Abstract
BackgroundThe presence of hypoxic areas is common in all breast lesions but no data clearly correlate low oxygenation with the acquisition of malignant features by non-invasive cells, particularly by cells from ductal carcinoma in situ (DCIS), the most frequently diagnosed tumor in women.MethodsBy using a DCIS-derived cell line, we evaluated the effects of low oxygen availability on malignant features of non-invasive breast tumor cells and the possible role of all-trans retinoic acid (ATRA), a well-known anti-leukemic drug, in counteracting the effects of hypoxia. The involvement of the β2 isoform of PI-PLC (PLC-β2), an ATRA target in myeloid leukemia cells, was also investigated by specific modulation of the protein expression.ResultsWe demonstrated that moderate hypoxia is sufficient to induce, in DCIS-derived cells, motility, epithelial-to-mesenchymal transition (EMT) and expression of the stem cell marker CD133, indicative of their increased malignant potential.Administration of ATRA supports the epithelial-like phenotype of DCIS-derived cells cultured under hypoxia and keeps down the number of CD133 positive cells, abrogating almost completely the effects of poor oxygenation. We also found that the mechanisms triggered by ATRA in non-invasive breast tumor cells cultured under hypoxia is in part mediated by PLC-β2, responsible to counteract the effects of low oxygen availability on CD133 levels.ConclusionsOverall, we assigned to hypoxia a role in increasing the malignant potential of DCIS-derived cells and we identified in ATRA, currently used in treatment of acute promyelocytic leukemia (APL), an agonist potentially useful in preventing malignant progression of non-invasive breast lesions showing hypoxic areas.
Highlights
The presence of hypoxic areas is common in all breast lesions but no data clearly correlate low oxygenation with the acquisition of malignant features by non-invasive cells, by cells from ductal carcinoma in situ (DCIS), the most frequently diagnosed tumor in women
Hypoxia induces malignant properties in DCIS-derived cells In order to assess the role of low oxygen availability in breast cancer progression, the effects of hypoxia were investigated in the MCF10DCIS cell line, the only wellestablished model of DCIS [24]
Among the molecules up-regulated by hypoxia through the activity of hypoxia-inducible factors (HIFs)-1α, the cell surface protein carbonic anhydrase IX (CAIX) is one of the more specific for non-invasive breast cancer cells [25], this protein was evaluated in MCF10DCIS cells cultured under hypoxia
Summary
The presence of hypoxic areas is common in all breast lesions but no data clearly correlate low oxygenation with the acquisition of malignant features by non-invasive cells, by cells from ductal carcinoma in situ (DCIS), the most frequently diagnosed tumor in women. Hypoxia is defined as a reduced oxygen availability and solid tumors, including breast cancer, often contain hypoxic regions because of their rapid and uncontrollable cell proliferation combined with a structurally and functionally abnormal vasculature [1]. Even if the presence of hypoxic areas is common in all breast lesions, no data clearly correlate low oxygenation with the acquisition of malignant features by non-invasive cells, by cells from ductal carcinoma in situ (DCIS), that constitutes the 20–25% of newly diagnosed breast cancers in industrialized countries [7, 8]. The pleotropic effects of ATRA in breast cancer cells were correlated to non-genomic and multi-layered pathways aimed to target the cancer stem cells-like population [17, 18]
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