Recent findings suggest that combination treatment with anti-estrogen and anti-RET may offer a novel treatment strategy in a subset of breast cancer patients. We investigated the role of RET in potentiating the effects of anti-estrogen response and examined whether RET expression predicted the ability for tyrosine kinase inhibitor (TKI) to effect ERK1/2 activation in primary breast cancer.

Growth response, ERK1/2 activation, Ki-67 and TUNEL was assessed in breast cancer cell lines in vitro and in xenografts with vandetanib and/or tamoxifen. Thirty tumors with matched normal breast tissue were evaluated for RET expression and response to TKI treatment.

Vandetanib potentiated the inhibitory effect of tamoxifen in hormone responsive (p=0.01) and hormone insensitive (p<0.001) ERα-positive breast cancer cells. Vandetanib significantly repressed tumorigenesis of MCF-7 xenografts (p<0.001), which displayed decreased activation of ERK1/2 and AKT. Vandetanib and tamoxifen reduced the growth of established tumors with a greater effect of dual therapy compared to single agent (p=0.003), with tamoxifen reducing proliferative index and vandetanib inducing apoptosis. In primary breast cancers, RET expression correlated with the ERα-positive subtype. Relative decrease in ERK1/2 phosphorylation with TKI treatment was 42% (p<0.001) in RET-positive tumors vs. 14% (p=ns) in RET-negative tumors.

Vandetanib potentiated the anti-growth effects of tamoxifen in breast cancer, which was mediated through RET activation. RET predicted response to TKI therapy with minimal effects on ERK1/2 activation in RET-negative tumors. The preclinical data support evaluation of anti-estrogen in combination with TKI as a potential treatment strategy for RET-positive luminal breast cancer.