Estrogen Receptor 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 Universityof Chicago, Chicago IL

Fibromatosis

• Locally aggressive, non-metastasizing tumor of fibroblasts

• APC (familial) or catenin (sporadic) gene mutation

• Recurrence frequent (positive margin)• No adequate chemotherapy

Hormones in fibromatosis?

• Grow during pregnancy, involute after pregnancy

• Involution after HRT cessation

• Anecdotal response to Tamoxifen or torimifene

ER in Fibromatosis

Author Year Positive Cases

Methodology

Hayry 1982 3/4 Ligand binding

Weiss 1986 1/3 Ligand binding

Lim 1986 5/15 Ligand binding

Maddalozo 1993 2/4 Ligand binding

Rasbridge 1993 0/6 IHC

Devouassoux-Shisheboran

2000 0/33 IHC

Sorensen 2002 0/72 IHC

ER and

1880’s Oophorectomy for breast cancer

50’s-70’s Hormonal ablation

60’s Estrogen binding protein recognized

1986 ER () cloned

1996 ER discovered in rat prostate

DBD F

1 185 251

TAF Hinge LBD

355 549 595

1 45 148 214 304 500 530

16 97 30 59 18

ER

ER

ER vs ER Protein

TAF: Transcription activating functionDBD: DNA binding domainLBD: Ligand binding domain

Tissue Distribution

Breast

Liver CNS

Bone

Cardiovascular

GI

UrogenitalUterus

ER ER ER & ER

Endothelium

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 and ER expression by IHC

0, 1+ (<10%), 2+ (11% to 50%), or 3+ (>50%)

Results

82% ER3+

APC

-Catenin

-Catenin

-catenin

Wnt

Wnt target genes

Proliferation

tcf-lef

-catenin and ER

Co-precipitation

Transactivation reporter genes

Reciprocal recruitment to response elements

Ligand dependent

Ligand independent

Kouzmenko et al, 2004

Serpell et al, 1996Lanari, 1983Brooks et al, 1992Tonelli et al, 2003

Anti-Estrogen Therapy

ResponseDrug Cases

Tamoxifen 4137%

Toremifene 75% 20

Raloxifene 100% 13

Progesterone 55% 11

Future Directions

Clinical trials

Newer ER antagonists

Fibromatosis and SERM’s in vitro

Questions

Should anti-estrogens be considered in non-surgical

fibromatosis?

Should pathologists offer ER IHC?