Recurrence of
estrogen receptor (ER)-positive
breast tumors despite curative-intent adjuvant
therapy is thought to be due to enrichment of tumor initiating cells (
TIC) during endocrine
therapy (ET). Recently, it was identified that by antagonizing the ER, ET promotes rapid degradation of the death-associated factor 6 (DAXX)
protein, which is necessary and sufficient to potently inhibit
TICs. Thus, the goal of the current study was to identify a DAXX-inducing agent to inhibit
TICs and prevent proliferation of the
tumor.
Phytoestrogens (
naringenin,
resveratrol,
genistein,
apigenin, and
quercetin) were screened for DAXX
protein expression, anti-
TIC and anti-proliferative efficacy in vitro and in vivo. Specific DAXX-inducing
phytoestrogens were tested to assess selectivity towards ERα and/or ERβ. Results showed that
phytoestrogens tested induced DAXX
protein expression and inhibited survival of
TICs from ER+ MCF-7 and T47D cells. Only
naringenin,
resveratrol, and
quercetin did not stimulate total cell proliferation.
Naringenin,
resveratrol, but not
quercetin inhibited survival of
TICs in vitro and in vivo in a DAXX-dependent manner.
Naringenin-induced DAXX
protein expression and inhibition of
TICs seemed to be more selective towards ERβ while
resveratrol was more selective through ERα.
Naringenin or
resveratrol inhibited the rate of
tumor initiation and rate of
tumor growth in a DAXX-dependent manner. These results suggest that a therapeutic approach using a
phytoestrogen to induce DAXX
protein expression could potently inhibit
TICs within a
tumor to delay or prevent
tumor initiation. Therefore, a DAXX-promoting
phytoestrogen should be explored for prevention of
tumor progression in advanced disease and relapse in the adjuvant setting.