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.

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 Endocrine resistance in hormone-responsive breast cancer: mechanisms and therapeutic strategies

2016 ◽  
Vol 23 (8) ◽  
pp. R337-R352 ◽  
Author(s):  
Conleth G Murphy ◽  
Maura N Dickler
Keyword(s):  
Breast Cancer ◽  
Endocrine Therapy ◽  
Hormone Receptors ◽  
De Novo ◽  
Feedback Inhibition ◽  
Acquired Resistance ◽  
Endocrine Resistance ◽  
Breast Cancers ◽  
Potential Relief ◽  
Rational Therapy

The majority of breast cancers may be considered hormone responsive due to expression of hormone receptors (HR+). Although endocrine therapy is always considered for advanced HR+ breast cancer, the emergence of resistance is inevitable over time and is present from the start in a proportion of patients. In this review, we explore the mechanisms underlyingde novoand acquired resistance to endocrine therapy. We comprehensively review newly approved and emerging therapies that have been developed to counteract specific mechanisms of resistance. We discuss the challenges pertinent to this therapeutic arena including the potential relief of negative regulatory feedback inhibition with compensatory pathway activation and the evolution of molecular changes in HR+ breast cancers during treatment. We discuss strategies to address these challenges in order to develop rational therapy approaches for patients with advanced HR+ breast cancer.

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.

Controversies in Adjuvant Endocrine Therapy for Breast Cancer

2012 ◽  
pp. 20-26
Author(s):  
Stephen R. Johnston
Keyword(s):  
Breast Cancer ◽  
Endocrine Therapy ◽  
Aromatase Inhibitors ◽  
Early Stage ◽  
Premenopausal Women ◽  
Adjuvant Endocrine Therapy ◽  
Risk Of Recurrence ◽  
Er Positive ◽  
Added Benefit ◽  
Positive Breast Cancer

Overview: Adjuvant endocrine therapy for early-stage breast cancer has had the single biggest impact on improving survival from the disease—with tamoxifen alone contributing to saving many thousands of lives. In postmenopausal women, additional progress has been made by the incorporation of aromatase inhibitors into the treatment of early-stage, estrogen receptor (ER)–positive breast cancer, as several large well-conducted trials have established either “up-front” or “switch” strategies that are now widely used. To date, both have been shown to be beneficial when compared with tamoxifen alone, although controversy exists as to which approach is superior. Increasingly, extended adjuvant therapy is being considered, as “longer may be better” for some women who have an ongoing risk of recurrence beyond 5 years. However, controversy remains as to how long adjuvant endocrine therapy should be given for; in clinical practice, clinicians balance the level of risk for individual patients versus any ongoing toxicity concerns. For premenopausal women, with ER-positive breast cancer, tamoxifen remains the gold standard with uncertainty in the added overall benefit of ovarian suppression. Important clinical trials have recently been completed that may help answers this question, including whether complete estrogen deprivation using a luteinizing hormone releasing hormone (LHRH) agonist plus aromatase inhibitors (AIs) is of added benefit. In recent years, molecular profiling of ER-positive breast cancer has started to distinguish those women with a low risk of recurrence on endocrine therapy who may not need chemotherapy. Thus, with more therapy options and greater tumour stratification, modern, adjuvant endocrine therapy is becoming increasingly personalised to suit each individual patient's risk.

scholarly journals Preoperative endocrine therapy for breast cancer.

2000 ◽  
pp. 131-141 ◽  
Author(s):  
K L Cheung ◽  
A Howell ◽  
J F Robertson
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Endocrine Therapy ◽  
Locally Advanced ◽  
Breast Conservation ◽  
Perioperative Period ◽  
Current Data ◽  
Breast Cancers ◽  
Additional Advantage ◽  
Er Positive

The preoperative use of systemic therapy for primary breast cancer has the potential to downstage tumours. This would render suitable for breast conservation some tumours that were unsuitable at initial presentation, or would convert some inoperable locally advanced breast cancers into tumours that are operable. No survival benefit has been demonstrated for neoadjuvant chemotherapy compared with the same therapy given in an adjuvant setting. Preoperative endocrine therapy, in contrast to neoadjuvant chemotherapy, has fewer side effects and has the potential additional advantage that it can be continued throughout the perioperative period. Current data have shown that, in patients with an oestrogen receptor (ER)-positive tumour, a response approaching 70% could be reached in approximately 3 months using traditional endocrine manipulation such as tamoxifen. Randomised clinical trials are warranted to demonstrate the superiority of preoperative endocrine therapy over conventional adjuvant endocrine therapy, to define the optimum duration of therapy, and to identify the best endocrine agents. Both clinical and laboratory studies are also required to identify factors (in addition to ER) that would precisely predict the response and hence to select appropriate patients and to improve existing methods of monitoring response.

scholarly journals The effects of adjuvant endocrine therapy on bone health in women with breast cancer

2019 ◽  
Vol 241 (3) ◽  
pp. R111-R124 ◽  
Author(s):  
Sabashini K Ramchand ◽  
Yee-Ming Cheung ◽  
Belinda Yeo ◽  
Mathis Grossmann
Keyword(s):  
Breast Cancer ◽  
Fracture Risk ◽  
Postmenopausal Women ◽  
Endocrine Therapy ◽  
Aromatase Inhibitors ◽  
Bone Health ◽  
Oestrogen Receptor ◽  
Breast Tissue ◽  
Premenopausal Women ◽  
Er Positive

In women with oestrogen receptor (ER)-positive early breast cancer, oestradiol is important for breast cancer development and progression. Endocrine therapy prevents the deleterious effects of oestradiol in breast tissue by systemically depleting oestradiol concentration (aromatase inhibitors) or preventing its local action in breast tissue (selective oestrogen receptor modulators i.e. tamoxifen), thereby improving oncological outcomes. Use of aromatase inhibitors in postmenopausal women and ovarian function suppression with either tamoxifen or aromatase inhibition in premenopausal women, consequent to systemic oestradiol depletion, exerts detrimental effects on skeletal health. The oestradiol-deficient state causes increased bone remodelling and a negative bone balance. This results in bone loss, microstructural deterioration and bone fragility predisposing to fractures. Similar effects are also seen with tamoxifen in premenopausal women. In contrast, use of tamoxifen in postmenopausal women appears to exert protective effects on bone but studies on fracture risk are inconclusive. The longevity of women with ER-positive breast cancer treated with adjuvant endocrine therapy emphasises the need to mitigate the adverse skeletal effects of these therapies in order to maximise benefit. In general, fractures are associated with increased morbidity, mortality and are a high socioeconomic burden. Whilst the efficacy of antiresorptive therapy in preventing bone mineral density loss in postmenopausal women has been established, further clinical trial evidence is required to provide guidance regarding fracture risk reduction, when to initiate and stop treatment, choice of agent and optimal management of bone health in premenopausal women receiving endocrine therapy. In addition, potential oncological benefits of antiresorptive therapies will also need to be considered.

scholarly journals Neuroglobin: A New Possible Marker of Estrogen-Responsive Breast Cancer

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1986
Author(s):  
Virginia Solar Fernandez ◽  
Marco Fiocchetti ◽  
Manuela Cipolletti ◽  
Marco Segatto ◽  
Paolo Cercola ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endocrine Therapy ◽  
De Novo ◽  
Ductal Carcinoma ◽  
Strong Association ◽  
Therapeutic Interventions ◽  
Breast Cancer Cell Lines ◽  
Breast Cancers ◽  
Data Set

The expression of the α-subtype of Estrogen Receptor (ERα) characterizes most breast cancers (more than 75%), for which endocrine therapy is the mainstay for their treatment. However, a high percentage of ERα+ breast cancers are de novo or acquired resistance to endocrine therapy, and the definition of new targets for improving therapeutic interventions and the prediction of treatment response is demanding. Our previous data identified the ERα/AKT/neuroglobin (NGB) pathway as a common pro-survival process activated in different ERα breast cancer cell lines. However, no in vivo association between the globin and the malignity of breast cancer has yet been done. Here, we evaluated the levels and localization of NGB in ERα+ breast ductal carcinoma tissue of different grades derived from pre-and post-menopausal patients. The results indicate a strong association between NGB accumulation, ERα, AKT activation, and the G3 grade, while no association with the menopausal state has been evidenced. Analyses of the data set (e.g., GOBO) strengthen the idea that NGB accumulation could be linked to tumor cell aggressiveness (high grade) and resistance to treatment. These data support the view that NGB accumulation, mainly related to ER expression and tumor grade, represents a compensatory process, which allows cancer cells to survive in an unfavorable environment.

scholarly journals Tamoxifen resistance alters sensitivity to 5-fluorouracil in a subset of estrogen receptor-positive breast cancer

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0252822
Author(s):  
Takayuki Watanabe ◽  
Takaaki Oba ◽  
Keiji Tanimoto ◽  
Tomohiro Shibata ◽  
Shinobu Kamijo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Estrogen Receptor ◽  
Endocrine Therapy ◽  
Chemotherapeutic Agents ◽  
Breast Cancers ◽  
Mcf7 Cells ◽  
Er Positive ◽  
Tamoxifen Resistant ◽  
Positive Breast Cancer

Sequential treatment with endocrine or chemotherapy is generally used in the treatment of estrogen receptor (ER)-positive recurrent breast cancer. To date, few studies have investigated the effect of long-term endocrine therapy on the response to subsequent chemotherapy in ER-positive breast cancer. We examined whether a preceding endocrine therapy affects the sensitivity to subsequent chemotherapy in ER-positive breast cancer cells. Three ER-positive breast cancer cell lines (T47D, MCF7, BT474) and tamoxifen-resistant sublines (T47D/T, MCF7/T, BT474/T) were analyzed for sensitivity to 5-fluorouracil, paclitaxel, and doxorubicin. The mRNA levels of factors related to drug sensitivity were analyzed by RT-PCR. MCF7/T cells became more sensitive to 5-fluorouracil than wild-type (wt)-MCF7 cells. In addition, the apoptosis induced by 5-fluorouracil was significantly increased in MCF7/T cells. However, no difference in sensitivity to chemotherapeutic agents was observed in T47D/T and BT474/T cells compared with their wt cells. Dihydropyrimidine dehydrogenase (DPYD) mRNA expression was significantly decreased in MCF7/T cells compared with wt-MCF7 cells. The expression of DPYD mRNA was restored with 5-azacytidine treatment in MCF7/T cells. In addition, DPYD 3′-UTR luciferase activity was significantly reduced in MCF7/T cells. These data indicated that the expression of DPYD mRNA was repressed by methylation of the DPYD promoter region and post-transcriptional regulation by miRNA in MCF7/T cells. In the mouse xenograft model, capecitabine significantly reduced the tumor volume in MCF7/T compared with MCF7. The results of this study indicate that endocrine therapy could alter the sensitivity to chemotherapeutic agents in a subset of breast cancers, and 5-fluorouracil may be effective in tamoxifen-resistant breast cancers.

Sign in / Sign up

Export Citation Format

Share Document