The Role of Everolimus in the Treatment of Breast Cancer

The development of resistance to chemotherapy, endocrine therapy and anti HER2 agents in breast cancer is an important and common problem that impacts in the management of patients, particularly in the metastatic setting. This resistance has been explained in part by the activation of signal transduction pathways, including the PI3K/AKT/mTOR. The blockade with mTOR inhibitors such as everolimus is a new target agent for therapy that attempts to enhance treatment efficacy and restore tumor sensitivity. In this review article, we present the data about the use of everolimus for the treatment of breast cancer in all tumor phenotypes. Future studies that evaluate biomarkers for treatment response are needed to identify the specific populations that have the highest benefit of this new targeted therapy.

miR-129对乳腺癌肿瘤干细胞自我更新能力的调控作用及其机制探讨

目的:探究miR-129在乳腺癌中对肿瘤干细胞自我更新能力的调控作用及其机制。方法:应用免疫组化检测乳腺癌肿瘤干细胞在肿瘤组织与癌旁组织中的数量及其与乳腺癌肿瘤分期的关系,验证miR-129和Numb与乳腺癌肿瘤干细胞之间的相关关系。在体外实验中应用Western Blotting及RT-PCR验证miR-129通过阻断雌激素受体alpha(ER alpha,ESR1)对Notch信号通路的调节作用及其调节的具体机制;应用裸鼠成瘤实验验证miR-129在裸鼠体内水平对乳腺癌肿瘤干细胞的影响。结果:肿瘤组织中乳腺癌肿瘤干细胞的比例高于癌旁组织并与肿瘤分期具有相关性;乳腺癌肿瘤干细胞比例与临床样本中miR-129和Numb的表达水平呈负相关;乳腺癌肿瘤干细胞中miR-129的过表达与Notch信号通路的抑制直接相关,这种作用很可能是miR-129通过调控ESR1所引起的Let-7b的表达下调进而导致Numb的释放来实现的;miR-129在裸鼠体内实验中可以抑制乳腺癌肿瘤干细胞的成瘤。结论:miR-129在乳腺癌组织中可以通过调控Notch信号通路影响乳腺癌肿瘤干细胞自我更新的能力,具体的调节机制可能是通过调控ESR1所引起的Let-7b的表达下调进而导致Numb的释放来最终抑制Notch信号通路的激活。

Organ-specific enhancement of metastasis by spontaneous ploidy duplication and cell size enlargement

Aneuploidy is commonly observed in breast cancer and is associated with poor prognosis. One frequent type of aneuploidy, hypertetraploidy, may derive from ploidy duplication of hyperdiploid cells. However, the pathological consequences of ploidy duplication in breast cancer progression have not been characterized. Here, we present an experimental system demonstrating spontaneous appearance of hypertetraploid cells from organ-specific metastatic variants of the MDA-MB-231 breast cancer cell line through ploidy duplication in vitro and in vivo. The hypertetraploid progenies showed increased metastatic potential to lung and brain, but not to bone, which may be partially explained by the distinct capillary structures in these organs that confer differential lodging advantages to tumor cells with enlarged size. Our results suggest a potential mechanistic link between ploidy duplication and enhancement of metastatic potentials, as was observed in previous clinical studies of breast cancer.

MEK inhibition activates STAT signaling to increase breast cancer immunogenicity via MHC-I expression

Aim:Immunotherapy and immune checkpoint inhibitors(ICI)have changed cancer care for many patients;however,breast cancers have exhibited minimal response to single agent ICI therapy.There is a significant need to identify novel targets capable of increasing cancer cell immunogenicity and response to ICIs in breast cancer.Mitogen activated protein kinase(MAPK)signaling is essential for many cellular processes but the relationship between MAPK signaling and cancer cell immunogenicity is less well understood.Recent reports suggest that MEK inhibition(MEKi)affects the tumor-immune microenvironment by altering the expression of interferon responsive PD-L1 and MHC-I through unknown mechanisms.Methods:Using western blotting and flow cytometry,we sought to determine whether MEKi affects JAK-STAT signaling upstream of PD-L1 and MHC-I expression in a panel of mouse mammary cancer and triple negative breast cancer cell lines.Results:The cell lines tested exhibited increased STAT activation in response to MEKi treatment.Furthermore,MEKi-induced MHC-I and PD-L1 expression are dependent upon STAT1 in MMTV-Neu cells.Interestingly,MEKiinduced STAT activation and interferon-responsive protein expression are abrogated with ErbB-family inhibitor co-treatment in MMTV-Neu cells,suggesting ErbB receptor signaling dependence,but not in basal-like cell lines.Importantly,analysis of basal-like breast cancer patient samples exhibited an inverse relationship between STAT1 and Ras/MAPK activation signatures.Conclusion:These findings suggest that MAPK signaling and STAT activation are inversely related in both mouse and human mammary tumors.This work also supports further study of MEKi to increase STAT signaling and potentially,immunotherapy responses through increased MHC-I and PD-L1 expression.

对完成最初化疗方案后6～12个月内复发的卵巢癌患者进行卡培他滨治疗的Ⅱ期临床试验,并探讨TS、DDP、TP与治疗的关系:妇科肿瘤组的一项研究

Purpose. A phase II trial was conducted to evaluate the antitumor activity and adverse effects of capecitabine in women with measurable platinum- sensitive ovarian cancer or platinum- sensitive primary peritoneal cancer and to explore the ability of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and thymidine phosphorylase (TP) to predict response and toxicities. Experimental design. Patients were treated with a daily starting dose of 2500 mg/m2/day (divided in two doses given every 12 h) for 14 days of each 21- day cycle. Genotyping in the 5′ and 3′ ends of TS was performed in DNA from 23/23 pre- treatment blood specimens. Relative gene expression of TS, DPD, and TP was quantified in 18/21 paraffin- embedded tumor specimens. Results. Of the 27 patients enrolled on study, 2 were never treated leaving 25 patients evaluable. Two patients (8.0% ) achieved a partial response, 13 (52% ) exhibited stable disease, 5 (20% ) displayed increasing disease, and response could not be assessed in 5 (20% ). The median time to progression and survival was 3.9 and 21.2 months, respectively. The most common serious toxicities were nausea/vomiting, gastrointestinal, and dermatological. There was one treatment- related death. TS expression was associated with severe nausea/vomiting (P = 0.039), but not with other severe toxicities. TS genotype or expression of DPD or TP was not associated with any of the severe toxicities. Conclusions. Based on the low response rate, this trial was closed after the first stage of accrual, the drug was not selected for further study in this patient population, and biomarker associations with response could not be assessed.

选择性雌激素受体调节剂以及浸润性乳腺癌的预防

本年度美国有20万以上的妇女被诊断患有浸润性乳腺癌。过去20年的研究已将对基础生物学的了解转化为治疗实践，导致乳腺癌患者生存率和生活质量的很大改善。对预防乳腺癌的其他策略也进行了研究。这些策略包括改变生活方式（如饮食、酒精摄入、理想体重、外源性雌激素治疗）、手术切除（预防性乳房切除术、卵巢切除术或二者同时进行）以及最近采用的选择性雌激素受体调节剂（selective estrogen receptor modulators，SERMs）如他莫西芬进行化学预防。

Studies of postpartum mammary gland involution reveal novel pro-metastatic mechanisms

Postpartum involution is the process by which the lactating mammary gland returns to the pre-pregnant state after weaning. Expression of tumor-promotional collagen, upregulation of matrix metalloproteinases, infiltration of M2 macrophages, and remodeling of blood and lymphatic vasculature are all characteristics shared by the involuting mammary gland and breast tumor microenvironment. The tumor promotional nature of the involuting mammary gland is perhaps best evidenced by cases of postpartum breast cancer (PPBC), or those cases diagnosed within 10 years of most recent childbirth. Women with PPBC experience more aggressive disease and higher risk of metastasis than nulliparous patients and those diagnosed outside the postpartum window. Semaphorin 7a (SEMA7A), cyclooxygenase-2 (COX-2), and collagen are all expressed in the involuting mammary gland and, together, predict for decreased metastasis free survival in breast cancer. Studies investigating the role of these proteins in involution have been important for understanding their contributions to PPBC. Postpartum involution thus represents a valuable model for the identification of novel molecular drivers of PPBC and classical cancer hallmarks. In this review, we will highlight the similarities between involution and cancer in the mammary gland, and further define the contribution of SEMA7A/COX-2/collagen interplay to postpartum involution and breast tumor progression and metastasis.