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Estrogen Receptor b in Fibromatosis

Estrogen Receptor b in Fibromatosis. 1 Andrea T. Deyrup, M.D., Ph.D., 2 Maria Tretiakova, M.D., Ph.D. and 2 Anthony G. Montag, M.D. 1 Emory University, Atlanta GA and 2 The University of Chicago, Chicago IL. Fibromatosis. Locally aggressive, non-metastasizing tumor of fibroblasts

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Estrogen Receptor b in Fibromatosis

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  1. Estrogen Receptor b in Fibromatosis 1Andrea T. Deyrup, M.D., Ph.D., 2Maria Tretiakova, M.D., Ph.D. and 2Anthony G. Montag, M.D. 1Emory University, Atlanta GA and 2The University of Chicago, Chicago IL

  2. Fibromatosis • Locally aggressive, non-metastasizing tumor of fibroblasts • APC (familial) or b catenin (sporadic) gene mutation • Recurrence frequent (positive margin) • No adequate chemotherapy

  3. Hormones in fibromatosis? • Grow during pregnancy, involute after pregnancy • Involution after HRT cessation • Anecdotal response to Tamoxifen or torimifene

  4. ER in Fibromatosis

  5. ER a and b 1880’s Oophorectomy for breast cancer 50’s-70’s Hormonal ablation 60’s Estrogen binding protein recognized 1986 ER (a) cloned 1996 ERb discovered in rat prostate

  6. 1 185 251 355 549 595 TAF DBD Hinge LBD F 1 45 148 214 304 500 530 16 97 30 59 18 ERa vs ERb Protein ERa ERb TAF: Transcription activating function DBD: DNA binding domain LBD: Ligand binding domain

  7. Tissue Distribution ERa ERb ERa & ERb Liver GI CNS Uterus Urogenital Cardiovascular Breast Endothelium Bone

  8. Methodology 40 cases of extra-abdominal fibromatosis: 11M : 29F 5 – 74 years (mean 33.4, med 32) Buttock, ext, trunk, neck, flank 9 recurrent Assessed for ER a and ER b expression by IHC 0, 1+ (<10%), 2+ (11% to 50%), or 3+ (>50%)

  9. Results 82% ERb 3+

  10. b-Catenin Wnt APC b-Catenin b-catenin tcf-lef Wnt target genes Proliferation

  11. b-catenin and ERa Ligand independent Co-precipitation Ligand dependent Transactivation reporter genes Reciprocal recruitment to response elements Kouzmenko et al, 2004

  12. Anti-Estrogen Therapy Drug Response Cases Tamoxifen 37% 41 Toremifene 75% 20 Progesterone 55% 11 Raloxifene 100% 13 Serpell et al, 1996 Lanari, 1983 Brooks et al, 1992 Tonelli et al, 2003

  13. Future Directions Clinical trials Newer ER antagonists Fibromatosis and SERM’s in vitro

  14. Questions Should anti-estrogens be considered in non-surgical fibromatosis? Should pathologists offer ERb IHC?

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