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The rearranged during transfection/papillary thyroid carcinoma tyrosine kinase is an estrogen-dependent gene required for the growth of estrogen receptor positive breast cancer cells

Abstract

The rearranged during transfection/papillary thyroid carcinoma (RET/PTC) tyrosine kinase is an oncogene implicated in the tumorigenesis of thyroid cancer. Recent studies by us and others have shown that RET/PTC kinase expression is induced by estrogen in breast cancer cells. Due to the critical involvement of estrogen-regulated genes in the pathogenesis of breast cancer, we investigated the expression, regulation, and function of RET/PTC kinase in breast cancer cells. We found that RET/PTC kinase expression correlates with estrogen receptor (ER) expression in breast cancer cells and tumor specimens, and that RET/PTC kinase expression is associated with a poor prognosis in ER-positive breast cancer patients. We found that estrogen rapidly induces RET/PTC kinase expression in an ER-dependent manner in breast cancer cells and that this induction is through a transcriptional regulatory mechanism. Using reporter assays, small interfering RNA (siRNA) assays, and chromatin immunoprecipitation (ChIP) assays, we demonstrated the necessity of crosstalk between ER and the forkhead box A1 (FOXA1) transcription factor in regulating RET/PTC kinase expression. In functional studies, increased expression of RET/PTC kinase induced by estrogen stimulation resulted in elevated phosphorylation of multiple downstream kinase signaling pathways. Conversely, knockdown of RET/PTC expression was associated with the inhibition of these same kinase signaling pathways, and, in fact, decreased the stimulatory effect of estrogen on the proliferation of ER-positive breast cancer cells. These results demonstrate a novel pathway of ER and FOXA1 transcription factor crosstalk in regulating RET/PTC kinase expression, and demonstrate that RET/PTC kinase is a critical regulator for the proliferation of ER-positive breast cancer cells. Taken together, our study suggests that RET/PTC kinase may serve as a novel prognostic biomarker and therapeutic target for prevention and treatment of ER-positive breast cancer.

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Abbreviations

ER:

Estrogen receptor

ERE:

Estrogen-response element

FHRE:

Forkhead responsive element

RET/PTC kinase gene:

Rearranged during transfection/papillary thyroid carcinoma

MEN2A:

Multiple endocrine neoplasia type 2A

ActD:

Actinomycin D

CHX:

Cycloheximide

ChIP:

Chromatin immunoprecipitation

siRNA:

Small interfering RNA

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Acknowledgments

This study was supported by the NIH grant R01-CA123246 (PB). The authors thank Michelle Savage for proofreading and editing the manuscript.

Conflict of interest

None declared.

Author information

Correspondence to Powel H. Brown.

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Wang, C., Mayer, J.A., Mazumdar, A. et al. The rearranged during transfection/papillary thyroid carcinoma tyrosine kinase is an estrogen-dependent gene required for the growth of estrogen receptor positive breast cancer cells. Breast Cancer Res Treat 133, 487–500 (2012). https://doi.org/10.1007/s10549-011-1775-9

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Keywords

  • Estrogen
  • Breast cancer
  • Rearranged during transfection
  • Papillary thyroid carcinoma
  • Kinase
  • Transcription factor crosstalk