Neu In Breast Cancer Research Articles

Discordance of the estrogen receptor and HER-2/neu in breast cancer from primary lesion to first and second metastatic site.

BackgroundHormone receptor and HER-2/neu discordance between the primary lesion and first metastasis has been reported. This study was performed to determine further biomarker discordance rates between the first and subsequent metastatic breast cancer lesions.MethodsWe performed a retrospective review of paired biomarkers from primary breast cancers compared to first reported and subsequent metastases from 103 patients with breast cancer. The estrogen receptor (ER), progesterone receptor (PR), and HER-2/neu status were reported at all three time points. In addition, hormone, cytotoxic, and targeted treatments were recorded for primary and metastatic disease, and survival was determined.ResultsBetween the primary and first metastases, discordance rates for ER, PR, and HER-2/neu were 15.8%, 33.7%, and 14.3%, respectively. There was discordance between the first and second metastases for the ER receptor in 18.8%, PR receptor in 19.8%, and HER-2/neu in 10.7%. Overall, there was discordance between the primary tumor and either the first or second metastases for ER in 27.7%, PR receptor in 40.7%, and HER-2/neu in 19.6% of cases. Discordance of either ER or PR affected survival, with worse survival experienced by those patients with all three hormone receptors remaining negative, and intermediate survival reported for those with discordant tumors (ER χ2=14.27, p=0.0008; PR χ2=11.31, p=0.0035). There was no difference in survival for patients whose HER-2/neu tumors were discordant.ConclusionThis study demonstrated that continued metastatic disease evolution may be associated with different tumor biology and that studies of metastatic lesions appear warranted, especially if targeted therapy is an option.

The effect of neoadjuvant chemotherapy on hormone receptor status, HER2/neu and prolactin in breast cancer.

Histological and immunohistochemical findings may vary in cases of breast cancer. Possible changes in tumor markers between biopsies performed before and after neoadjuvant chemotherapy are controversial and pose a challenge when a clinical decision is needed. The objectives of the present study were: (i) to compare the immunohistochemical expression of estrogen, progesterone and prolactin receptors and HER-2/neu in breast cancer before and after neoadjuvant chemotherapy; and (ii) to correlate the expression of these tumor markers with partial tumor response to neoadjuvant chemotherapy. Immunohistochemical staining for breast tumor markers was performed in 90 cases of breast cancer. Statistical analysis was carried out using Fisher's exact test, McNemar's test, Spearman's correlation and the Kappa index with linear weighting (k). Agreement between markers before and after neoadjuvant chemotherapy was fair to moderate (k = 0.37-0.51). The immunohistochemical expression of HER-2/neu and prolactin receptors showed a significant, albeit weak correlation before and after neoadjuvant chemotherapy (HER-2/neu, rho = 0.34; P = 0.0009; k = 0.35 [95% CI, 0.19-0.51]). Prolactin status changed in 28/90 cases (P = 0.001; McNemar's test), whereas no changes were found in estrogen or progesterone receptors. No association was found between tumor marker expression and tumor response. It seems prudent to reevaluate immunohistochemical markers such as HER-2/neu after neoadjuvant chemotherapy, since the findings will guide the strategy for implementation of adjuvant systemic treatment. No correlation was found between the tumor markers analyzed in the present study and partial tumor response to neoadjuvant chemotherapy.

Life after Trastuzumab: Neu Strategies for HER2-positive Breast Cancer

The importance of neu in breast cancer provided the rationale and impetus for developing agents that targeted the receptor. Proof of therapeutic principle was subsequently established with trastuzumab. Although not minimal, the improved clinical outcomes with the antibody were somewhat counterbalanced by disease relapses which occurred in advanced and adjuvant therapy settings. What this observation suggests is that while tumor response may be due principally to uncoupling the link between cell surface message reception and nuclear gene expression, disease progression appears to involve a re-programmable cellular mainframe that enables alternative tumor growth and survival pathways to become operational. The goal of this paper is to meld biological and therapeutic concepts that have resulted in further advances in the treatment of neu-amplified breast cancers.

Detection of HER-2/neu Amplification on Fine Needle Aspirates of Breast Cancer Using Fluorescence in Situ Hybridization

The accuracy of diagnostic assays for HER-2/neu in breast cancer is extremely important as HER-2/neu status is essential in tailoring adjuvant and/or neoadjuvant treatment in every patient. FNAC is widely practiced in Egypt in preoperative diagnosis of breast cancer for its low cost and high diagnostic accuracy. Since the determination of HER-2/neu protein expression on cytological preparations was previously found to be unreliable for clinical use, we opted for the assessment of HER-2/neu status in fine needle aspirates using FISH. The main objective of this study was to evaluate the reliability of HER-2/neu status assessment by FISH on fine needle aspirates of breast cancers by comparing the results with IHC and FISH on FFPE tissue sections obtained from corresponding surgically resected specimens. Fine needle aspirates from 40 breast cancer patients with pathologically confirmed breast cancer were included in the study. They were submitted for HER-2/neu evaluation by FISH. After surgery, the corresponding FFPE sections were evaluated for HER-2/neu by FISH and by IHC. FNAs from 11 cases proved to be amplified by FISH, while 29 cases were not amplified. Apart from two cases that showed lack of signals, all specimens evaluated by FISH on the corresponding FFPE sections showed matched results. The Measurement of Agreement between FISH on FNAs and FISH on FFPE sections was 86.7%, while that between FISH on FNAs and IHC was 72.5%. The high concordance rate in the present study between FISH evaluation of HER-2/neu gene amplification on FNAC samples and their corresponding FFPE samples indicate that FISH may be a reliable technique for HER-2/neu assessment on FNAs. Furthermore, FISH on FNAs gave us better hybridization signals than their corresponding FFPE tissue sections. Finally, we also conclude that all score (2+) cases by IHC should be reevaluated by FISH which is crucial for the patient management.

The Effect of Neoadjuvant Chemotherapy on Hormone Receptor Status, HER2/neu and Prolactin in Breast Cancer

Histological and immunohistochemical findings may vary in cases of breast cancer. Possible changes in tumor markers between biopsies performed before and after neoadjuvant chemotherapy are controversial and pose a challenge when a clinical decision is needed. The objectives of the present study were: (i) to compare the immunohistochemical expression of estrogen, progesterone and prolactin receptors and HER-2/neu in breast cancer before and after neoadjuvant chemotherapy; and (ii) to correlate the expression of these tumor markers with partial tumor response to neoadjuvant chemotherapy. Immunohistochemical staining for breast tumor markers was performed in 90 cases of breast cancer. Statistical analysis was carried out using Fisher's exact test, McNemar's test, Spearman's correlation and the Kappa index with linear weighting (k). Agreement between markers before and after neoadjuvant chemotherapy was fair to moderate (k = 0.37-0.51). The immunohistochemical expression of HER-2/neu and prolactin receptors showed a significant, albeit weak correlation before and after neoadjuvant chemotherapy (HER-2/neu, rho = 0.34; P = 0.0009; k = 0.35 [95% CI, 0.19-0.51]). Prolactin status changed in 28/90 cases (P = 0.001; McNemar's test), whereas no changes were found in estrogen or progesterone receptors. No association was found between tumor marker expression and tumor response. It seems prudent to reevaluate immunohistochemical markers such as HER-2/neu after neoadjuvant chemotherapy, since the findings will guide the strategy for implementation of adjuvant systemic treatment. No correlation was found between the tumor markers analyzed in the present study and partial tumor response to neoadjuvant chemotherapy.

Exposure to depleted uranium does not alter the co-expression of HER-2/neu and p53 in breast cancer patients

BackgroundAmongst the extensive literature on immunohistochemical profile of breast cancer, very little is found on populations exposed to a potential risk factor such as depleted uranium. This study looked at the immunohistochemical expression of HER-2/neu (c-erbB2) and p53 in different histological types of breast cancer found in the middle Euphrates region of Iraq, where the population has been exposed to high levels of depleted uranium.FindingsThe present investigation was performed over a period starting from September 2008 to April 2009. Formalin-fixed, paraffin-embedded blocks from 70 patients with breast cancer (62 ductal and 8 lobular carcinoma) were included in this study. A group of 25 patients with fibroadenoma was included as a comparative group, and 20 samples of normal breast tissue sections were used as controls. Labeled streptavidin-biotin (LSAB+) complex method was employed for immunohistochemical detection of HER-2/neu and p53.The detection rate of HER-2/neu and p53 immunohistochemical expression were 47.14% and 35.71% respectively in malignant tumors; expression was negative in the comparative and control groups (p < 0.05).HER-2/neu immunostaining was significantly associated with histological type, tumor size, nodal involvement, and recurrence of breast carcinoma (p < 0.05), p53 immunostaining was significantly associated with tumor size, nodal involvement and recurrence of breast cancer (p < 0.05). There was greater immunoexpression of HER-2/neu in breast cancer in this population, compared with findings in other populations.Both biomarkers were positively correlated with each other. Furthermore, all the cases that co-expressed both HER-2/neu and p53 showed the most unfavorable biopathological profile.ConclusionP53 and HER-2/neu over-expression play an important role in pathogenesis of breast carcinoma. The findings indicate that in regions exposed to high levels of depleted uranium, although p53 and HER-2/neu overexpression are both high, correlation of their expression with age, grade, tumor size, recurrence and lymph node involvement is similar to studies that have been conducted on populations not exposed to depleted uranium. HER-2/neu expression in breast cancer was higher in this population, compared with results on non-exposed populations.

Cancer biomarker HER-2/neu in breast cancer in Indian women

In Indian women with breast cancer, the HER-2/neu gene is amplified in 30% of cases. Elevated serum HER-2/neu levels have been shown to be associated with a poor clinical prognosis and decreased survival in early stage breast cancer patients, and testing for this may help to manage the disease. The present study was therefore to estimate serum HER-2/neu levels in breast cancer patients and associate these with other prognostic factors. Serum HER-2/neu levels were studied in 207 patients with breast cancer, 15 with benign breast diseases, (BBD) and 175 age-matched healthy controls. Patients' age, menopausal status, node, and estrogen receptor (ER) and progesterone receptor (PgR) status were compared with serum HER-2/neu levels. Serum HER-2/neu overexpression was associated with age, disease stage and positive nodal status but not with menopausal status. Serum HER-2/neu levels were negatively correlated with hormone receptor positivity. HER-2/neu serum tests should be done more frequently in Indian women with breast cancer, irrespective of their ER and PgR hormone receptor status. ELISA is a reliable and economical tool to assess the HER-2/neu status in tumors, when breast tissue samples are not available.

New Trends in Molecular Biomarker Discovery for Breast Cancer

Breast cancer is one of the most common and leading causes of cancer death in women. Early diagnosis, selection of appropriate therapeutic strategies, and efficient follow-up play an important role in reducing mortality. Recently, HER-2/neu in breast cancer has been routinely used to guide treatment of using Trastuzumab in less than 25-30% of patients. More new biomarkers will be still expected in the future to tailor treatments. However, there are still many obstacles in developing clinically useful biomarker tests for clinical practice. A lack of specificity of tumor markers and lack of sensitivity of testing systems have been noticed, which limit their clinical use. Finding biomarkers for breast cancer could allow physicians to identify individuals who are susceptible to certain types and stages of cancer to tailor preventive and therapeutic modalities based on the genotype and phenotype information. These biomarkers should be cancer specific, and sensitively detectable in a wide range of specimen(s) containing cancer-derived materials, including body fluids (plasma, serum, urine, saliva, etc.), tissues, and cell lines. This review highlights the new trends and approaches in breast cancer biomarker discovery, which could be potentially used for early diagnosis, development of new therapeutic approaches, and follow-up of patients.

0025 A comparative study of immunohistochemical staining and fluorescence in situ hybridization method of HER-2/neu in breast cancer

0025 A comparative study of immunohistochemical staining and fluorescence in situ hybridization method of HER-2/neu in breast cancer

P21 is a Prognostic Marker for Renal Cell Carcinoma: Implications for Novel Therapeutic Approaches

Kidney cancer, although relatively rare compared to other malignancies, is the most lethal of the common urological malignancies. Current treatments are inadequate as evidenced by a poor 5-year survival of patients with metastatic disease. Since there exists a significant disparity in the survival of patients with localized vs metastatic disease, efforts are under way to identify molecular markers of progression as well as targets for novel therapeutic approaches. The apoptosis and cell cycle regulatory protein, p21(waf1/cip1), has been investigated as a possible target in other cancers since it is involved in the repair and apoptotic response of normal and malignant cells to DNA damage. We performed immunohistochemical analysis of a tissue array of 366 patients for which we have data on grade, stage and survival. We found that nuclear p21 is most highly expressed in collecting duct carcinoma and lowest in oncocytoma. Cytosolic p21 staining was highest in oncocytoma. In clear cell renal cell carcinoma p21 has prognostic value, which is a function of whether patients have localized or metastatic disease at diagnosis, suggesting the existence of 2 discrete classes of this disease. In localized disease higher levels of nuclear p21 were associated with a better prognosis, but in patients with metastatic disease at diagnosis higher levels of nuclear and cytosolic p21 were associated with worse survival. Based on our findings p21 may be useful in prognostication, and it may have a role in the differing biological behaviors of localized and metastatic renal cell carcinoma.

Mechanisms of Tumor Regression and Resistance to Estrogen Deprivation and Fulvestrant in a Model of Estrogen Receptor–Positive, HER-2/neu-Positive Breast Cancer

HER-2/neu in breast cancer is associated with tamoxifen resistance, but little data exist on its interaction with estrogen deprivation or fulvestrant. Here, we used an in vivo xenograft model of estrogen receptor (ER)-positive breast cancer with HER-2/neu overexpression (MCF7/HER-2/neu-18) to investigate mechanisms of growth inhibition and treatment resistance. MCF7/HER-2/neu-18 tumors were growth inhibited by estrogen deprivation and with fulvestrant, but resistance developed in 2 to 3 months. Inhibited tumors had reductions in ER, insulin-like growth factor-I receptor (IGF-IR), phosphorylated HER-2/neu (p-HER-2/neu), and phosphorylated p42/44 mitogen-activated protein kinase (p-MAPK). p27 was increased especially in tumors sensitive to estrogen deprivation. Tumors with acquired resistance to these therapies had complete loss of ER, increased p-HER-2/neu, increased p-MAPK, and reduced p27. In contrast, IGF-IR and phosphorylated AKT (p-AKT) levels were markedly reduced in these resistant tumors. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib, which can block EGFR/HER-2/neu signaling, significantly delayed the emergence of resistance to both estrogen deprivation and fulvestrant. Levels of p-MAPK and p-AKT decreased with gefitinib, whereas high ER levels were restored. Eventually, however, tumors progressed in mice treated with gefitinib combined with estrogen deprivation or fulvestrant accompanied again by loss of ER and IGF-IR, increased p-HER-2/neu, high p-MAPK, and now increased p-AKT. Thus, estrogen deprivation and fulvestrant can effectively inhibit HER-2/neu-overexpressing tumors but resistance develops quickly. EGFR/HER-2/neu inhibitors can delay resistance, but reactivation of HER-2/neu and signaling through AKT leads to tumor regrowth. Combining endocrine therapy with EGFR/HER-2/neu inhibitors should be tested in clinical breast cancer, but a more complete blockade of EGFR/HER-2/neu may be optimal.

Microarray-Assisted Pathway Analysis Identifies Mitogen-Activated Protein Kinase Signaling as a Mediator of Resistance to the Green Tea Polyphenol Epigallocatechin 3-Gallate in Her-2/neu–Overexpressing Breast Cancer Cells

Overexpression of the epidermal growth factor receptor family member Her-2/neu in breast cancer leads to autophosphorylation of the receptor and induction of multiple downstream signaling pathways, including the Akt kinase to nuclear factor-kappaB (NF-kappaB) cascade that is associated with poor prognosis. Previously, we showed that the green tea polyphenol epigallocatechin 3-gallate (EGCG) inhibits growth of NF639 Her-2/neu-driven breast cancer cells via reducing receptor autophosphorylation and downstream Akt and NF-kappaB activities. Interestingly, upon prolonged culture in the presence of EGCG, cells resistant to the polyphenol could be isolated. Here, we report that resistant cells have lost tyrosine phosphorylation on the Her-2/neu receptor. Surprisingly, they displayed elevated NF-kappaB activity, and inhibition of this activity sensitized cells to EGCG. Data from microarray studies of the original and resistant NF639 populations of cells were subjected to Gene Set Enrichment Analysis pathway assessment, which revealed that the mitogen activated protein kinase (MAPK) pathway was activated in the resistant cells. Treatment of the resistant cells with the MAPK inhibitor U0216 reduced growth in soft agar and invasive phenotype, whereas the combination of EGCG and U0216 resulted in cells with a cobblestone epithelial phenotype. Thus, activation of the MAPK pathway mediates resistance to EGCG.

The expression level and clinical signification of soluble HER-2/neu in breast cancer

目的 分析乳腺癌血清可溶性HER-2/neu水平并探讨其临床意义.方法用ELISA方法分析105例乳腺癌患者、24例乳腺良性疾病及30名健康体检者血清可溶性HER-2/neu水平,并用免疫组化(IHC)方法分析乳腺癌组织切片中癌细胞的着色情况.结果乳腺癌患者血清中可溶性HER-2/neu水平与正常对照和良性乳腺疾病相比,差异有统计学意义(P<0.05).随病程进展乳腺癌患者可溶性HER-2/neu的阳性率逐步升高,Ⅲ+Ⅳ期的阳性率(63.3 %) 与Ⅰ期(7.7 %)或Ⅱ期阳性率(14.5 %)相比,差异有统计学意义(P<0.05);发生转移的乳腺癌患者可溶性HER-2/neu的阳性率(37.5 %)与未转移患者(6.1 %)相比,差异有统计学意义(P<0.05).血清HER-2/neu水平与IHC结果有显著正相关(P<0.05).结论检测血清可溶性HER-2/neu水平可弥补免疫组化的不足,在乳腺癌监测随访、疗效观察尤其是用Herceptin治疗后的疗效观察中发挥其独到的作用。

Long-term prognostic significance of HER-2/neu in untreated node-negative breast cancer depends on the method of testing

IntroductionThe prognostic significance of HER-2/neu in breast cancer is a matter of controversy. We have performed a study in 101 node-negative breast cancer patients with long-term follow-up not treated in the adjuvant setting, and analysed the prognostic significance of immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH), both separately and in combination, in comparison with traditional prognostic factors.MethodsOverexpression was classified semiquantitatively according to a score (0 to 3+) (HER-2_SCO). FISH was used to analyse HER2/neu amplification (HER-2_AMP). Patients classified 2+ by IHC were examined with FISH for amplification (HER-2_ALG). Patients with 3+ overexpression as well as amplification of HER-2/neu were positive for the combined variable HER2_COM. These variables were compared with tumour size, histological grade and hormone receptor status.ResultsHER-2_SCO was 3+ in 20% of all tumours. HER-2_ALG was positive in 22% and amplification (HER-2_AMP) was found in 17% of all tumours. Eleven percent of the tumours showed simultaneous 3+ overexpression and amplification. Only histological grade (relative risk [RR] 3.22, 95% confidence interval [CI] 1.73–5.99, P = 0.0002) and HER-2_AMP (RR 2.47, 95% CI 1.12–5.48, P = 0.026) were significant for disease-free survival in multivariate analysis. For overall survival, both histological grade (RR 3.89, 95% CI 1.77–8.55, P = 0.0007) and HER-2_AMP (RR 3.08, 95% CI 1.24–7.66, P = 0.016) retained their independent significance.ConclusionThe prognostic significance of HER-2/neu in node-negative breast cancer depends on the method of testing: only the amplification of HER-2/neu is an independent prognostic factor for the long-term prognosis of untreated node-negative breast cancer.

Putting the rap on Akt.

The protein kinase Akt is activated in a wide variety of cancers, and this activation results in enhanced resistance to apoptosis through multiple mechanisms. This article reviews the control of Akt activation by the opposing actions of the oncogene phosphoinositide 3-kinase (PI3-K) and the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10. The activation of Akt by transforming mutations, such as the amplification of HER-2/neu in breast cancer and the formation of the BCR/ABL fusion gene in chronic myelogenous leukemia, seems to be essential for the transforming activity of these oncogenes. We discuss several of the proposed mechanisms for the antiapoptotic effect of activated Akt, including the inhibition of the proapoptotic protein Bad, downregulation of death receptors, and enhancement of the glycolytic rate. Increased glycolysis is seen in many malignancies and forms the basis for the increasing use of positron emission tomography imaging for diagnosis and staging. Finally, we discuss rapamycin and its analogs, which are now in trials as antineoplastic therapy; these agents show particular promise in tumors in which Akt has been activated.

Clinical Utility of Serum HER2/ neu in Breast Cancer

Clinical Utility of Serum HER2/ neu in Breast Cancer

HER-2/neu overexpression and its effect on survival in solid tumors

9559 Background: Overexpression of HER-2/neu in breast cancer is associated with an adverse outcome. Little definitive data exists in other solid tumors. We studied the prevalence and predictive role of overexpression of HER-2/neu in >1200 samples obtained from patients with extensive stage small cell lung cancer (ESSCLC), malignant melanoma, pancreatic carcinoma, hepatocellular carcinoma, malignant brain tumors and soft tissue sarcomas (STS). Methods: HER-2/neu overexpression was assessed by immunohistochemistry (IHC) (DAKO Hercep test) performed on archival paraffin-embedded tissue specimens. A trained pathologist, who was blinded from the clinical history, interpreted all the results. An IHC score of >/= 2+ was considered positive for overexpression. Results: HER-2/neu overexpression by tumor type and its effects on survival are shown in Table 1. Studying large cohorts of patients with pancreatic adenocarcinoma and STS [except malignant fibrous histiocytoma (MFH), dermatofibrosarcoma (DFS) and carcinosarcomas (CS)] did not reveal a role for HER-2/neu testing. However in ESSCLC, the median survival for patients who were HER-2/neu +ve was 8 months (range: 1–25.5) while that in the HER-2/neu -ve group was 16 months (range: 2–34) (p<0.001, Mann Whitney U test). Furthermore, amongst patients with glioblastoma multiforme (GBM), median survival for patients who were HER-2/neu +ve was 4 months compared to 8 months in those who were HER-2/neu -ve. In addition, HER-2/neu overexpression increased the odds of early mortality (<3 months) (p<0.01). Conclusions: HER-2/neu overexpression seems to be associated with a poor prognosis in ESSCLC, STS and GBM. HER-2/neu overexpression is not uniform in all STS. Unlike other sarcomas, MFH, DFS and CS are more likely to overexpress HER-2/neu. HER-2/neu overexpression is not seen/has no clinical value in hepatocellular carcinoma, pancreatic adenocarcinoma or malignant melanoma. No significant financial relationships to disclose.

FISH for HER-2/neu in breast cancer: Standardization makes the difference!

Overexpression of HER-2/neu oncogene in breast cancer patients is correlated with disease free survival (DFS) and overall survival (OS). The most commonly used methods for the detection of HER-2/neu status are immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). However, therse is a lot of controversy with regard to the best method. Most of the FISH studies chose arbitrary cut-off levels for positive results (10%) and had no validation. In order to address these issues, we designed a pilot study of 38 samples with known IHC status representing all 4 categories. FISH was performed using Vysis Pathvysion probe. For validation, 5 cases of reduction mammoplasty were analyzed using same protocols. Our results showed significant discordance between FISH and IHC. The rate of discordance was much higher in the 0, 1+, and 2+ categories compared to published literature. This could be due to the lower cut-off rates for positive amplification established by validation in our study (5.7% vs 10%). Our analysis showed that FISH positive and IHC negative patients have a poor prognosis in terms of DFS and OS compared to FISH negative and IHC negative patients. Further, our results also showed that IHC in comparison to FISH has a comparable specificity (98%), but has a very low sensitivity (46%). Based on these results, we consider FISH to be the gold standard for detecting HER-2/neu status in breast cancer.

Cytoplasmic p21WAF1/CIP1 expression is correlated with HER-2/ neu in breast cancer and is an independent predictor of prognosis.

HER-2 (c-erbB2/Neu) predicts the prognosis of and may influence treatment responses in breast cancer. HER-2 activity induces the cytoplasmic location of p21WAFI/CIPI in cell culture, accompanied by resistance to apoptosis. p21WAFI/CIPI is a cyclin-dependent kinase inhibitor activated by p53 to produce cell cycle arrest in association with nuclear localisation of p21WAFI/CIPI. We previously showed that higher levels of cytoplasmic p21WAFI/CIPI in breast cancers predicted reduced survival at 5 years. The present study examined HER-2 and p21WAFI/CIPI expression in a series of breast cancers with up to 9 years of follow-up, to evaluate whether in vitro findings were related to clinical data and the effect on outcome. The CB11 anti-HER2 monoclonal antibody and the DAKO Envision Plus system were used to evaluate HER-2 expression in 73 patients. p21WAFI/CIPI staining was performed as described previously using the mouse monoclonal antibody Ab-1 (Calbiochem, Cambridge, MA, USA). HER-2 was evaluable in 67 patients and was expressed in 19% of cases, predicting reduced overall survival (P = 0.02) and reduced relapse-free survival (P = 0.004; Cox regression model). HER-2-positive tumours showed proportionately higher cytoplasmic p21WAFI/CIPI staining using an intensity distribution score (median, 95) compared with HER-2-negative cancers (median, 47) (P = 0.005). There was a much weaker association between nuclear p21WAFI/CIPI and HER-2 expression (P = 0.05), suggesting an inverse relationship between nuclear p21WAF1/CIP1 and HER-2. This study highlights a new pathway by which HER-2 may modify cancer behaviour. HER-2 as a predictor of poor prognosis may partly relate to its ability to influence the relocalisation of p21WAFI/CIPI from the nucleus to the cytoplasm, resulting in a loss of p21WAFI/CIPItumour suppressor functions. Cytoplasmic p21WAFI/CIPI may be a surrogate marker of functional HER-2 in vivo.

Dysregulation of cellular signaling by HER2 /neu in breast cancer

Human epidermal growth factor receptor-2 (HER2/ neu; erbB2) belongs to a family of four transmembrane receptor tyrosine kinases involved in signal transduction pathways that regulate cell growth and proliferation. Amplification or overexpression of HER2/ neu occurs in about 30% of human breast and ovarian cancers and is associated with a poor clinical outcome, including short survival time and short time to relapse. Recent advances in our understanding of HER2/ neu signaling pathways have greatly increased our knowledge of breast cancer tumorigenesis and have provided new targets for treating breast and ovarian tumors that overexpress HER2/ neu. This review will focus on the signaling network mediated by HER2/ neu in breast cancer and discuss our understanding of these pathways, which seem to be particularly important in mediating cell survival and growth under a wide variety of circumstances in breast cancer.