Impact of estrogen receptor (ER) and human epidermal growth factor receptor-2 (HER2) co-expression on breast cancer disease characteristics: implications for tumor biology and research.

ER and HER2 are critical drivers of breast cancer biology and can interact when co-expressed, but less data describe the impact of ER/HER2 co-expression on clinical disease characteristics. We studied the impact of ER and HER2 (co)-expression in a cohort of 1,187 patients with invasive breast cancer and compared disease characteristics among different groups according to ER and HER2 status. Age, tumor size, grade, nodal status, TNM stage, and metastatic sites were compared and significance determined using the appropriate t tests. All p values were two-tailed. Compared to ER-negative/HER2-negative disease as the control group, ER expression was associated with older age, smaller tumors, lower grade, earlier TNM stage, and increased bone involvement in de novo metastasis, while HER2 had no significant impact on these characteristics. ER and HER2 co-expression was associated with lower grade and higher bone involvement in de novo metastasis, reflecting a retained impact for ER. HER2 impact on ER-positive disease was reflected by younger age, higher grade and TNM stage, and increased frequency of visceral involvement in de novo metastasis. Within the ER-positive/HER2-positive group, triple positive breast cancer (ER+/PgR+/HER2+) was associated with younger age compared to ER+/PgR-/HER2+ disease (mean age of 50.8 vs. 56 years, p = 0.0226). PgR was also associated with younger age in ER+/HER2- disease with a mean age of 57.6 years in ER+/PgR+/HER2- disease vs. 63.4 years in ER+/PgR-/HER2- disease (p < 0.0001). In conclusion, ER has a profound impact on breast cancer characteristics, including a retained impact when co-expressed with HER2. Similarly, HER2 dramatically modulates ER-positive breast cancer making it more aggressive. PgR association with young age may be related to hormonal levels of the premenopausal state, with HER2 providing an earlier growth advantage in triple positive disease, suggesting a specific dependence for this subset on high estrogen levels.

A phase II study of combined fulvestrant and everolimus in patients with metastatic estrogen receptor (ER)-positive breast cancer after aromatase inhibitor (AI) failure.

Fulvestrant, which degrades ER, is used after AI failure in metastatic breast cancer but resistance develops quickly. We hypothesized that using everolimus to inhibit mTOR, a key signaling pathway in endocrine resistance, may delay fulvestrant resistance in patients and thus improve its efficacy. We conducted a phase II trial of combined fulvestrant and everolimus in postmenopausal women with disease progression or relapse after an AI. Primary endpoint was time to progression (TTP) and secondary endpoints included objective response rate, clinical benefit rate (CBR), safety, and biomarker correlates. Tumor blocks were collected and biopsy of accessible tumor was done for future biomarker analysis. Of 33 patients enrolled two were ruled ineligible after enrollment and were excluded from study analysis, for a total of 31 evaluable patients. Median age was 54 years (range 45-85). Prior therapy included tamoxifen (81 %), chemotherapy (71 %), with 26 % of patients having received 3 or more endocrine agents. Median TTP was 7.4 months (95 % CI 1.9-12.1) with an objective response rate of 13 % and CBR of 49 %. Of particular note, 32 % of patients exhibited de novo resistance to study treatment with disease progression as their best response. Most common adverse events (AEs) were elevated AST (87 %) and ALT (77 %), anemia (74 %), hyperglycemia (71 %), and hypercholesterolemia (68 %). Prominent clinical toxicities were mucositis (58 %), weight loss (48 %), and rash (42 %). Most AEs were grade 1 or 2 and largely reversible with infrequent need for everolimus dose reduction. To conclude, everolimus plus fulvestrant is effective after AI failure in heavily pretreated metastatic ER-positive breast cancer and has manageable toxicity. Further study of this combination is warranted in randomized studies. Since not all patients experience benefit, and in view of potential toxicities, biomarker examination is critical to help select patients most likely to benefit from this strategy in future studies.

Impact of adding the multikinase inhibitor sorafenib to endocrine therapy in metastatic estrogen receptor-positive breast cancer.

BACKGROUND: Targeting growth factor and survival pathways may delay endocrine-resistance in estrogen receptor-positive breast cancer. MATERIALS & METHODS: A pilot Phase II study adding sorafenib to endocrine therapy in 11 patients with metastatic estrogen receptor-positive breast cancer was conducted. Primary end point was response by RECIST after 3 months of sorafenib. Secondary end points included safety, time to progression and biomarker modulation. The study closed early owing to slow accrual. RESULTS: Eight out of 11 patients had progressive disease on study entry and three had stable disease. Of the ten evaluable patients, seven experienced stable disease (70%) and three experienced progressive diseas (30%), with a median time to progression of 6.1 months (8.4 months in the seven patients on tamoxifen). The serum samples demonstrated a significant reduction in VEGF receptor 2 and PDGF receptor-α. Microarray analysis identified 32 suppressed genes, no induced genes and 29 enriched Kyoto Encyclopedia of Genes and Genomes pathways. CONCLUSION: The strategy of adding a targeted agent to endocrine therapy upon resistance may be worthwhile testing in larger studies.

Resolution of extensive leptomeningeal metastasis and clinical spinal cord compression from breast cancer using weekly docetaxel chemotherapy.

Metastatic breast cancer to the leptomeninges is a late event in the disease course and is associated with significant morbidity and a grave prognosis. Treatment typically involves direct intrathecal injection of chemotherapy into the cerebrospinal fluid compartment since systemic chemotherapy penetrates poorly to the central nervous system. Here we report an interesting clinical observation involving a patient presenting with leptomeningeal spread of breast cancer causing extensive spinal cord compression with obliteration of the subarachnoid space, thus precluding the use of direct intrathecal chemotherapy. We administered systemic chemotherapy using weekly docetaxel with complete radiographic resolution of her disease and recovery from clinical spinal cord compression. While this is a single clinical observation, weekly administration of docetaxel in this circumstance may have been associated with improved drug "escape" into the central nervous system and better antitumor effect. Because leptomeningeal disease is typically a late event in metastatic breast cancer, resistance to therapeutic intervention may reflect intrinsically resistant disease in the setting of extensive prior therapy rather than a routine problem with systemic drug delivery to the CNS. Studying patterns of disease relapse in patients who had received adjuvant weekly taxanes may provide insights into this hypothesis.

A prognostic model of early breast cancer relapse after standard adjuvant therapy and comparison with metastatic disease on initial presentation.

Breast cancer can metastasize at any time during its course, but timing of systemic relapse cannot be predicted by traditional TNM staging. Characteristics of distant recurrence within the first 3 years of diagnosis may identify a group of patients who could benefit from novel strategies to prevent systemic relapse. Of 1,089 patients with breast cancer treated at our institution between January 2007 and May 2011, we identified 76 with de novo metastases (on presentation) and 40 with systemic relapse after a median follow up of 2.2 years. Compared to relapse, de novo metastatic disease was more likely to be grade 1 or 2 (43.1 vs. 18.4 %, p = 0.032), estrogen receptor (ER) positive (69.7 vs. 47.5 %, p = 0.019), progesterone receptor (PgR) positive (56.6 vs. 32.5 %, p = 0.014), and HER2-positive (27.5 vs. 10.3 %, p = 0.035). In the 815 patients with stage I-III disease who were at risk of systemic relapse, univariate analyses were performed for age, tumor size, grade, ER, PgR, HER2, lymph nodes, and TNM stage. A multivariate Cox regression model was built using step-wise model selection and identified 4 covariates that were significantly associated with risk of early relapse: stage-III (p < 0.001), grade-III (p = 0.002), PgR-negative status (p = 0.014), and HER2-negative status (p = 0.033). A risk-score was developed based on the linear combination of these covariates and time-dependent predictive curves were used to evaluate the predictive accuracy of the proposed risk-score. The highest risk-score group had a 1, 2, and 3-year relapse probabilities of 11.5, 41.2, and 52.5 %, respectively. The corresponding 1, 2, and 3-year relapse probabilities for the overall population were 1.2, 4.4, and 6.3 %, respectively. Our proposed model can be used to select patients at high-risk of early relapse who could benefit from enrollment on clinical trials with novel therapies designed for this group.

Upregulation of mucin4 in ER-positive/HER2-overexpressing breast cancer xenografts with acquired resistance to endocrine and HER2-targeted therapies.

We studied resistance to endocrine and HER2-targeted therapies using a xenograft model of estrogen receptor positive (ER)/HER2-overexpressing breast cancer. Here, we report a novel phenotype of drug resistance in this model. MCF7/HER2-18 xenografts were treated with endocrine therapy alone or in combination with lapatinib and trastuzumab (LT) to inhibit HER2. Archival tumor tissues were stained with hematoxylin and eosin and with mucicarmine. RNA extracted from tumors at early time points and late after acquired resistance were analyzed for mucin4 (MUC4) expression by microarray and quantitative reverse transcriptase-PCR. Protein expression of the MUC4, ER, and HER2 signaling pathways was measured by immunohistochemistry and western blotting. The combination of the potent anti-HER2 regimen LT with either tamoxifen (Tam + LT) or estrogen deprivation (ED + LT) can cause complete eradication of ER-positive/HER2-overexpressing tumors in mice. Tumors developing resistance to this combination, as well as those acquiring resistance to endocrine therapy alone, exhibited a distinct histological and molecular phenotype-a striking increase in mucin-filled vacuoles and upregulation of several mucins including MUC4. At the onset of resistance, MUC4 mRNA and protein were increased. These tumors also showed upregulation and reactivation of HER2 signaling, while losing ER protein and the estrogen-regulated gene progesterone receptor. Mucins are upregulated in a preclinical model of ER-positive/HER2-overexpressing breast cancer as resistance develops to the combination of endocrine and anti-HER2 therapy. These mucin-rich tumors reactivate the HER2 pathway and shift their molecular phenotype to become more ER-negative/HER2-positive.

Pathologic changes in breast cancer after anti-estrogen therapy.

Breast cancer patients do not commonly receive anti-estrogens prior to surgical excision. We reviewed a cohort of patients who received preoperative anti-estrogen therapy after baseline biopsy and then had a repeat biopsy after several weeks on treatment. Patients with estrogen receptor positive tumors received anastrozole and fulvestrant in combination with gefitinib. Core needle biopsies were performed at day 1 and 21, and tumors were completely excised if operable at day 112. All patients were postmenopausal. Following treatment, tumors had degenerative changes including smudged nuclei, decreased nuclear size, intranuclear vacuoles, vacuolated cytoplasm, and increased cellular discohesion. In addition, increased tubule formation and intracytoplasmic lumina were seen in 6/9 cases (66.7%) and decreased mitotic rate was demonstrated in 7/9 cases (77.8%). These findings indicate increased differentiation of the tumor cells in response to anti-estrogen therapy and that may correlate with clinical response.

A phase II neoadjuvant trial of anastrozole, fulvestrant, and gefitinib in patients with newly diagnosed estrogen receptor positive breast cancer.

Endocrine therapy in patients with breast cancer can be limited by the problem of resistance. Preclinical studies suggest that complete blockade of the estrogen receptor (ER) combined with inhibition of the epidermal growth factor receptor can overcome endocrine resistance. We tested this hypothesis in a phase II neoadjuvant trial of anastrozole and fulvestrant combined with gefitinib in postmenopausal women with newly diagnosed ER-positive breast cancer. After a baseline tumor core biopsy, patients were randomized to receive anastrozole and fulvestrant or anastrozole, fulvestrant, and gefitinib (AFG) for 3 weeks. After a second biopsy at 3 weeks, all patients received AFG for 4 months and surgery was done if the tumor was operable. The primary endpoint was best clinical response by RECIST criteria and secondary endpoints were toxicity and change in biomarkers. The study closed after 15 patients were enrolled because of slow accrual. Median patient age was 67 years and median clinical tumor size was 7 cm. Four patients had metastatic disease present. Three patients withdrew before response was assessed. In the remaining 12 patients, there were two complete clinical responses (17%), three partial responses (25%), five had stable disease (41%), and two (17%) had progressive disease. Most common adverse events were rash in four patients, diarrhea in four, joint symptoms in three, and abnormal liver function tests in three. There were no grade 4 toxicities and all toxicities were reversible. At 3 weeks, cell proliferation as measured by Ki-67 was significantly reduced in the AFG group (P value = 0.01), with a parallel reduction in the expression of the Cyclin D1 (P value = 0.02). RNA microarray data showed a corresponding decrease in the expression of cell cycle genes. These results suggest that AFG was an effective neoadjuvant therapy and consistently reduced proliferation in ER-positive tumors.

Unraveling the mechanisms of endocrine resistance in breast cancer: new therapeutic opportunities.

Two thirds of breast cancers express the estrogen receptor (ER), which contributes to tumor development and progression. ER-targeted therapy is therefore widely used in breast cancer to inhibit signaling through ER and disrupt breast cancer growth. This therapeutic strategy, particularly using the antiestrogen tamoxifen, is proven to increase the cure rates in early breast cancer, improve patient outcomes in advanced disease, and reduce breast cancer incidence in the prevention setting. Despite the recent integration of more powerful endocrine agents into breast cancer care, resistance to all forms of endocrine therapy remains a major problem. New insight into ER biology and progress in understanding resistance mechanisms, mediated by molecular crosstalk between ER and various growth factor signaling pathways, are generating tremendous promise for new therapeutic opportunities to target resistance and improve breast cancer disease outcomes.

Molecular Characterization and Mortality From Breast Cancer in Men.

Purpose Limited data exist on the molecular biology, treatment, and outcomes of breast cancer in men, and much of our understanding in this area remains largely an extrapolation from data in women with breast cancer. Materials and Methods We studied men and women with hormone receptor-positive breast cancer and the 21-gene Breast Recurrence Score (RS) results. Differences in clinical characteristics and gene expression were determined, and distribution of RS results was correlated with 5-year breast cancer-specific survival (BCSS) and overall survival. Results There were 3,806 men and 571,115 women. Men were older than women (mean age, 64.2 v 59.1 years; P < .001). RS < 18 predominated in both genders, but RS ≥ 31 was more frequent in men (12.4% v 7.4%; P < .001), as were very low scores (RS < 11; 33.8% v 22.1%; P < .001). Mean gene expression was higher in men for the estrogen receptor (ER), proliferation, and invasion groups. ER was lowest and progesterone receptor was highest in women younger than 50 years of age, with a progressive increase in ER with age. Men younger than 50 years of age had slightly lower ER and progesterone receptor compared with older men. Survival data were available from SEER for 322 men and 55,842 women. Five-year BCSS was 99.0% (95% CI, 99.3% to 99.9%) and 95.9% (95% CI, 87.6% to 98.7%) for men with RS < 18 and RS 18-30, respectively, and for women, it was 99.5% (95% CI, 99.4% to 99.6%) and 98.6% (95% CI, 98.4% to 98.8%), respectively. RS ≥ 31 was associated with an 81.0% 5-year BCSS in men (95% CI, 53.3% to 93.2%) and 94.9% 5-year BCSS (95% CI, 93.9% to 95.7%) in women. Five-year BCSS and overall survival were lower in men than in women. Conclusion This study reveals some distinctive biologic features of breast cancer in men and an important prognostic role for RS testing in both men and women.

Intrinsic apoptotic pathway activation increases response to anti-estrogens in luminal breast cancers.

Estrogen receptor-α positive (ERα+) breast cancer accounts for approximately 70-80% of the nearly 25,0000 new cases of breast cancer diagnosed in the US each year. Endocrine-targeted therapies (those that block ERα activity) serve as the first line of treatment in most cases. Despite the proven benefit of endocrine therapies, however, ERα+ breast tumors can develop resistance to endocrine therapy, causing disease progression or relapse, particularly in the metastatic setting. Anti-apoptotic Bcl-2 family proteins enhance breast tumor cell survival, often promoting resistance to targeted therapies, including endocrine therapies. Herein, we investigated whether blockade of anti-apoptotic Bcl-2 family proteins could sensitize luminal breast cancers to anti-estrogen treatment. We used long-term estrogen deprivation (LTED) of human ERα+ breast cancer cell lines, an established model of sustained treatment with and acquired resistance to aromatase inhibitors (AIs), in combination with Bcl-2/Bcl-xL inhibition (ABT-263), finding that ABT-263 induced only limited tumor cell killing in LTED-selected cells in culture and in vivo. Interestingly, expression and activity of the Bcl-2-related factor Mcl-1 was increased in LTED cells. Genetic Mcl-1 ablation induced apoptosis in LTED-selected cells, and potently increased their sensitivity to ABT-263. Increased expression and activity of Mcl-1 was similarly seen in clinical breast tumor specimens treated with AI + the selective estrogen receptor downregulator fulvestrant. Delivery of Mcl-1 siRNA loaded into polymeric nanoparticles (MCL1 si-NPs) decreased Mcl-1 expression in LTED-selected and fulvestrant-treated cells, increasing tumor cell death and blocking tumor cell growth. These findings suggest that Mcl-1 upregulation in response to anti-estrogen treatment enhances tumor cell survival, decreasing response to therapeutic treatments. Therefore, strategies blocking Mcl-1 expression or activity used in combination with endocrine therapies would enhance tumor cell death.

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

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.

Crosstalk between estrogen receptor and growth factor receptor pathways as a cause for endocrine therapy resistance in breast cancer.

Data suggest that breast cancer growth is regulated by coordinated actions of the estrogen receptor (ER) and various growth factor receptor signaling pathways. In tumors with active growth factor receptor signaling (e.g., HER2 amplification), tamoxifen may lose its estrogen antagonist activity and may acquire more agonist-like activity, resulting in tumor growth stimulation. Because treatments designed to deprive the ER of its ligand estrogen will reduce signaling from both nuclear and membrane ER, aromatase inhibitors might be expected to be superior to tamoxifen in tumors with high growth factor receptor content, such as those overexpressing HER2. Recent clinical studies suggest that this is the case in humans, as trials of aromatase inhibitors show superior results compared with tamoxifen, especially in tumors overexpressing HER2. Although estrogen deprivation therapy is often effective in ER-positive breast cancer, de novo and acquired resistance are still problematic. Experimental models suggest that in one form of resistance to estrogen deprivation therapy, the tumor becomes supersensitive to low residual estrogen concentrations perhaps because of activation of mitogen-activated protein kinase. Such tumors respond to additional treatment with fulvestrant or even tamoxifen. On the other hand, in tumors overexpressing HER2, acquired resistance to estrogen deprivation therapy involves the loss of ER and ER-regulated genes and further up-regulation of growth factor signaling rendering the tumor hormonal therapy resistant. This process can be delayed or reversed by simultaneous treatment with growth factor pathway inhibitors. This strategy is now being tested in clinical trials.

Prevalence of hormone receptors and HER2/neu in breast cancer cases in Jordan.

The management and prognosis of breast cancer nowadays require the evaluation of Estrogen (ER), Progesterone Receptors (PR) and HER2/neu. Ethnic variation in the expression of these receptors is well documented. The aim of this study is to determine the prevalence of ER, PR and HER2/neu among Jordanian women with breast cancer of ductal and lobular types. A retrospective analysis was performed on 267 cases of breast cancer referred for treatment at King Hussein Cancer Center, Jordan between the period of June 2003 and June 2004. Standard immune stains were used for evaluation of hormone receptors and HER2/neu. In addition, evaluation of HER2/neu was done by FISH in selected cases. Of these 267 cases, 240 (89.9%) were ductal carcinomas of various histological grades, 122 (50.8%) of which were ER-positive, 138 (57.5%) PRpositive and 42 (17.5%) HER2/neu-positive. Twentytwo (8.2%) of all cases were lobular carcinomas, 15 (68%) of which were ER-positive, 20 (90.9%) PRpositive and 3 (13.6%) HER2/neu-positive. Five (1.9%) of the total cases were of mixed lobular and ductal types, 4 (80%) of which were ER-positive, 3 (60%) PR-positive and none were positive for HER2/neu. The prevalence of hormone receptor positivity in breast cancer of Jordanian women is lower than that of the western populations and close to other populations such as the Chinese and the minor ethnic groups of Northern America (African Americans).

Endocrine therapy and strategies to overcome therapeutic resistance in breast cancer.

Despite the remarkable success of endocrine therapy in the treatment of patients with estrogen receptor (ER)- positive breast cancer, not all patients derive benefit from such therapy, or may benefit only temporarily before disease progression or relapse occurs. The value of endocrine therapy, which blocks ER signaling by a variety of strategies, lies in its simplicity, lower toxicity, and better alignment with preserved quality of life, particularly when compared to chemotherapy, which is more toxic and has only modest benefits for many patients with ER-positive breast cancer. It is therefore critical that we discover ways to extend endocrine therapy benefit in patients and prevent therapeutic resistance whenever possible. The tremendous evolution in our understanding of endocrine resistance mechanisms, coupled with the increasing availability of novel agents that target resistance pathways, has led to enhanced treatment approaches for patients with ER-positive breast cancer, primarily through combinations of endocrine agents with a variety of pathway inhibitors. Despite these treatment advances and our changing view of ER-positive breast cancer, there is much work that needs to be done. It remains a problem that we cannot reliably predict which subsets of patients will experience disease relapse or progression on endocrine therapy, and as such, combination strategies with targeted agents have largely been used in unselected patients with ER-positive breast cancer, including those who continue to have endocrine-sensitive disease. Patient selection is a significant issue since most of the targeted therapeutics that we use with endocrine therapy are expensive and can be toxic, and we may be inadvertently overtreating patients whose disease can still be controlled with endocrine therapy alone. In this article, we will review current and future strategies in the treatment of ER-positive breast cancer, as well as the evolving role of targeted therapy in the management of endocrine-resistance.

Special considerations in the evaluation and management of breast cancer in men.

Breast cancer in men is relatively uncommon but its incidence has been rising. Traditionally, the management of breast cancer in men is based on extrapolation from clinical trials of breast cancer in women, due to the much more extensive data available in women with this disease. There are, however, unique characteristics that distinguish breast cancer in men and these should be taken into consideration when managing this patient population. Breast cancer in men is more frequently estrogen receptor (ER) and progesterone receptor (PgR) positive, and less frequently HER2 amplified. Lobular carcinoma, which accounts for 10-15% of breast cancers in women, is exceptionally rare in men. Genetic risk factors, particularly BRCA2 mutations, are increasingly recognized as a key risk factor for breast cancer in men and genetic testing is now routinely recommended for all men diagnosed with breast cancer. Tamoxifen remains the gold standard endocrine therapy for breast cancer in men, but other endocrine agents such as the aromatase inhibitors (AI) and fulvestrant are increasingly being used. While superior to tamoxifen in postmenopausal women, the use of AIs for adjuvant therapy in men with breast cancer may not be optimal since the physiology of hormonal regulation in men resembles that of premenopausal rather than postmenopausal women. Emerging areas of investigation include the role of genomic risk stratification to gain further insight into the biology of breast cancer in men, the study of the androgen receptor (AR) as a therapeutic target, and the role of gonadal suppression in the management of the disease. There is clearly a more consorted effort to study breast cancer in men as a unique disease in order to have a better understanding of its biology and we are likely to witness further advances that will help us better manage this unique disease situation.

Blockade of AP-1 Potentiates Endocrine Therapy and Overcomes Resistance.

UNLABELLED: The transcription factor AP-1 is downstream of growth factor (GF) receptors (GFRs) and stress-related kinases, both of which are implicated in breast cancer endocrine resistance. Previously, we have suggested that acquired endocrine resistance is associated with increased activity of AP-1 in an in vivo model. In this report, we provide direct evidence for the role of AP-1 in endocrine resistance. First, significant overlap was found between genes modulated in tamoxifen resistance and a gene signature associated with GF-induced estrogen receptor (ER) cistrome. Interestingly, these overlapping genes were enriched for key signaling components of GFRs and stress-related kinases and had AP-1 motifs in their promoters/enhancers. Second, to determine a more definitive role of AP-1 in endocrine resistance, AP-1 was inhibited using an inducible dominant-negative (DN) cJun expressed in MCF7 breast cancer cells in vitro and in vivo AP-1 blockade enhanced the antiproliferative effect of endocrine treatments in vitro, accelerated xenograft tumor response to tamoxifen and estrogen deprivation in vivo, promoted complete regression of tumors, and delayed the onset of tamoxifen resistance. Induction of DN-cJun after the development of tamoxifen resistance resulted in dramatic tumor shrinkage, accompanied by reduced proliferation and increased apoptosis. These data suggest that AP-1 is a key determinant of endocrine resistance by mediating a global shift in the ER transcriptional program. IMPLICATIONS: AP-1 represents a viable therapeutic target to overcome endocrine resistance. Mol Cancer Res; 14(5); 470-81. ©2016 AACR.