The tyrosine kinase receptor EphB4 and its ligand ephrin-B2 interact through cell-to-cell contacts. Upon interaction, EphB4 transmits bidirectional signals. A forward signal inside EphB4-expressing cells is believed to suppress tumor growth, while inside the ephrin-expressing cells, an oncogenic reverse signal arises. In breast cancer cells with a high EphB4 receptor expression the forward signal is low, in part due to the low expression of the ligand ephrin-B2. Therefore, we hypothesized that by re-introducing the ligand in EphB4-positive cells, tumor suppression could be induced by the stimulation of the forward signal. This question was addressed in vitro by the stable lentiviral infection of breast cancer cells with either wild-type EFNB2 or with a mutant EFNB2-5F, unable to transmit reverse signaling. Furthermore, we investigated ephrin-B and EphB4 protein expression in 216 paraffin-embedded tumors using immunohistochemistry. The in vitro results indicated that ephrin-B2 expression was associated with a lower cell proliferation, migration and motility compared with the control cells. These effects were more pronounced when the cells lacked the ability to transmit the reverse signal (B2-5F). In clinical material, ephrin-B protein expression was associated with a positive estrogen receptor (ER) status, a low HER-2 expression and was negatively associated with Nottingham histologic grade (NHG) III. Ephrin-B expression indicated a good prognosis, whereas EphB4 expression was associated with a shorter metastasis-free survival in univariate and multivariate analysis. Furthermore, the prognostic value of EFNB2 and EPHB4 was confirmed at the gene expression level in public datasets. Thus, on the whole, the findings of this study suggest that ephrin-B2 expression is associated with less proliferation and lower motility of breast cancer cells and with a longer patient survival in breast cancer.
The majority of breast cancer tumors are estrogen receptor-positive (ER+) and can be treated with endocrine therapy. However, certain patients may exhibit a good prognosis without systemic treatment. The aim of the present study was to identify novel prognostic factors for patients with ER+ breast cancer tumors using gene copy data, and to investigate if these factors have prognostic value in subgroups categorized by progesterone receptor status (PR). Public data, including the whole genome gene copy data of 199 systemically untreated patients with ER+ tumors, were utilized in the present study. To assess prognostic value, patients were divided into two groups using the median gene copy number as a cut-off for the SNPs that were the most variable. One SNP was identified, which indicated that the Ras-related protein Rab-6C (RAB6C) gene may exhibit prognostic significance. Therefore, RAB6C protein expression was subsequently investigated in a second independent cohort, consisting of 469 systematically untreated patients (of which 310 were ER+) who received long term follow-up. In the public data set, a distant recurrence risk reduction of 55% was determined for copy numbers above the median value of RAB6C compared with numbers below [multivariable adjusted hazard ratio (HR), 0.45; 95% CI 0.28–0.72; P=0.001)]. It was also more pronounced in the ER+/PR− subgroup (HR, 0.15; 95% CI, 0.05–0.46; P=0.001). In the second cohort, patients of the ER+/PR− subgroup who exhibited high RAB6C expression had a reduced distant recurrence risk (HR, 0.17; 95% CI, 0.05–0.60; P=0.006). However, this was not identified among ER+/PR+ tumors (HR, 1.31; 95% CI, 0.69–2.48; P=0.41). The results of the present study indicated that RAB6C serves as an independent prognostic factor of distant recurrence risk in systemically untreated patients with an ER+/PR− tumor.
Over the last few decades, improved and more individualized treatment has contributed to the increased survival rate of patients with breast cancer. However, certain patients may receive excessive treatment resulting in undesired side effects. In a previous study, it was demonstrated that systemically untreated patients with estrogen receptor (ER)-positive/progesterone receptor (PR)-negative tumors with high Ras-related protein Rab-6C (RAB6C) expression levels (RAB6C +) had prolonged distant recurrence-free survival compared with that of patients exhibiting low RAB6C (RAB6C-)-expressing tumors. The aim of the present study was to investigate whether RAB6C predicts the effectiveness of tamoxifen treatment. The present study used a dataset comprising 486 female patients with ER + tumors from a randomized study conducted by the Stockholm Breast Cancer Study Group between November 1976 and August 1990. The patients were considered as low-risk if their tumor size was ≤30 mm and their lymph node status was negative. Patients were followed up until distant recurrence, mortality or when 25 years after randomization was achieved, whichever occurred first. For patients with ER + /PR-/RAB6C + tumors, prolonged distant recurrence-free survival could not be observed if the patients were treated with tamoxifen [hazard ratio (HR), 1.82; 95% confidence interval (CI), 0.69-4.79; P= 0.23], whereas patients with ER + /PR-/RAB6Ctumors had 75% reduced distant recurrence risk (HR, 0.25; 95% CI, 0.09-0.70; P=0.008). In the ER + /PR + subgroup, patients with RAB6Cand RAB6C + tumors benefited from tamoxifen treatment, though it was most evident in the RAB6C + group (HR, 0.27; 95% CI, 0.13-0.58; P= 0.001). The results of the present study indicated that, for patients with ER + /PRtumors, those with low RAB6C expression benefited from tamoxifen treatment, whereas no benefit was observed in patients with high RAB6C levels.
The inositol hexakisphosphate kinase ( IP6K ) 1 and 2 genes are localized at 3p21.31, a highly altered gene-dense chromosomal region in cancer. The IP6Ks convert IP6 to IP7, which inhibits activation of the tumor-promoting PI3K/Akt/mTOR signaling pathway. IP6K2 has been suggested to be involved in p53-induced apoptosis, while IP6K1 may stimulate tumor growth and migration. The present study aimed to elucidate the role of the two IP6Ks in predicting outcome in patients with breast cancer. To the best of our knowledge, the role of IP6K was analyzed for the first time in tumors from three cohorts of patients with breast cancer; one Swedish low-risk cohort, one Dutch cohort and the TCGA dataset. Analyses of gene -and protein expression and subcellular localization were included. IP6K2 gene expression was associated with ER positivity and nuclear p-Akt. Improved prognosis was detected with high IP6K2 gene expression compared with low IP6K2 gene expression in systemically untreated patients in the Swedish low-risk and Dutch cohorts. In the TCGA dataset, IP6K2 prognostic value was significant when selecting for tumors with wild-type TP53 . A multivariable analysis testing IP6K2 against other cancer-related genes at 3p.21.31, including IP6K1 and clinical biomarkers, revealed that IP6K2 was associated with decreased risk of distant recurrence. IP6K1 was associated with increased risk of distant recurrence in the multivariable test and protein analysis revealed trends of worse prognosis with high IP6K1 in the cytoplasm. The expression levels of IP6K1 and IP6K2 were associated to a high extent; however, a diverging prognostic value of the two genes was observed in breast cancer. The present data suggest that IP6K2 can be a favorable prognostic factor, while IP6K1 may not be.
The PIK3CA gene, encoding the p110α catalytic subunit of PI 3-kinase (PI3K), is mutated in more than 30% of breast cancers. Most mutations concentrate to the hotspots E542K and E545K and H1047R and are associated with hyperactivation of the phosphatidylinositol 3′-kinase/Akt pathway in vitro. The estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) (ER+/HER2-) breast cancers stand for more than 40% of the PIK3CA mutations where these constitute a new therapeutic target for endocrine-treatment resistant advanced breast cancers. Although PIK3CA is an oncogene, its mutations are associated with good prognosis. Here, we explored the prognostic and predictive role of PIK3CA hotspot mutations for low-risk postmenopausal breast cancer patients randomized to receive tamoxifen vs. no systemic treatment, followed for over 25 years and with extensive clinical records. Mutation analysis was performed using formalin-fixed paraffin-embedded tumors with digital droplet PCR (ddPCR). PIK3CA mutations were present in 35,6% of patients, predominantly within the ER+/HER2- subtype (49,8%) compared with the HER2+ and TNBC subtypes. The most frequent mutation found in all patients was H1047R (18%) followed by E545K (14%) and E542K (6%). Significant associations were found between all hotspot mutations and low grade, positive progesterone receptor (PR) expression, HER2 negative status, low Ki-67 (proliferation marker), and high expression score of a PIK3CA-mutation-associated gene module. Moreover, PIK3CA mutations were often found in patients with ultralow risk to develop distant recurrences according to the 70-gene signature. All PIK3CA mutations were coupled with longer distant recurrence-free interval (DRFI) in all patients in univariate and multivariable analysis after adjusting for tumor size, receptor status (ER, PR, HER2), tumor grade, Ki-67 and tamoxifen: HR multivariable (95% CI)=0.53 (0.28-0.98). In agreement with our previous results, PIK3CA mutations indicated good prognosis for patients with highly proliferative tumors (Ki-67>15%): H.R multivariable (95% CI)=0.15 (0.03-0.69) and high risk by the 70-gene signature: HR multivariable (95% CI)=0.14 (0.03-0.61) but not for low proliferative tumors (Ki-67<15%). In fact, PIK3CA mutations indicated adverse prognosis within those patients with ultralow risk where the registered survival was 100% in presence of the PIK3CA wild type genotype. PIK3CA mutations did not have predictive value for tamoxifen. In conclusion, PIK3CA mutations predominate within the ER+/HER2- subtype, are coupled with good clinical markers and longer DRFI in all patients and especially among aggressive tumors but not in ultralow risk patients. Further investigation will be needed to decipher the role of PIK3CA in patients with ultralow risk or indolent tumors who may present long-term relapses and specially benefit from PI3K inhibition. Citation Format: Carolin Jönsson, Zeinab Alkashaf, Josefine Sandström, Annelie Johansson, Tommy Fornander, Linda S. Lindström, Gizeh Perez Tenorio. PIK3CA hotspot mutations as biomarkers for prognosis and treatment prediction in low-risk postmenopausal breast cancer patients [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B027.
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