Contrasting hypoxic effects on breast cancer stem cell hierarchy is dependent on ERα status.

• Tumor hypoxia is often linked to decreased survival in breast cancer patients and current therapeutic strategies aim to target the hypoxic response. One way in which this is done is by blocking hypoxia induced angiogenesis. Anti-angiogenic therapies show some therapeutic potential with increased disease free survival but these initial promising results are short lived and followed by tumor progression. We hypothesized that this may be due to altered cancer stem cell (CSC) activity resulting from increased tumor hypoxia. We studied the effects of hypoxia on CSC activity, using in vitro mammosphere and holoclone assays as well as in vivo limiting dilution experiments, in 13 patient-derived samples and 4 cell lines. There was a HIF1-alpha-dependent CSC increase in ER-alpha-positive cancers following hypoxic exposure which was blocked by inhibition of estrogen and Notch signaling. A contrasting decrease in CSC was seen in ER-alpha-negative cancers. We next developed a xenograft model of cell lines and patient-derived samples to assess the hypoxic-CSC response. Varying sizes of xenografts were collected and analyzed for HIF1-alpha expression and CSC. The same ER-alpha-dependent contrasting hypoxic-CSC response was seen validating the initial observation. These data suggest that ER-alpha-positive and negative breast cancer sub-types respond differently to hypoxia and, as a consequence, anti-angiogenic therapies will not be suitable for both subgroups.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine (hsv//eng)

Nyckelord

Hypoxia

Breast Cancer Stem Cells

Notch

Oestrogen

Publikations- och innehållstyp

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