The Estrogen receptor story is not so simple either

[Lani]

Clin Cancer Res. 2008 Aug 15;14(16):5228-35.

Nuclear and Cytoplasmic Expression of ER{beta}1, ER{beta}2, and ER{beta}5 Identifies Distinct Prognostic Outcome for Breast Cancer Patients.

Shaaban AM, Green AR, Karthik S, Alizadeh Y, Hughes TA, Harkins L, Ellis IO, Robertson JF, Paish EC, Saunders PT, Groome NP, Speirs V.
Authors' Affiliations: YCR and Liz Dawn Pathology and Translational Sciences Centre, Leeds Teaching Hospitals and Leeds Institute of Molecular Medicine, University of Leeds, Leeds, United Kingdom.
PURPOSE: Previous conflicting results about the prognostic significance of estrogen receptor (ER)-beta in breast cancer may be explained by contribution of isoforms, of which five exist. Our aim was to elucidate the prognostic significance of ERbeta1, ERbeta2, and ERbeta5 by immunohistochemistry in a large cohort of breast carcinomas with long-term follow-up. EXPERIMENTAL DESIGN: Tissue microarrays were stained with ERbeta1, ERbeta2, and ERbeta5 antibodies and scored as percentage of positive tumor cells and using the Allred system. Nuclear and cytoplasmic staining was evaluated and correlated with histopathologic characteristics, overall survival (OS), and disease-free survival (DFS). RESULTS: Nuclear ERbeta2 and ERbeta5, but not ERbeta1, significantly correlated with OS (P = 0.006, P = 0.039, and P = 0.099, respectively), and ERbeta2 additionally with DFS (P = 0.013). ERbeta2 also predicted response to endocrine therapy (P = 0.036); correlated positively with ERalpha, progesterone receptor, androgen receptor, and BRCA1; and correlated inversely with metastasis and vascular invasion. Tumors coexpressing ERbeta2 and ERalpha had better OS and DFS. Cytoplasmic ERbeta2 expression, alone or combined with nuclear staining, predicted significantly worse OS. Notably, patients with only cytoplasmic ERbeta2 expression had significantly worse outcome (P = 0.0014). CONCLUSIONS: This is the first study elucidating the prognostic role of ERbeta1, ERbeta2, and ERbeta5 in a large breast cancer series. ERbeta2 is a powerful prognostic indicator in breast cancer, but nuclear and cytoplasmic expression differentially affect outcome. Measuring these in clinical breast cancer could provide a more comprehensive picture of patient outcome, complementing ERalpha.
PMID: 18698041 [PubMed - in process

ER beta 1,2 and 5 testing is not commonly performed and even only rarely in clinical trials it appears.
The location of the ER subtype (nuclear vs cytoplasmic) seems to make a difference as well.

Until we know more, making conclusions about breast cancer vs subtypes of breast cancer is fraught with danger. We are looking at a fruit salad with dozens of ingredients and assuming everything in it is apples or oranges.

[Hopeful]

Lani, can you please explain the difference between nuclear and cytoplasmic staining? Am I correct that this has to do with the location of the receptor?

Hopeful

[Lani]

originally they thought there was only one estrogen receptor which was located in the nucleus of the cells containing estrogen receptors. Then they found there was another group of estrogen receptors responsible for effects of estrogen which happen much more quickly, that was located in the cytoplasm near the cytoplasmic membrane (between the cytoplasm and the outside of the cell) which was responsible for actions of estrogen which happened very quickly (faster than the more lengthy processes which estrogen turns on in the nucleus involving DNA, RNA, etc)

Now they are aware of subtypes of estrogen receptors, each of which may be turned on, off and work in different ways and be associated with different subtypes of bc and may be influenced by different treatments potentially.

The nuclear vs cytoplasmic staining refers to the fact that when they apply IHC immunohistochemical stains against the various estrogen receptors there is a difference in where the stains highlight in the cells and therefore where the different estrogen receptors are located ie, in the cytoplasm --"cytoplasmic staining" --vs in the nucleus--"nuclear staining"

Hope this helps

[Hopeful]

Thanks, Lani, that helps a great deal.

Hopeful