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Wnt-5a signaling restores tamoxifen sensitivity in estrogen receptor-negative breast cancer cells.

ABSTRACT: One third of all breast cancers are estrogen receptor alpha (ERalpha) negative, carry a poor overall prognosis, and do not respond well to currently available endocrine therapies. New treatment strategies are therefore required. Loss of Wnt-5a has previously been correlated with loss of ERalpha in clinical breast cancer samples, and we sought to investigate this association further. Three breast cancer cell lines (MDA-MB-231, MDA-MB-468, and 4T1) lacking expression of ERalpha and Wnt-5a, and one breast cancer cell line (T47D) expressing both proteins were used in this study. Wnt-5a signaling was generated in ERalpha-negative cell lines via stimulation with either recombinant Wnt-5a protein or a Wnt-5a-derived hexapeptide (Foxy-5) possessing Wnt-5a signaling properties. ERalpha expression was restored at both mRNA and protein level, after treatment with recombinant Wnt-5a or Foxy-5. This restoration of expression occurred in parallel with a reduction in methylation of the ERalpha promoter. Up-regulated ERalpha could be activated, initiate transcription of progesterone receptor and pS2, and activate an estrogen response element reporter construct. Significantly, breast cancer cells re-expressing ERalpha responded to treatment with the selective estrogen receptor modulator tamoxifen, as measured by induction of apoptosis and cell growth inhibition. Finally, Foxy-5 also increased ERalpha expression in an in vivo model of ERalpha-negative breast cancer. This represents the first evidence that Wnt-5a signaling acts to re-establish ERalpha expression in ERalpha-negative breast cancer cells. Our data suggest that combinatorial therapy with Foxy-5 and tamoxifen should be considered as a future treatment possibility for ERalpha-negative breast cancer patients.

SUBMITTER: Ford CE

PROVIDER: S-EPMC2656180 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Wnt-5a signaling restores tamoxifen sensitivity in estrogen receptor-negative breast cancer cells.

Ford Caroline E CE Ekström Elin J EJ Andersson Tommy T

Proceedings of the National Academy of Sciences of the United States of America 20090223 10

One third of all breast cancers are estrogen receptor alpha (ERalpha) negative, carry a poor overall prognosis, and do not respond well to currently available endocrine therapies. New treatment strategies are therefore required. Loss of Wnt-5a has previously been correlated with loss of ERalpha in clinical breast cancer samples, and we sought to investigate this association further. Three breast cancer cell lines (MDA-MB-231, MDA-MB-468, and 4T1) lacking expression of ERalpha and Wnt-5a, and one ...[more]

PMID: 19237581

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Project description:IntroductionThe inhibition of estrogen receptor (ER) ? action with the ER antagonist tamoxifen is an established treatment in the majority of breast cancers. De novo or acquired resistance to this therapy is common. Expression of ER? in breast tumors has been implicated as an indicator of tamoxifen sensitivity. The mechanisms behind this observation remain largely uncharacterized. In the present study, we investigated whether ER? can modulate pathways implicated in endocrine resistance development.MethodsT47-D and MCF-7 ER?-expressing breast cancer cells with tetracycline-regulated expression of ER? were used as a model system. Expression levels and activity of known regulators of endocrine resistance were analyzed by performing quantitative polymerase chain reaction assays, Western blot analysis and immunostaining, and sensitivity to tamoxifen was investigated by using a cell proliferation kit.ResultsExpression of ER? in ER?-positive T47-D and MCF-7 human breast cancer cells resulted in a decrease in Akt signaling. The active form of an upstream regulator of Akt, proto-oncogene c-ErbB-2/receptor tyrosine kinase erbB-3 (HER2/HER3) receptor dimer, was also downregulated by ER?. Furthermore, ER? increased expression of the important inhibitor of Akt, phosphatase and tensin homologue deleted on chromosome 10 (PTEN). Importantly, ER? expression increased the sensitivity of these breast cancer cells to tamoxifen.ConclusionsOur results suggest a link between expression of ER? and endocrine sensitivity by increasing PTEN levels and decreasing HER2/HER3 signaling, thereby reducing Akt signaling with subsequent effects on proliferation, survival and tamoxifen sensitivity of breast cancer cells. This study supports initiatives to further investigate whether ER? presence in breast cancer samples is an indicator for endocrine response. Current therapies in ER?-positive breast cancers aim to impair ER? activity with antagonists or by removal of endogenous estrogens with aromatase inhibitors. Data from this study could be taken as indicative for also using ER? as a target in selected groups of breast cancer.

Dataset Information

Wnt-5a signaling restores tamoxifen sensitivity in estrogen receptor-negative breast cancer cells.

Publications

Wnt-5a signaling restores tamoxifen sensitivity in estrogen receptor-negative breast cancer cells.

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