ABSTRACT
Breast cancers that are positive for hormone receptor but negative for human epidermal growth factor receptor 2 (abbreviated as HR+/HER2-) account for approximately 60% of total cases. Targeting estrogen signaling is one of the most important therapeutic strategies for HR+/HER2- breast cancer. However, the management of endocrine-resistant HR+/HER2- breast cancer remains a difficult issue in clinical practice. Previous multi-omic analysis and translational research have identified the mechanisms underlying endocrine-resistance including genomic alteration and abnormal epigenetic modification. To overcome endocrine-resistance, we have established a comprehensive and coherent therapeutic strategy. In addition, several novel therapies have shown promising efficacy in previous clinical trials and will emerge as alternative options for targeting endocrine-resistant HR+/HER2- breast cancer. In this review, we will introduce the mechanisms of endocrine-resistance, explain the current therapeutic strategy for endocrine-resistant HR +/HER2 - breast cancer and discuss the possible targeted therapies in the future.
ABSTRACT
Breast cancer, one of the most frequent cancer types, is a leading cause of death in women worldwide. Estrogen receptor (ER) α is a nuclear hormone receptor that plays key roles in mammary gland development and breast cancer. About 75% of breast cancer cases are diagnosed as ER-positive; however, nearly half of these cancers are either intrinsically or inherently resistant to the current anti-estrogen therapies. Recent studies have identified an ER coactivator, Mediator Subunit 1 (MED1), as a unique, tissue-specific cofactor that mediates breast cancer metastasis and treatment resistance. MED1 is overexpressed in over 50% of human breast cancer cases and co-amplifies with another important breast cancer gene, receptor tyrosine kinase HER2. Clinically, MED1 expression highly correlates with poor disease-free survival of breast cancer patients, and recent studies have reported an increased frequency of MED1 mutations in the circulating tumor cells of patients after treatment. In this review, we discuss the biochemical characterization of MED1 and its associated MED1/Mediator complex, its crosstalk with HER2 in anti-estrogen resistance, breast cancer stem cell formation, and metastasis both in vitro and in vivo. Furthermore, we elaborate on the current advancements in targeting MED1 using state-of-the-art RNA nanotechnology and discuss the future perspectives as well.
ABSTRACT
Breast cancer, one of the most frequent cancer types, is a leading cause of death in women worldwide. Estrogen receptor (ER) a is a nuclear hormone receptor that plays key roles in mammary gland development and breast cancer. About 75% of breast cancer cases are diagnosed as ER-positive; however, nearly half of these cancers are either intrinsically or inherently resistant to the current anti-estrogen therapies. Recent studies have identified an ER coactivator, Mediator Subunit 1 (MED1), as a unique, tissue-specific cofactor that mediates breast cancer metastasis and treatment resistance. MED1 is overexpressed in over 50% of human breast cancer cases and co-amplifies with another important breast cancer gene, receptor tyrosine kinase HER2. Clinically, MED1 expression highly correlates with poor disease-free survival of breast cancer patients, and recent studies have reported an increased frequency of MED1 mutations in the circulating tumor cells of patients after treatment. In this review, we discuss the biochemical characterization of MED1 and its associated MED1/Mediator complex, its crosstalk with HER2 in anti-estrogen resistance, breast cancer stem cell formation, and metastasis both in vitro and in vivo. Furthermore, we elaborate on the current advancements in targeting MED1 using state-of-the-art RNA nanotechnology and discuss the future perspectives as well.
ABSTRACT
Objective To compare the efficacy and safety of everolimus combined with endocrine therapy and fulvestrant in patients with estrogen receptor-positive advanced breast cancer progressed after endocrine thera-py. Methods Ninety-three breast cancer patients were selected from January 2014 to February 2017. The primary end points were progression-free survival and clinical benefit rate and the secondary end points was tolerability. Re-sults The progression-free survival in fulvestrant group was slightly higher than that in the everolimus group(13.4 months vs 12.2 months,P = 0.297). The clinical benefit rates were 46.15% and 31.71% in fulvestrant group and everolimus group,respectively. Patients treated with fewer than 2 lines and endocrine resistant patients benefited more from fulvestrant but without statistical difference. The main adverse events related to everolimus were stomati-tis,with a prevalence rate of about 26% and a localized pneumonia with a prevalence rate of about 10%. The main adverse reaction of fulvestrant was the injection site reaction. Conclusions The efficacy of everolimus in combina-tion with endocrine therapy is not superior to that of fulvestrant for the treatment of advanced breast cancer pro-gressed after endocrine therapy. After weighing the clinical benefits and quality of life,fulvestrant may be better for patients treated with fewer than 2 lines and endocrine resistance.
ABSTRACT
Objective To evaluate the efficacy and security of metformin in the treatment of endocrine resistance and postmenopausal hormone receptor positive advanced breast cancer. Methods 60 cases of postmenopausal HR+advanced breast cancer whose first-line or second-line endocrine therapy failed were randomly divided into study group(n=30),treated with metformin combined with AI and control group(n=30),treated with placebo combined with AI. Standard RECIST guidelines were used to evaluate the clinical response. The objective response rate(ORR),clinical benefit rate(CBR),progression-free survival,and adverse reactions of two groups were compared. Results The ORR of two groups were 16.7%and 10%respectively and the difference was not statistically significant(P > 0.05). But CBR in study group was significantly higher than that in control group (63.3%vs 36.7%),and the difference was statistically significant(P<0.05). The median PFS in study group was slightly longer than that in control group (3.7 m vs 4.2 m),but there was no statistical difference. Multivariate regression analysis showed that PFS was only associated with the previous endocrine therapy. No serious adverse reactions occurred in two groups. Conclusion Metformin is expected to improve secondary endocrine resistance in breast cancer,but large prospective clinical studies are needed to confirm it.
ABSTRACT
Background and purpose:Tumor suppressor gene P53 has long been studied in tumors, including breast cancer. More studies focused on the relationship between P53 and prognosis of breast cancer and found that P53 overexpression suggested a bad prognosis. However, the effect of P53 on early stage postmenopausal patients with ER-positive breast cancer has not been clariifed yet. This study was to investigate the role of P53 plays in aromatase inhibitor (AI) resistance among early stage postmenopausal patients with ER-positive breast cancer patients. Methods:A total number of 293 operable breast cancer patients who received surgical treatment during Jul. 2000 to Jul. 2006 in Fudan University Shanghai Cancer Center were enrolled into this study. All patients received AI treatment. The SPSS 12.0 software was used to estimate the survival rate. Univariate and multivariate analysis were also performed via above software. Results:The median follow-up time is 72 months (6-140 months). The 5 year disease free survival (DFS) of P53 positive and negative were 78%and 89%. The results showed that P53 overexpression (HR=1.729, 95%CI:1.038-2.880, P=0.035), pathological stage (HR=2.270, 95%CI:1.399-3.681, P=0.001);histological grade (HR=2.328, 95%CI:1.312-4.133, P=0.004); age (HR=1.988, 95%CI:1.511-2.617, P<0.005) were still the independent risk factors of recurrence and metastasis in breast cancer patients treated with AI. Conclusion:P53 overexpression correlated strongly with AI resistance in early stage postmenopausal patients with ER-positive breast cancer patients who were treated with AI and conifrmed the relevance of previously described prognostic factors. It is reasonable to take P53 expression into account when we evaluate the risk of breast cancer patients and decide the anti-cancer treatment strategy.
ABSTRACT
Objective To evaluate the effect and the best concentration of Rg 3 combined with delaying tamoxifen resistance in breast cancer .Methods The tamoxifen-resistant(TAM-R)cell line with TAM was es-tablished.TAM-R cell line and WT -MCF-7 cell line were cultured in TAM at different concentrations and then detected the growth of cells .WT-MCF-7 cell line was cultured medium in TAM which contained Rg 3 at different levels .The growing situation of cells was detected with MTT method .Results Compared with wild -type WT-MCF-7 cells,TAM-R showed higher curves when they were both at TAM treatment .Rg3 could be associated with delaying the emergency of tamoxifen resistance and the best concentration was 1 ×10 -8 mol/L and 5 ×10 -8 mol/L.Conclusion It might be useful to reduce the tamoxifen resistance incidence by clinically com-bined Rg3 with TAM treatment .
ABSTRACT
Therapies targeting endocrine receptors and human epidermal growth factor receptor 2 have become important treat-ment modes for patients with hormone receptor breast cancer. Despite the availability of these options, however, development of prima-ry or secondary drug resistance and subsequent disease progression in patients with advanced disease continue to occur. Mammalian tar-get of rapamycin (mTOR), a key regulator of cell growth and proliferation, has been implicated in the induction of cellular processes leading to the uncontrolled growth of cancer cells. Recent studies have suggested that overactivation of the mTOR pathway may be in-volved in the development of endocrine resistance. Interrupting this signaling cascade may alleviate such resistance and help restore drug sensitivity. A number of agents targeting the mTOR pathway have shown potent anti-tumorigenic effects in vitro, and several agents show great potential for treating breast cancer patients. Many clinical studies have shown that combining endocrine therapy with mTOR inhibitors could significantly increase the survival rate of breast cancer patients. In this study, we focus on recent research prog-ress on mTOR and its inhibitors in endocrine therapy resistance in breast cancer.