A Novel Differentiation Therapy Approach to Reduce the Metastatic Potential of Basal, Highly Metastatic, Triple-Negative Breast Cancers
Annual summary rept. 15 Apr 2010-14 Apr 2014
GENEVA FOUNDATION LAKEWOOD WA
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Underlying mechanisms that account for the increased risk of aggressive, metastatic disease associated with basal type breast cancers compared to the more differentiated, luminal tumor subtype have not been well established. Our work demonstrates that the transcription factor GATA3, essential for luminal differentiation during mammary gland development, is sufficient to promote global changes in basal triple-negative breast cancer BTNBC cells resulting in both 1 reduced metastasis via LOX downregulation and 2 acquisition of luminal features, thus offering a direct link between these two processes. GATA3 promoted global alterations of the transcriptome of BTNBC cells resulting in molecular and cellular changes associated with a more differentiated, luminal tumor subtype and a concomitant reduction in primary tumor growth, lung metastasis, and macrophage recruitment at the metastatic site. Importantly, we demonstrate that the inhibition of metastases by GATA3 results from the suppression of lysyl oxidase LOX expression, a metastasis promoting matrix remodeling protein, via epigenetic changes. MDA-MB-231 breast cancer cells overexpressing GATA3 showed increased methylation at the LOX promoter compared to control cells. Expression of LOX and GATA3 in breast cancer cells were inversely correlated. Most importantly, elevated LOX and reduced GATA3 expression levels predicted poor survival in breast cancer patients. Thus, altering transcription factor expression that promotes differentiation may be an important approach to mitigate aggressive tumor characteristics and to identify therapeutic targets such as LOX for the prevention or treatment of metastatic disease.
- Medicine and Medical Research