 1a (HIF-1a) is the major modulator of hypoxic condition and is constitutively produced under low-oxygen conditions, which typically occurs at distances greater than 180 μm from blood vessel [5]. HIF-1a affects tumor progression and angiogenesis by modulating the expression of genes involved in the adaptation to oxygen-and nutrient-deficiency, leading to increased cell survival, inhibition of apoptosis and migration [6,7]. Among these genes, carbonic anhydrase IX (CA IX) and glucose transporter 1 (GLUT1) play crucial roles in cellular adaptation, by altering the energy metabolism of neoplastic cells, which begin to show high rates of anaerobic glycolysis [2,[5][6][7]. The change in metabolic profile is followed by altered expression of enzymes involved in aerobic and anaerobic glycolysis, sugar

Glycobiology Modifications in Intratumoral Hypoxia: The Breathless Side of Glycans Interaction

“…We also observed that Gal-1 expression was found mainly in the extracellular matrix and tumor-associated stromal cells, demonstrating their importance in the relationship between a tumor and its microenvironment [226, 227]. …”

Soy and Breast Cancer: Focus on Angiogenesis

“…In general, it has been shown that the main role of galectin-1 in cancer progression represents its immunosuppressive effect, which facilitates pro-tumorigenic microenvironment [145,146] and stimulates angiogenesis [147]. Similarly, over-expression of galectin-3 in hypoxic breast tumors was associated with the presence of more aggressive tumors leading to a poor prognosis [148,149]. Galectin-3 is also an important mediator of VEGF- and bFGF-mediated angiogenic response [150].…”

Modulação da expressão de galectina-3 frente às pressões seletivas de pH e oxigenação: um mecanismo para a heterogeneidade intratumoral?

“…Zeng et al (2007) também mostraram que HIF-1α regula a expressão de galectina-3 no disco intervertebral de ratos através da interação com elementos responsivos à hipóxia (HRE -hypoxia response elements) presentes na região promotora do gene dessa lectina. Além disso, altos níveis de expressão de galectina-3 foram relacionados com áreas de hipóxia in vivo em carcinomas mamários, tanto para o subtipo carcinoma ductal in situ (REGO, et al, 2013) como para o carcinoma ductal invasivo (REGO, et al, 2014). Em nosso laboratório, também se observou a colocalização in vivo por imunoistoquímica de galectina-3 em áreas de pseudopaliçada em modelo de glioblastoma humano, sendo estas descritas como áreas hipercelulares organizadas ao redor de ambientes necróticos e, portanto, hipóxicos.…”