Developments in the Management of Metastatic HER2-Positive Breast Cancer: A Review

Approximately 20% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2), providing an actionable target for many different therapies. In the metastatic setting, prognosis has improved greatly with the use of anti-HER2 drugs such as trastuzumab, pertuzumab, and trastuzumab-emtansine. In the third line setting and beyond, several emerging treatments have shown benefits, including novel small molecule targeted agents and antibody-drug conjugates. Systemic treatment of brain metastases in HER2-positive patients and the role of endocrine-based treatment for patients with hormone receptor (HR) positive disease remain areas of research interest. This article will review the current approach to systemic management of metastatic HER2-positive breast cancer in Canada, and present novel treatments that may be available in the near future.     

Skp2和p27蛋白在乳腺癌中表达及临床意义

 目的 探讨Skp2与p27蛋白在乳腺癌中的表达及临床意义。方法 采用免疫组织化学方法对50例乳腺癌和12例正常乳腺组织中Skp2与p27蛋白表达水平进行研究。结果 乳腺癌中Skp2和p27蛋白表达水平与正常乳腺组织比较有显著差异(P<0．05)。Skp2与p27蛋白的表达水平与乳腺癌的临床分期、腋淋巴结受累及远处转移显著相关(P<0．05)；肿瘤大小，c-erbB-2表达，局部复发与p27蛋白表达水平显著相关，与Skp2表达无显著相关。Skp2与p27蛋白在乳腺癌中的表达呈负相关(P<0．05)。结论 Skp2与p27蛋白在乳腺癌的发生、发展及预后中起重要作用，对判断肿瘤的生物学行为和预后具有参考价值。     

Prognostic Value of Pretreatment Neutrophil-to-Lymphocyte Ratio in HER2-Positive Metastatic Breast Cancer

This study aimed to examine the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) and other clinicopathological features in HER2+ MBC patients who received first-line anti-HER2 therapy. A total of 129 patients were assigned to NLR-low and NLR-high groups based on a cutoff value of 3.0 at baseline. Peripheral blood lymphocyte subsets and gene mutations in circulating tumor DNA were analyzed by flow cytometry and Next-generation sequencing, respectively. Survival was evaluated by the Kaplan–Meier method and Cox regression analysis. Of the 129 patients, 77 and 52 were assigned to the NLR-low (≤3) and NLR-high (>3) groups, respectively. Compared with NLR-high patients, the NLR-low patients had significantly longer median progression-free survival (PFS) (11.7 vs. 7.7 months) (p = 0.001, HR = 2.703 95% CI 1.543–4.736 and overall survival (OS) (37.4 vs. 28.7 months) (p = 0.044, HR = 2.254 95% CI 1.024–4.924). Furthermore, this association was independent of metastatic sites or estrogen receptor status. Peripheral blood CD3+ (p = 0.034) and CD4+ (p = 0.010) T cell numbers were significantly higher in the NLR-low group than the NLR-high group. The mutational profile of MBC was generally similar between the two groups. Baseline NLR was a prognostic factor of PFS and OS for patients with HER2+ MBC in the first-line setting. These results may facilitate the selection of patients who will benefit most from anti-HER2 treatment.     

Increased signalling of EGFR and IGF1R, and deregulation of PTEN/PI3K/Akt pathway are related with trastuzumab resistance in HER2 breast carcinomas

Background:

Trastuzumab resistance hampers its well-known efficacy to control HER2-positive breast cancer. The involvement of PI3K/Akt pathway in this mechanism is still not definitively confirmed.

Methods:

We selected 155 patients treated with trastuzumab after development of metastasis or as adjuvant/neoadjuvant therapy. We performed immunohistochemistry for HER2, ER/PR, epidermal growth factor 1-receptor (EGFR), α-insulin-like growth factor 1-receptor (IGF1R), phosphatase and tensin homologue (PTEN), p110α, pAkt, pBad, pmTOR, pMAPK, MUC1, Ki67, p53 and p27; mutational analysis of PIK3CA and PTEN, and PTEN promoter hypermethylation.

Results:

We found 46% ER/PR-positive tumours, overexpression of EGFR (15%), α-IGF1R (25%), p110α (19%), pAkt (28%), pBad (22%), pmTOR (23%), pMAPK (24%), MUC1 (80%), PTEN loss (20%), and PTEN promoter hypermethylation (20%). PIK3CA and PTEN mutations were detected in 17% and 26% tumours, respectively. Patients receiving adjuvant trastuzumab with α-IGF1R or pBad overexpressing tumours presented shorter progression-free survival (PFS) (all P⩽0.043). Also, p110α and mTOR overexpression, liver and brain relapses implied poor overall survival (OS) (all P⩽0.041). In patients with metastatic disease, decreased PFS correlated with p110α expression (P=0.024), whereas for OS were the presence of vascular invasion and EGFR expression (P⩽0.019; Cox analysis).

Conclusion:

Our results support that trastuzumab resistance mechanisms are related with deregulation of PTEN/PI3K/Akt/mTOR pathway, and/or EGFR and IGF1R overexpression in a subset of HER2-positive breast carcinomas.     

p27蛋白在乳腺癌中的表达及其意义

目的 探索ｐ２７蛋白在乳腺癌中的表达及其意义。方法 采用免疫组织化学法检测８例正常乳腺癌组织、２４例良性乳腺癌疾病组织、６６例乳腺癌组织ｐ２７蛋白的表达，探讨与临床病理学特征的关系。结果 正常乳腺组织和良性乳腺疾病组织中ｐ２７蛋白的表达率为１００．０％（３２／３２），癌组织为５３．０％（３５／６６）；ｐ２７蛋白表达与肿瘤临床分期、淋巴结转移、局部复发、远处转移显著相关。结论 ｐ２７蛋白的表达与乳腺     

MiR-18b-5p对大肠癌PTEN/PI3K/Akt2信号通路的调控

目的:探讨miR-18b-5p对大肠癌PTEN/PI3K/Akt2信号转导通路的调控。方法:qRT-PCR方法检测33例大肠癌患者癌组织中miR-18b-5p表达水平,将患者临床病理特征与癌组织miR-18b-5p表达水平进行独立样本t检验和多元线性回归分析。应用microrna.org预测miR-18b-5p靶基因,miR-18b-5p 类似物、抑制物转染肠癌细胞SW480及HCT116,qRT-PCR检测细胞PTEN、PI3K、Akt2 mRNA表达水平。结果:在大肠癌患者癌组织中,miR-18b-5p表达水平显著增高,为癌旁组织的3.6倍(P<0.01 ),其表达水平与肿瘤分化程度、淋巴结转移及TNM分期相关。Microrna.org预测PTEN可能是miR-18b-5p的靶基因,大肠癌细胞转染类似物后PTEN含量明显降低,其下游基因PI3K、Akt2表达增高。结论:miR-18b-5p下调抑癌基因PTEN表达,诱导PI3K/Akt2信号转导通路持续活化,促进了大肠癌的发生发展。     

乳腺癌HER2 过度表达预后相关因素研究

 目的　研究乳腺癌患者HER2 过度表达与其他临床预后因素的相关性及对预后的影响。方法 　收集我院2002 年1 月～2003 年12 月乳腺癌Ⅰ～ Ⅲ期患者共176 例,检测HER2 表达,与其他临床预 后因素进行相关分析;同时比较HER2 过度表达和阴性表达患者的预后。结果　本组患者HER2 过度 表达与PR( P = 0. 002) 、ER( P = 0. 031) 表达呈负相关,而与其他预后因素无相关性。多因素分析表明 HER2 是无病生存时间的独立预后因素( P = 0. 018) 。结论　HER2 过度表达可作为乳腺癌无病生存时 间的独立预后因素并指导乳腺癌的治疗。     

Immune Effective Score as a Predictor of Response to Neoadjuvant Trastuzumab Therapy and a Prognostic Indicator for HER2-Positive Breast Cancer

Background: HER2-positive breast cancer (BC) is a highly aggressive phenotype. The role of the host immune features in predictive response to anti-HER2 therapies and prognosis in BC has already been suggested. We aimed to develop a predictive and prognostic model and examine its relevance to the clinical outcomes of patients with HER2-positive BC. Methods: Immune effective score (IES) was constructed using principal component analysis algorithms. A bioinformatic analysis using four independent cohorts ({"type":"entrez-geo","attrs":{"text":"GSE66305","term_id":"66305"}}GSE66305, n = 88; {"type":"entrez-geo","attrs":{"text":"GSE130786","term_id":"130786"}}GSE130786, n = 110; TCGA, n = 123; METABRIC, n = 236) established associations between IES and clinical outcomes. Results: Genes associated with neoadjuvant trastuzumab therapy response were enriched in pathways related to antitumor immune activities. IES was demonstrated to be a predictive biomarker to neoadjuvant trastuzumab therapy benefits ({"type":"entrez-geo","attrs":{"text":"GSE66305","term_id":"66305"}}GSE66305: area under the curve (AUC) = 0.804; {"type":"entrez-geo","attrs":{"text":"GSE130786","term_id":"130786"}}GSE130786: AUC = 0.704). In addition, IES was identified as an independent prognostic factor for overall survival (OS) in the TCGA cohort (p = 0.036, hazard ratio (HR): 0.66, 95% confidence interval (CI): 0.449–0.97) and METABRIC cohort (p = 0.037, HR: 0.9, 95% CI: 0.81–0.99). Conclusion: IES has a predictive value for response to neoadjuvant trastuzumab therapy and independent prognostic value for HER2-positive breast cancer.     

Clinical significance of p95HER2 overexpression,PTEN loss and PI3K expression in p185HER2-positive metastatic breast cancer patients treated with trastuzumab-based therapies

Background:

Overexpression of p185HER2 is an established poor prognostic factor in breast cancer, portending an aggressive course and potential for early metastasis. On the other hand, monoclonal antibody trastuzumab is widely used in the clinic to target this overexpressed oncogene. Unfortunately, ∼30–40% of all patients overexpressing HER2 respond to trastuzumab, warranting further research regarding the structure and additional modulation of the receptor. In this study, we aimed to investigate the response to trastuzumab in terms of the potential roles of several oncogenic pathways (phosphatase and tensin homologue (PTEN) and phosphatidylinositol 3-kinase (PI3K)) and a truncated receptor protein, p95HER2, retrospectively.

Materials and methods:

Paraffin-embedded primary tumour tissues of 100 HER2-positive metastatic breast cancer patients who received trastuzumab with combination cytotoxic chemotherapy were analysed with immunohistochemical method for p95HER2, p85 (PI3K) and PTEN. Relationship between variables were tested via χ², Fischer''s exact test and Mann–Whitney U tests, wherever appropriate. Progression-free survival (PFS) and overall survival (OS) periods were calculated with Kaplan–Meier method and survival curves of subgroups were compared with log-rank test.

Results:

Percentage of patients was found to be 33%, 57% and 42% positive for p95 expression, PTEN and PI3K, respectively. p95-expressing tumours had statistically lower response rates for trastuzumab than tumours not expressing p95 (P=0.001). On the contrary, PTEN-expressing tumours had statistically higher response rates for trastuzumab than tumours not expressing PTEN (P=0.012). PI3K expression had no significant effect on trastuzumab response. Median PFS for p95-expressing and not expressing tumours were 8 months (95% CI, 2.5–13.4 months) and 22 months (95% CI, 9.9–34 months), respectively (P=0.0001). Median PFS for PTEN-expressing and not expressing tumours were 15.3 months (95% CI, 12.6–34 months) and 12.1 months (95% CI, 7.9–16.2 months), respectively (P=0.04). Median OS for p95-expressing and not expressing tumours were 24 months (95% CI, 8.3–40.4 months) and 29.1 months (95% CI, 8.6–43.2 months), respectively (P=0.045). Median OS for PTEN-expressing and not expressing tumours were 25.1 months (95% CI, 7.5–40.1 months) and 26.8 months (95% CI, 8.1–42 months), respectively, which was not statistically significant (P=0.5). Level of PI3K expression had no effect on PFS and OS in our patient population. Presence of visceral metastases HR=2.38 ((95% CI, 1.2–4.5), P=0.009), p95 expression HR=2.1 ((95% CI, 1.1–3.7), P=0.03) and response to trastuzumab HR=2.2 ((95% CI, 1.18–4.47), P=0.014) are identified as factors independently affecting PFS. Response to trastuzumab HR=1.7 ((95% CI, 1.14–3.47), P=0.013) was identified as the single parameter influencing survival by Cox regression analysis.

Conclusions:

Presence of p95 predicted a poorer response to trastuzumab treatment, shorter PFS and OS in our HER2-positive metastatic breast cancer cohort. In addition, loss of PTEN predicted a poorer response to trastuzumab treatment and shorter PFS but not OS. We could not find an effect of PI3K expression on the above-mentioned parameters.     

CKS1和p27在乳腺癌中的表达及其意义

目的 探讨CKS1和p27在乳腺癌中的表达情况及其临床意义。方法 应用免疫组织化学SP法检测149例乳腺癌患者组织标本中CKS1和p27的表达水平,结合临床病理资料进行统计学分析。结果 乳腺癌组织中CKS1的表达与淋巴结转移和临床分期有统计学意义（P<0.05）。p27的表达与淋巴结转移显著负相关（P<0.05）,与临床分期和肿瘤分化程度无相关性。多因素分析发现临床分期（P<0.01）、淋巴结转移（P<0.01）、CKS1（P<0.01）和p27（P<0.01）的表达对预后的影响有统计学意义。CKS1与p27表达呈显著负相关（P<0.05）。结论 CKS1和p27可能在乳腺癌的发生发展中发挥重要的作用,二者将来可能作为乳腺癌治疗的靶点之一。     

HER3在乳腺癌中的表达及临床意义

目的探讨乳腺癌患者HER3与HER2、ER和PR之间的关系及其对乳腺癌预后的影响。方法采用免疫组织化学SP法检测癌组织中HER3、HER2、ER和PR蛋白的表达,对患者随访,随访终点为总生存时间(overall survival,OS)。结果 HER2、HER3、ER和PR在136例乳腺癌患者中的阳性表达率分别为:50%、41.18%、60.9%和27.21%。HER3与年龄、淋巴结转移、分期、肿瘤类型以及化疗状态的差异无统计学意义(P>0.05)。HER3阳性与阴性患者OS差异有统计学意义(P=0.015)。HER3(+)HER2(+)组乳腺癌患者较其他组OS明显缩短(P=0.047)。HER3的表达与PR表达无明显关系(P=0.214),但可抑制ER产生(P=0.001)。HER2阳性和HER3的过度表达高度相关(P=0.000)。结论HER3可作为独立的临床预后因子,HER3阴性患者OS较长。     

PI3K、Akt以及PTEN在胃肠道间质瘤中的表达及意义

目的:探讨PI3K、Akt以及PrEN的表达与GIST临床病理特征及预后的相关性,并探讨它们间的相互关系,以揭示其在GIST发生发展过程中的作用,为进一步的肿瘤靶点治疗提供理论依据.方法:选择临床病理资料完整、随访结果确切的中国医科大学附属盛京医院1990年-2007年2月手术切除、病理证实的GIST新鲜组织标本124例.男性64例、女性60例,平均年龄54.6岁.RT-PCR检测PI3K、Akt以及PTEN在GIST及对照组的mRNA水平.结果:PI3K mRNA水平随NIH分级表达上调(P＜0.05),PI3K的阳性表达率与黏膜受侵和肿瘤侵袭转移均显著相关(P＜0.05).Akt mRNA水平随NIH分级表达上调,其中在高、中危肿瘤组之间不明显,无统计学意义,其余各组有意义;Akt的阳性表达率与肿瘤侵袭转移和黏膜受侵显著相关,提示Akt的过表达促进了GIST的肿瘤侵袭转移.同时PTENmRNA随NIH分级表达下调(P＜0.05),随着肿瘤恶性程度的增加,PTEN的缺失率增高;PTEN的阳性表达率与肿瘤侵袭转移和黏膜受侵关系密切.结论:PI3 K/Akt与PTEN在GIST的发生发展中可能互相拮抗共同作用,PI3K、Akt蛋白阳性表达之间呈显著正相关(r =0.292.P=0.031);PI3K与PTEN蛋白阳性表达之间呈显著负相关(r=-0.412,P =0.036);PTEN与Akt蛋白阳性表达之间呈显著负相关(r=-0.386,P=0.024).     

Significance of Skp2 expression in human gastric carcinoma and the relationship between Skp2, p27 and PTEN expression

Objective： S-phase kinase-associated protein 2 （Skp2） is a positive regulator of G1-S transition and promotes ubiquitin-mediated proteolysis of the cyclin-dependent kinase inhibitor p27. Its overexpression has been implicated in cell transformation and oncogenesis. In this study, we investigated significance of Skp2 expression in human gastric carcinoma and the relationship between Skp2, p27 and PTEN expression. Methods： Immunohistochemical analysis was performed on 138 surgical resected primary gastric carcinoma specimens, 102 paired metastasis carcinoma tissue specimens in lymph node from the same set of 138 surgical resected primary gastric carcinoma specimens, 30 dysplasia specimens, 30 intestinal metaplasia specimens, and 20 normal gastric mucosa specimens for Skp2 and performed on the same set of 138 surgical resected primary gastric carcinoma specimens for p27 and PTEN. Results： Skp2 labeling frequency % was increased dramatically in intestinal metaplasia, dysplasia, and primary gastric carcinoma compared with normal gastric mucosa （P=0.000, all the same）. Skp2 labeling frequency % in metastasis gastric carcinoma in lymph node was significantly higher than primary gastric carcinoma （P=0.037）. Skp2 labeling frequency % was positively associated with differentiated degree （rho=0.315, P=0.000）, vessel invasion （rho=0.303, P=0.000） and lymph node metastasis （rho=0.254, P=0.000） respectively. An inverse correlation of Skp2 was observed with both its biochemical target p27 expression in gastric carcinoma （rho=-0.451, P=0.000） and with its putative negative regulator, the PTEN tumor suppressor protein （rho=-0.480, P=0.000）. p27 expression had positive relationship with PTEN expression in gastric carcinoma （rho=0.642, P=0.000）. Conclusion： Skp2 overexpression is correlated with carcinogenesis and progression of gastric carcinoma： elevated Skp2 expression is correlated with decreased p27 and PTEN in gastric carcinoma, and p27 expression is parallel with PTEN expression. These suggest that PTEN may regulate expression of p27 through the Skp2 pathway, and the effects of Skp2, p27 and PTEN together play an important role in carcinogenesis and progression of gastric carcinoma.     

Activation of PI3K/Akt signaling and hormone resistance in breast cancer

Akt is a serine/threonine kinase that has been demonstrated to play an important role in survival when cells are exposed to different apoptotic stimuli. Recent studies show that aberrant activation of Akt in breast carcinoma is associated with a poor prognosis and resistance to endocrine therapy and chemotherapy. The Akt signaling pathway is currently attracting considerable attention as a new target for effective therapeutic strategies. We investigated the incidence of Akt activation in 252 primary breast carcinomas and relationships among the activation of Akt, HER2 overexpression, hormone receptor expression, and alteration of the PTEN gene. Eighty-four cases (33.3%) were positive for pAkt expression. pAkt was significantly associated with HER2 overexpression (p<0.0001) and LOH at the PTEN gene locus (p<0.01). There was an inverse correlation between pAkt and PR (p<0.05). We also retrospectively examined the relationship between Akt activation and the efficacy of endocrine therapy for metastatic breast cancer. Of these 36 metastatic breast cancer cases, 12 cases (33.4%) were considered to show positive pAkt expression. In the pAkt-positive patients, endocrine therapy demonstrated worse efficacy than in pAkt-negative patients (p<0.01). In addition, the clinical benefit was the smallest in the patients positive both for HER2 and pAkt (p<0.01). The clinical benefit rate of estrogen deprivation therapy with AI or LH-RH agonist was significantly lower in the pAkt-positive patients than that in the pAkt-negative ones (p<0.05), and there was a tendency for the clinical benefit of SERM to be smaller in the pAkt-positive patients (p=0.09). These findings therefore suggest that Akt activation induces endocrine resistance in metastatic breast cancer, irrespective of the kind of endocrine agents that were administered. Our findings indicate that the activation of Akt in the downstream pathway of HER2 plays an important role in resistance to endocrine therapy for breast cancer. Our findings suggest that pAkt may be a useful predictor of resistance to endocrine therapy for breast cancer, while also suggesting that the inhibition of Akt may increase the efficacy of endocrine therapy.     

乳腺导管内增生性病变中Skp2和p27kip1的表达及意义

目的从蛋白水平研究导管内增生性病变中Skp2和p27kip1表达异常与乳腺癌发生之间的相关性。方法采用免疫组织化学法分别检测120例导管内增生性病变,包括普通型导管上皮增生(usualductal hyperplasia,UDH),平坦型上皮不典型性病变(flat epithelial atypia,FEA),不典型导管上皮增生(atypical ductal hyperplasia,ADH),导管原位癌(ductal carcinoma in situ,DCIS)各30例石蜡包埋组织,以及健康对照组中Skp2和p27kip1蛋白表达水平,分析比较四组病变中Skp2和p27kip1蛋白阳性表达率以及这两种蛋白表达的相关性。结果四个亚型Skp2蛋白阳性表达率均高于健康对照组(P<0.05),DCIS组、ADH组和FEA组Skp2蛋白阳性表达率均高于UDH组(P<0.05),DCIS组Skp2蛋白阳性表达率高于ADH组和FEA组(P<0.05);p27kip1蛋白在UDH组、FEA组、ADH组、DCIS组的阳性表达率均低于健康对照(P<0.05),p27kip1蛋白在DCIS组阳性表达率低于UDH组、ADH组和FEA组(P<0.05)。Skp2与p27kip1阳性细胞率在四组导管内增生性病变中的蛋白表达阳性率总体上呈负相关(r=-0.411,P=0.000)。在UDH组与DCIS组内Skp2与p27kip1表达均呈负相关(r=-0.406,P=0.026;r=-0.544,P=0.002)。结论 Skp2蛋白表达水平升高p27kip1蛋白水平下降与乳腺导管上皮不典型增生和乳腺癌发生相关。     

前列腺癌中泛素降解途径蛋白的表达及与临床病理特征的相关性

目的 探讨泛素降解途径蛋白Skp2、p27kipl和PTEN在前列腺癌中的表达及与前列腺癌各项临床病理特征的关系,并探讨三者的相关性.方法 应用免疫组织化学法和图像分析系统研究41例前列腺癌标本、20例开放手术切除良性前列腺增生标本中Skp2、p27kipl和PTEN的表达情况.并使用Mann-Whitney检验、Spearman等级相关分析临床病理资料与免疫组化的结果及Skp2、p27kipl和PTEN之间的相关性.结果 在前列腺癌中,Skp2蛋白染色阳性率显著高于良性前列腺增生(P<0.001),p27kipl蛋白染色阳性率显著低于良性前列腺增生(P<0.001),PTEN蛋白染色阳性率显著低于良性前列腺增生(P<0.001).Skp2 蛋白表达与前列腺癌术前PSA水平、肿瘤穿透前列腺被膜、肿瘤分期、病理分级密切相关(P<0.05).而p27kipl和PTEN蛋白表达与上述临床病理特征负相关(P<0.05).Spearman 等级相关分析表明,Skp2与p27kipl蛋白表达呈负相关(r=-0.572, P<0.001),Skp2与PTEN 蛋白表达呈负相关(r=-0.433, P=0.005).结论 Skp2蛋白在前列腺癌中表达增加,与术前PSA水平、局部浸润、临床分期和病理分级呈正相关,而p27蛋白在前列腺癌中表达降低,与上述临床病理特征呈负相关,Skp2蛋白表达与p27蛋白表达之间呈负相关.Skp2表达与抑癌基因PTEN蛋白表达呈负相关.     

PTEN、p27蛋白在胃癌组织中的表达及其相关性

 目的　研究胃癌组织中PTEN和p27蛋白的表达及二者间的相关性。方法　应用免疫组织化学方法检测49例胃癌组织、49例癌旁组织和13例正常胃黏膜中PTEN和p27蛋白的表达情况。结果　胃癌组织中PTEN和p27蛋白的阳性表达率分别为61.22 %（30／49）和57.14 %（28／49）,较癌旁组[91.84 %（45／49）、93.88 %（46／49）]和正常组织[100 %（13／13）、100 %（13／13）]明显降低（均P＜0.05）。两者在胃癌中的表达有相关性（r＝0.580,P＝0.000）,且均与肿瘤的分化程度、淋巴结转移和PTNM分期有关。结论　PTEN和p27基因的异常改变可能参与胃黏膜细胞的恶性转化过程,且两者之间存在相关性。联合检测两者表达水平可作为评价胃癌病理生物学行为的客观指标之一。     

Coexistence of the loss of heterozygosity at the PTEN locus and HER2 overexpression enhances the Akt activity thus leading to a negative progesterone receptor expression in breast carcinoma

Serine/threonine kinase Akt/PKB is known to regulate divergent cellular processes, including apoptosis, proliferation, differentiation, and metabolism. Akt is activated by a variety of stimuli, through such growth factor receptors as HER2, in phosphoinositide-3-OH kinase (PI3K)-dependent manner. A loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) function also activates Akt. It has recently been shown that Akt activation is associated with a worse outcome among endocrine treated breast cancer patients and that it also inhibits the progesterone receptor (PR) expression via the PI3K/Akt pathway in breast cancer cells. Therefore, the PI3K/Akt signaling pathway has recently attracted considerable attention as a new target for effective therapeutic strategies. In the present study, we investigated the relationship between Akt activation and either HER2 overexpression or PTEN gene alteration, as well as the PR expression. We analyzed the incidence of LOH at the PTEN locus in 138 breast cancer patients, using our new system for microsatellite analysis, called high-resolution fluorescent microsatellite analysis (HRFMA). We showed Akt activation to significantly correlate with HER2 overexpression or LOH at the PTEN gene locus while inversely correlating with the PR expression. In addition, when LOH at the PTEN gene locus and HER2 overexpression occurred simultaneously, the incidence of Akt activation and reduced PR expression was significant. The association between Akt activation and PR negative expression was observed even in the ER-positive cases. Our results suggest that simultaneous PTEN LOH and HER2 overexpression enhances Akt activation and may thus lead to a negative PR expression. This study was supported by grants from the Ministry of Education, Culture, Sports Science, and Technology of Japan.