Biology of Progesterone Receptor Loss in Breast Cancer and Its Implications for Endocrine Therapy

2005 ◽  
Vol 23 (30) ◽  
pp. 7721-7735 ◽  
Author(s):  
Xiaojiang Cui ◽  
Rachel Schiff ◽  
Grazia Arpino ◽  
C. Kent Osborne ◽  
Adrian V. Lee
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Progesterone Receptor ◽  
Signaling Pathways ◽  
Endocrine Therapy ◽  
Aromatase Inhibitors ◽  
Growth Factor Signaling ◽  
Breast Cancers ◽  
Estrogen Withdrawal ◽  
Er Positive

The response to endocrine therapy in breast cancer correlates with estrogen receptor (ER) and progesterone receptor (PR) status. ER-positive/PR-negative breast cancers respond less well to selective ER modulator (SERM) therapy than ER-positive/PR-positive tumors. The predictive value of PR has long been attributed to the dependence of PR expression on ER activity, with the absence of PR reflecting a nonfunctional ER and resistance to hormonal therapy. However, recent clinical and laboratory evidence suggests that ER-positive/PR-negative breast cancers may be specifically resistant to SERMs, whereas they may be less resistant to estrogen withdrawal therapy with aromatase inhibitors, which is a result inconsistent with the nonfunctional ER theory. Novel alternative molecular mechanisms potentially explaining SERM resistance in ER-positive/PR-negative tumors have been suggested by recent experimental indications that growth factors may downregulate PR levels. Thus, the absence of PR may not simply indicate a lack of ER activity, but rather may reflect hyperactive cross talk between ER and growth factor signaling pathways that downregulate PR even as they activate other ER functions. Therefore, ER-positive/PR-negative breast tumors might best be treated by completely blocking ER action via estrogen withdrawal with aromatase inhibitors, by targeted ER degradation, or by combined therapy targeting both ER and growth factor signaling pathways. In this review, we will discuss the biology and etiology of ER-positive/PR-negative breast cancer, highlighting recent data on molecular cross talk between ER and growth factor signaling pathways and demonstrating how PR might be a useful marker of these activities. Finally, we will consider the clinical implications of these observations.

scholarly journals Estrogen and Progesterone Receptor Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Guideline Update

2020 ◽  
Vol 144 (5) ◽  
pp. 545-563 ◽  
Author(s):  
Kimberly H. Allison ◽  
M. Elizabeth H. Hammond ◽  
Mitchell Dowsett ◽  
Shannon E. McKernin ◽  
Lisa A. Carey ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Progesterone Receptor ◽  
Endocrine Therapy ◽  
Clinical Oncology ◽  
Expert Panel ◽  
Ductal Carcinoma ◽  
Breast Cancers ◽  
Cell Nuclei ◽  
Er Positive ◽  
American Society

Purpose.— To update key recommendations of the American Society of Clinical Oncology/College of American Pathologists estrogen receptor (ER) and progesterone receptor (PgR) testing in breast cancer guideline. Methods.— A multidisciplinary international Expert Panel was convened to update the clinical practice guideline recommendations informed by a systematic review of the medical literature. Recommendations.— The Expert Panel continues to recommend ER testing of invasive breast cancers by validated immunohistochemistry as the standard for predicting which patients may benefit from endocrine therapy, and no other assays are recommended for this purpose. Breast cancer samples with 1% to 100% of tumor nuclei positive should be interpreted as ER positive. However, the Expert Panel acknowledges that there are limited data on endocrine therapy benefit for cancers with 1% to 10% of cells staining ER positive. Samples with these results should be reported using a new reporting category, ER Low Positive, with a recommended comment. A sample is considered ER negative if < 1% or 0% of tumor cell nuclei are immunoreactive. Additional strategies recommended to promote optimal performance, interpretation, and reporting of cases with an initial low to no ER staining result include establishing a laboratory-specific standard operating procedure describing additional steps used by the laboratory to confirm/adjudicate results. The status of controls should be reported for cases with 0% to 10% staining. Similar principles apply to PgR testing, which is used primarily for prognostic purposes in the setting of an ER-positive cancer. Testing of ductal carcinoma in situ (DCIS) for ER is recommended to determine potential benefit of endocrine therapies to reduce risk of future breast cancer, while testing DCIS for PgR is considered optional. Additional information can be found at www.asco.org/breast-cancer-guidelines.

scholarly journals Minireview: Nuclear Receptors and Breast Cancer

2008 ◽  
Vol 22 (10) ◽  
pp. 2215-2228 ◽  
Author(s):  
Suzanne D. Conzen
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Cell Growth ◽  
Epithelial Cell ◽  
Signaling Pathways ◽  
Cancer Biology ◽  
Progesterone Receptors ◽  
Growth Factor Signaling ◽  
Breast Cancers ◽  
Breast Cancer Patients

Abstract Until recently, the study of nuclear receptor (NR) function in breast cancer biology has been largely limited to estrogen and progesterone receptors. The development of reliable gene expression arrays, real-time quantitative RT-PCR, and immunohistochemical techniques for studying NR superfamily members in primary human breast cancers has now revealed the presence and potential importance of several additional NRs in the biology of breast cancer. These include receptors for steroid hormones (including androgens and corticosteroids), fat-soluble vitamins A and D, fatty acids, and xenobiotic lipids derived from diet. It is now clear that after NR activation, both genomic and nongenomic NR pathways can coordinately activate growth factor signaling pathways. Advances in our understanding of both NR functional networks and epithelial cell growth factor signaling pathways have revealed a frequent interplay between NR and epithelial cell growth factor family signaling that is clinically relevant to breast cancer. Understanding how growth factor receptors and their downstream kinases are activated by NRs (and vice-versa) is a central goal for maximizing treatment opportunities in breast cancer. In addition to the estrogen receptor, it is predicted that modulating the activity of other NRs will soon provide novel prevention and treatment approaches for breast cancer patients.

scholarly journals Estrogen and Progesterone Receptor Testing in Breast Cancer: ASCO/CAP Guideline Update

2020 ◽  
Vol 38 (12) ◽  
pp. 1346-1366 ◽  
Author(s):  
Kimberly H. Allison ◽  
M. Elizabeth H. Hammond ◽  
Mitchell Dowsett ◽  
Shannon E. McKernin ◽  
Lisa A. Carey ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Progesterone Receptor ◽  
Endocrine Therapy ◽  
Expert Panel ◽  
Ductal Carcinoma ◽  
Standard Operating Procedure ◽  
Breast Cancers ◽  
Cell Nuclei ◽  
Additional Information ◽  
Er Positive

PURPOSE To update key recommendations of the American Society of Clinical Oncology/College of American Pathologists estrogen (ER) and progesterone receptor (PgR) testing in breast cancer guideline. METHODS A multidisciplinary international Expert Panel was convened to update the clinical practice guideline recommendations informed by a systematic review of the medical literature. RECOMMENDATIONS The Expert Panel continues to recommend ER testing of invasive breast cancers by validated immunohistochemistry as the standard for predicting which patients may benefit from endocrine therapy, and no other assays are recommended for this purpose. Breast cancer samples with 1% to 100% of tumor nuclei positive should be interpreted as ER positive. However, the Expert Panel acknowledges that there are limited data on endocrine therapy benefit for cancers with 1% to 10% of cells staining ER positive. Samples with these results should be reported using a new reporting category, ER Low Positive, with a recommended comment. A sample is considered ER negative if < 1% or 0% of tumor cell nuclei are immunoreactive. Additional strategies recommended to promote optimal performance, interpretation, and reporting of cases with an initial low to no ER staining result include establishing a laboratory-specific standard operating procedure describing additional steps used by the laboratory to confirm/adjudicate results. The status of controls should be reported for cases with 0% to 10% staining. Similar principles apply to PgR testing, which is used primarily for prognostic purposes in the setting of an ER-positive cancer. Testing of ductal carcinoma in situ (DCIS) for ER is recommended to determine potential benefit of endocrine therapies to reduce risk of future breast cancer, while testing DCIS for PgR is considered optional. Additional information can be found at www.asco.org/breast-cancer-guidelines .

Clinical significance of extranuclear expression of hormone receptors in breast cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 644-644
Author(s):  
R. Kim ◽  
M. Kaneko ◽  
K. Arihiro ◽  
M. Emi ◽  
K. Tanabe ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Signaling Pathways ◽  
Clinical Significance ◽  
Cross Talk ◽  
Hormone Receptors ◽  
Growth Factor Signaling ◽  
Breast Cancers ◽  
Er Positive ◽  
Her 2 ◽  
Positive Breast Cancer

644 Background: Hormone receptor (HR)-positive breast cancer cells grow through estrogen receptor (ER)-signaling pathways that mediate both genomic and nongenomic actions, which cross-talk with growth factors associated with resistance to tamoxifen. The aim of this study is to explore the clinical significance of extranuclear expression of ER and PR in the cross-talk between HR and growth factor signaling pathways. Methods: We examined the extranuclear expression of ER and PR in 219 primary breast cancers by immunohistochemical staining. Specimens showing such expression were further examined for the expression of pAkt and aromatase. Due to heterogeneity, staining was scored on the basis of intensity and distribution in the tumors. Results: Extranuclear expression of ER or PR was observed in 21 cases (9.5%), which included 4 cases (19.0%) for ER and 20 cases (95.2%) for PR. Among these patients, HER-2, pAkt, and aromatase-positivity were observed in 14 cases (66.6%), 13 cases (61.9%), and 14 cases (66.6%), respectively. On the basis of nuclear HR expression, 11 of these cases were categorized as ER-positive/PR-negative, while 2 were ER-negative/PR-positive. Of those 13 cases, increased pAkt staining was found in 11 cases (84.6%). In particular, among the 11 ER-positive/PR-negative, elevated pAkt and aromatase were found in 10 (90.9%; p<0.01) and 9 cases (81.8%), respectively. Conclusion: PR is more frequently expressed extranuclearly than ER in primary breast cancer, and extranuclear HRs cross-talk with the Akt/HER-2-signaling pathway and activation of aromatase, providing an explanation for the observation that aromatase inhibitors are more beneficial than tamoxifen for ER-positive/PR-negative patients. No significant financial relationships to disclose.

Growth factor signalling and response to endocrine therapy: the Royal Marsden Experience

2005 ◽  
Vol 12 (Supplement_1) ◽  
pp. S113-S117 ◽  
Author(s):  
M Dowsett ◽  
S Johnston ◽  
L-A Martin ◽  
J Salter ◽  
M Hills ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endocrine Therapy ◽  
Aromatase Inhibitors ◽  
De Novo ◽  
Acquired Resistance ◽  
Poor Response ◽  
Biological Data ◽  
Breast Cancers ◽  
Er Positive ◽  
Almost All

De novo resistance to endocrine therapy is a near-universal feature of oestrogen receptor (ER)- negative breast cancer. Although many ER-positive breast cancers also show no response to tamoxifen or aromatase inhibitors on objective clinical grounds the large majority show reduced proliferation indicating that some oestrogen dependence is present in almost all ER-positive breast cancer. In neoadjuvant studies HER2 positivity is associated with poor response rates to tamoxifen but not aromatase inhibitors, consistent with preclinical models. Acquired resistance to tamoxifen is associated with decreases in ER positivity but most recurrent lesions remain ER-positive. A small proportion of these show increased HER2 expression and in these patients increased phospho-p38 may contribute to the tamoxifen-resistant phenotype. There is an unfortunate paucity of clinical and biological data on acquired resistance to aromatase inhibitors.

Resistance to endocrine therapy in breast cancer: exploiting estrogen receptor/growth factor signaling crosstalk

2006 ◽  
Vol 13 (Supplement_1) ◽  
pp. S15-S24 ◽  
Author(s):  
Suleiman Massarweh ◽  
Rachel Schiff
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Growth Factor ◽  
Endocrine Therapy ◽  
Acquired Resistance ◽  
Growth Factor Signaling ◽  
Breast Cancer Patients ◽  
Signaling Crosstalk ◽  
Receptor Modulator ◽  
Signal Transduction Inhibitors

Targeting the estrogen receptor (ER) is the oldest form of molecular targeted therapy, and the widespread use of the selective estrogen receptor modulator tamoxifen in breast cancer is responsible for major improvements in cure rates, quality of life, and disease prevention in the last 25 years. Newer forms of endocrine therapy now available for the management of endocrine responsive breast cancer include a new generation of aromatase inhibitors, which lower the estrogen ligand for ER, and pure ER antagonists which destroy the receptor. Despite these recent clinical advances, intrinsic and acquired resistance to these endocrine therapies is still a common feature that limits the success of this therapeutic strategy. Recent research into the molecular biology of ER signaling has revealed a remarkably complex interactive signaling with other growth factor signaling pathways in breast cancer cells, potentially explaining some of the reasons behind endocrine therapy action as well as resistance. This view of a more complex ER signaling system has uncovered new molecular targets which, if present in a cancer cell, might be additionally targeted using various signal transduction inhibitors to overcome or prevent resistance to endocrine therapy. In addition, the dynamic inverse relationship between the expression of ER and growth factor receptors brings more excitement to the potential of restoring ER expression in apparently ER-negative cells by inhibition of growth factor signaling. Ongoing clinical trials of endocrine therapy combined with growth factor pathway inhibitors or their downstream signaling elements promise to further improve the present care for breast cancer patients.

Detection of estrogen receptor in bone marrow from patients with metastatic breast cancer.

1987 ◽  
Vol 5 (11) ◽  
pp. 1779-1782 ◽  
Author(s):  
U Berger ◽  
J L Mansi ◽  
P Wilson ◽  
R C Coombes
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Endocrine Therapy ◽  
Tumor Cells ◽  
Epithelial Membrane Antigen ◽  
Metastatic Breast ◽  
Breast Cancers ◽  
Double Staining ◽  
Primary Tumors ◽  
Er Positive

We devised a method of detecting estrogen receptors (ER) in bone marrow metastases from patients with breast cancer. The method involves a sequential double-staining immunocytochemical technique, with a monoclonal antibody to ER and a polyclonal antibody recognizing epithelial membrane antigen to confirm the epithelial nature of suspected tumor cells. Twenty-seven patients were assessed: ten were found to have ER-positive tumor cells in the bone marrow; ten had ER-negative cells; and the remaining seven patients had no tumor cells in the bone marrow smears. Of the ten patients with ER-positive cells, eight (80%) either had a response to endocrine therapy, implying that they possess ER-positive breast cancers, or had ER-positive primary tumors as determined by the dextran-coated charcoal biochemical assay (DCC). Of the ten patients with ER-negative cells in the bone marrow, eight failed to respond to endocrine therapy. This technique therefore provides a means of predicting which patients will respond to endocrine therapy, and is particularly important in those patients whose ER status is unknown.

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