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Background/aim: The fibroblast growth factor receptor (FGFR) signaling pathway is abnormally activated in human cancers, including breast cancer. Therefore, targeting the FGFR signaling pathway is a potent strategy to treat breast cancer. The purpose of this study was to find drugs that could increase sensitivity to FGFR inhibitor effects in BT-474 breast cancer cells, and to investigate the combined effects and underlying mechanisms of these combinations for BT-474 breast cancer cell survival., Materials and Methods: Cell viability was measured by MTT assay. Protein expression was determined by western blot analysis. mRNA expression was detected by Real-time PCR. Drug synergy effect was determined by isobologram analysis., Results: Nebivolol, a third generation β1-blocker, synergistically increased the sensitivity of BT-474 breast cancer cells to the potent and selective FGFR inhibitors erdafitinib (JNJ-42756493) and AZD4547. A combination of nebivolol and erdafitinib markedly reduced AKT activation. Suppression of AKT activation using specific siRNA and a selective inhibitor further enhanced cell sensitivity to combined treatment with nebivolol and erdafitinib, whereas SC79, a potent activator of AKT, reduced cell sensitivity to nebivolol and erdafitinib., Conclusion: Enhanced sensitivity of BT-474 breast cancer cells to nebivolol and erdafitinib was probably associated with down-regulation of AKT activation. Combined treatment with nebivolol and erdafitinib is a promising strategy for breast cancer treatment., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Although endocrine therapy with tamoxifen has improved survival in breast cancer patients, resistance to this therapy remains one of the major causes of breast cancer mortality. In the present study, we found that the expression level of YAP/TAZ in tamoxifen-resistant MCF7 (MCF7-TR) breast cancer cells was significantly increased compared with that in MCF7 cells. Knockdown of YAP/TAZ with siRNA sensitized MCF7-TR cells to tamoxifen. Furthermore, siRNA targeting PSAT1, a downstream effector of YAP/TAZ, enhanced sensitivity to tamoxifen in MCF7-TR cells. Additionally, mTORC1 activity and survivin expression were significantly decreased during cell death induced by combination treatment with YAP/TAZ or PSAT1 siRNA and tamoxifen. In conclusion, targeting the YAP/TAZ-PSAT1 axis could sensitize tamoxifen-resistant MCF7 breast cancer cells by modulating the mTORC1-survivin axis., Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Invasive breast carcinoma with a choriocarcinomatous pattern (IBC-CP) is extremely rare, and its molecular basis is yet unclear. The choriocarcinomatous pattern is characterized by the biphasic arrangement of multinucleated syncytiotrophoblast-like cells around clusters of monotypic tumor cells in a hemorrhagic background, along with β-human chorionic gonadotropin (β-hCG) expression. The differentiation of IBC-CP from metastatic choriocarcinoma of the breast (MC-B) is difficult due to the histologic similarity., Methods: Based on a literature review and our own case, the clinicopathologic differences between IBC-CP patients (n = 17) and MC-B patients (n = 8) were analyzed. Moreover, in our case of IBC-CP, next-generation sequencing (NGS) comparative analysis was conducted for both choriocarcinomatous and invasive breast carcinoma (IBC) components., Results: Compared to the MC-B patients, the IBC-CP patients were older (p < 0.001) and less frequently had past histories of gestational trophoblastic disease/pregnancy/abortion (p = 0.001) and distant metastases (p = 0.005). Our case, a 49-year-old female patient, presented with masses in the right breast and axilla. Following neoadjuvant chemotherapy, a radical mastectomy found an 8.5-cm-sized tumor. Microscopically, multinucleated syncytiotrophoblast-like cells were observed around mononuclear tumor cells with hemorrhage and necrosis. Some tumor cells showed β-hCG immunopositivity, which was compatible with IBC-CP. NGS results showed a missense mutation in exon 5 of the TP53 gene in both the choriocarcinomatous and IBC components. Meanwhile, copy number loss in the PTEN gene was only identified in the choriocarcinomatous components., Conclusion: The present IBC-CP case is triple-negative breast cancer with TP53 mutation. The PTEN gene may be associated with choriocarcinomatous differentiation. Obtaining a medical history is mandatory to exclude metastatic lesions., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Background/aim: Rictor is an adaptor protein essential for mTORC2, which regulates cell growth and survival. The aim of this study was to identify microRNAs (miR) that down-regulate Rictor and investigate their function on breast cancer cell survival., Materials and Methods: Trypan blue assay, MTT assay, polymerase chain reaction analysis, luciferase reporter assay and western blot analysis were carried out in breast cancer cell lines HCC1954, MDA-MB-231, SK-BR-3, and BT474., Results: miR-3188 overexpression suppressed the expression of Rictor and inhibited cell viability in HCC1954 and MDA-MB-231, highly Rictor-expressing breast cancer cells. In addition, miR-3188 overexpression decreased the protein level of p-AKT at Ser473, a substrate of mTORC2. Moreover, miRNA-3188 overexpression sensitized breast cancer cells to ionizing radiation (IR) by down-regulating Rictor and p-AKT., Conclusion: miR-3188 enhances IR sensitivity by affecting the mTORC2/AKT signalling pathway by altering the expression of Rictor, which could be a promising therapeutic strategy for the future treatment of breast cancer., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Peritumoral edema (PE) of breast cancer at T2-weighted MR images is considered a poor prognostic sign and may represent the microenvironment surrounding the tumor; however, its histopathological mechanism remains unclear. The purpose of the study was to identify and describe detailed histopathological characteristics associated with PE at preoperative breast MRI in breast cancer patients. This retrospective study included breast cancer patients who had undergone preoperative MRI and surgery between January 2011 and December 2012. Two radiologists determined the presence of PE in consensus based on the signal intensity surrounding the tumor at T2-weighted images. The following detailed histopathological characteristics were reviewed by two breast pathologists using four-tiered grades; lymphovascular invasion, vessel ectasia, stromal fibrosis, growth pattern, and tumor budding. Tumor necrosis and tumor infiltrating lymphocytes were assessed using a percent scale. Baseline clinicopathological characteristics, including age and histologic grade, were collected. The associations between detailed histopathologic characteristics and PE were examined using multivariable logistic regression with odds ratio (OR) calculation. A total of 136 women (median age, 49 ± 9 years) were assessed; among them 34 (25.0%) had PE. After adjustment of baseline clinicopathological characteristics that were significantly associated with PE (age, T stage, N stage, histologic grade, and subtype, all Ps < 0.05), lymphovascular invasion (P = 0.009), vessel ectasia (P = 0.021), stromal fibrosis (P = 0.024), growth pattern (P = 0.036), and tumor necrosis (P < 0.001) were also associated with PE. In comparison with patients without PE, patients with PE were more likely to have a higher degree of lymphovascular invasion (OR, 2.9), vessel ectasia (OR, 3.3), stromal fibrosis (OR, 2.5), lesser degree of infiltrative growth pattern (OR, 0.4), and higher portion of tumor necrosis (OR, 1.4). PE of breast cancer at MRI is associated with detailed histopathological characteristics of lymphovascular invasion, vessel ectasia, stromal fibrosis, growth pattern, and tumor necrosis, suggesting a relevance for tumor microenvironment.

Background: There is no proven primary preventive strategy for doxorubicin-induced subclinical cardiotoxicity (DISC), especially among patients without a cardiovascular (CV) risk. We investigated the primary preventive effect on DISC of the concomitant use of angiotensin receptor blockers (ARBs) or beta-blockers (BBs), especially among breast cancer patients without a CV risk., Methods: A total of 385 patients who were scheduled for doxorubicin chemotherapy were screened. Among them, 195 patients of the study populations were included and were randomly divided into two groups [candesartan 4 mg q.d. vs. carvedilol 3.125 mg q.d.] and patients who were unwilling to take one of the medications were evaluated as controls. The primary outcomes were the incidence of early DISC (DISC developing within 6 months after chemotherapy), and late DISC (DISC developing only at least 12 months after chemotherapy)., Result: Compared with the control group (8 out of 43 patients (18.6%)), only the candesartan group (4 out of 82 patients (4.9%)) showed a significantly lower incidence of early DISC (p = 0.022). Compared with the control group, the candesartan group demonstrated a significantly reduced decrease in left ventricular ejection fraction (LVEF) throughout the study period [-1.0% vs. -3.00 (p < 0.001) at the first follow-up, -1.10% vs. -3.40(p = 0.009) at the second follow-up]., Conclusions: Among breast cancer patients without a CV risk treated with doxorubicin-containing chemotherapy, subclinical cardiotoxicity is prevalent and concomitant administration of low-dose candesartan might be effective to prevent an early decrease in LVEF. Further large-scale, randomized controlled trials will be needed to confirm our findings., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: Neck ultrasonography (US), computed tomography (CT), and 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) are all known to be useful imaging modalities for detecting supraclavicular lymph node (SCN) metastasis in breast cancer. The authors compared the diagnostic values of neck US, CT, and PET/CT in the detection of SCN metastasis in breast cancer., Methods: SCN metastases identified in neck US, CT, or PET/CT during follow-up visits of patients with breast cancer were pathologically confirmed with the use of US-guided fine-needle aspiration cytology. The clinicopathological factors of the patients were analyzed, and the statistical parameters including sensitivity, specificity, positive and negative predictive values, false-positive and false-negative rates, and accuracy of neck US, CT, and PET/CT were compared., Results: Among 32 cases of suspicious SCNs, 24 were pathologically confirmed as metastasis of breast cancer. The sensitivity of US + CT was 91.7%, which was the same as that of PET/CT, while the sensitivity rates of US alone and CT alone were 87.5% and 83.3%, respectively. Accuracy was 99.8% in PET/CT alone and 98.1% in US + CT. The false-negative rate was 0.1% in US + PET/CT, while it was 0.2% in PET/CT and US + CT, 0.3% in US alone and 0.4% in CT alone., Conclusion: PET/CT can be the first choice for detecting SCN metastases in breast cancer. However, if PET/CT is unavailable for any reason, US + CT could be a good second option to avoid false-negative results.

Purpose: To compare the image quality of acquired diffusion-weighted imaging (DWI) and computed DWI and evaluate the lesion detectability and likelihood of malignancy in these datasets., Materials and Methods: This prospective study was approved by our institutional review board. A total of 29 women (mean age, 43.5 years) underwent DWI between August 2018 and April 2019 for 32 breast cancers and 16 benign breast lesions. Three radiologists independently reviewed the acquired DWI with b-values of 1000 and 2000 s/mm2 (A-b1000 and A-b2000) and the computed DWI with a b-value of 2000 s/mm2 (C-b2000). Image quality was scored and compared between the three DWI datasets. Lesion detectability was recorded, and the lesion's likelihood for malignancy was scored using a five-point scale., Results: The A-b1000 images were superior to the A-b2000 and C-b2000 images in chest distinction, fat suppression, and overall image quality. The A-b2000 and C-b2000 images showed comparable scores for all image quality parameters. C-b2000 showed the highest values for lesion detection among all readers, although there was no statistical difference in sensitivity, specificity, positive predictive value, negative predictive value, and accuracy between the DWI datasets. The malignancy scores of the DWI images were not significantly different among the three readers., Conclusions: A-b1000 DWI is suitable for breast lesion evaluations, considering its better image quality and comparable diagnostic values compared to that of A-b2000 and C-b2000 images. The additional use of computed high b-value DWI may have the potential to increase the detectability of breast masses., Competing Interests: S.H.K. is funded by Reyon Pharmaceutical, Co., Ltd. (Seoul, Korea), with no other competing interests to disclose. This does not alter our adherence to PLOS ONE policies on data and materials sharing.

Background: The authors compared the clinical features between familial (non-hereditary) and hereditary breast cancer. And we also analyzed their oncologic outcomes to establish appropriate surveillance protocol for familial (non-hereditary) and hereditary breast cancer., Methods: Among 232 patients with breast cancer who were performed BRCA gene evaluation, twenty-eight patients were diagnosed as hereditary breast cancer with BRCA gene mutation and one-hundred and seventy-six patients were familial (non-hereditary) breast cancer. The clinical characteristics and oncologic outcomes were compared between two groups., Results: While the incidence of multifocality was higher in familial (non-hereditary) breast cancer group (p < 0.001), the bilaterality was higher in hereditary breast cancer group (p < 0.001). And the rate of pathologic complete remission was also significantly higher in hereditary breast cancer group (p = 0.030). The characteristics of tumor were different between familial (non-hereditary) breast cancer and hereditary breast cancer. The oncologic outcome was better in familial (non-hereditary) breast cancer group than hereditary breast cancer group except death., Conclusion: The clinical characteristics of familial (non-hereditary) breast cancer were different from those of hereditary breast cancer but similar to those of sporadic breast cancer. The prognosis of the familial (non-hereditary) breast cancer was significantly better than hereditary breast cancer., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interests., (Copyright © 2020. Published by Elsevier Taiwan LLC.)

Background: Preoperative breast magnetic resonance imaging (MRI) provides more information than mammography and ultrasonography for determining the surgical plan for patients with breast cancer. This study aimed to determine whether breast MRI is more useful for patients with ductal carcinoma in situ (DCIS) lesions than for those with invasive ductal carcinoma (IDC)., Methods: A total of 1113 patients with breast cancer underwent mammography, ultrasonography, and additional breast MRI before surgery. The patients were divided into 2 groups: DCIS (n = 199) and IDC (n = 914), and their clinicopathological characteristics and oncological outcomes were compared. Breast surgery was classified as follows: conventional breast-conserving surgery (Group 1), partial mastectomy with volume displacement (Group 2), partial mastectomy with volume replacement (Group 3), and total mastectomy with or without reconstruction (Group 4). The initial surgical plan (based on routine mammography and ultrasonography) and final surgical plan (after additional breast MRI) were compared between the 2 groups. The change in surgical plan was defined as group shifting between the initial and final surgical plans., Results: Changes (both increasing and decreasing) in surgical plans were more common in the DCIS group than in the IDC group (P <  0.001). These changes may be attributed to the increased extent of suspicious lesions on breast MRI, detection of additional daughter nodules, multifocality or multicentricity, and suspicious findings on mammography or ultrasonography but benign findings on breast MRI. Furthermore, the positive margin incidence in frozen biopsy was not different (P = 0.138)., Conclusions: Preoperative breast MRI may provide more information for determining the surgical plan for patients with DCIS than for those with IDC.

Background: Using the Latissimus dorsi (LD) muscle flap is one of the popular surgical technique for breast reconstruction. However, usually, long postoperative scar was remained on donor site which does not have disease. The authors applied the endoscopy-assisted surgery to harvest the LD muscle flap for breast reconstruction., Methods: From July 2018 to July 2019, five consecutive patients with breast cancer underwent partial mastectomy with endoscopy-assisted LD muscle flap reconstruction. The clinic-pathologic factors were analyzed and the cosmetic outcomes were assessed with breast shape, scarring of breast and back. A 4-6 cm of lateral incision (donor site scar) was designed and LD muscle was harvested under endoscopic surgery without gas inflation. And the harvested LD muscle was inserted for partial breast reconstruction after the cancer surgery was done., Results: Mean operative time was 116.4 min (range, 92-134) and there was no major postoperative complication. The satisfactory degree of cosmetic outcomes were shown better in patient's survey than that of surgeon's., Conclusions: The endoscopy-assisted LD muscle flap harvesting would be useful technique to eliminate a large donor site incision in partial breast reconstruction.

Rationale: Filling materials for partial defect of the breast have rarely been developed because of safety and durability., Patient Concerns: Two female patients (ages, 53 and 50 years) with breast cancer underwent partial mastectomy with sentinel lymph node biopsy., Diagnosis: Core needle biopsy revealed an invasive ductal carcinoma in both patients. Breast ultrasound showed hypoechoic nodules with irregular margins. Breast magnetic resonance imaging showed an irregularly shaped enhancing mass with duct extension in Patient 1 and irregularly shaped multifocal, enhancing masses with non-mass enhancement in Patient 2., Intervention: A combination method using acellular dermal matrix and oxidized regenerated cellulose was used for partial breast reconstruction. The safety and cosmetic outcomes were evaluated for both patients., Outcomes: There were no significant complications, and the breast shape and volume were well maintained, even 2 years after surgery. There was no postoperative tumor recurrence., Conclusion: The combination of acellular dermal matrix and oxidized regenerated cellulose for partial breast reconstruction can be a good option based on oncological safety and cosmetic outcome.

Background After publication of the findings of the American College of Surgeons Oncology Group Z1071 trial, sentinel lymph node biopsy (SLNB) has been increasingly performed in patients with breast cancer after neoadjuvant chemotherapy (NAC). Purpose To investigate the pretreatment breast MRI and clinical-pathologic characteristics associated with failed sentinel node identification after NAC in patients with breast cancer. Materials and Methods Patients who underwent SLNB after NAC between January 2015 and January 2019 were retrospectively identified. Two radiologists independently reviewed the characteristics of axillary nodes (number, perinodal infiltration, cortical thickness, and maximal diameter) at pretreatment breast MRI. The associations of the clinical-pathologic and imaging characteristics of the axillary nodes with sentinel node identification were assessed by using the χ 2 test and/or the χ 2 test for trend and multivariable logistic regression with odds ratio (OR) calculation. Results A total of 276 women (mean age ± standard deviation, 48 years ± 9; range, 27-68 years) were included. Sentinel nodes were identified in 252 of the 276 patients (91%). Multivariable analysis showed that higher (stage 3 or 4) clinical T stages (OR = 5.2, P = .004 for radiologist 1; OR = 4.6, P = .01 for radiologist 2), use of a single tracer (OR = 4.3, P = .04 for radiologist 1; OR = 3.9, P = .046 for radiologist 2), a greater number (10 or more) of suspicious axillary nodes (OR = 11.5, P = .002 for radiologist 1; OR = 8.3, P = .01 for radiologist 2), and the presence of perinodal infiltration (OR = 7.0, P = .002 for radiologist 1; OR = 7.5, P = .003 for radiologist 2) were associated with failed sentinel node identification. Conclusion A greater number of suspicious axillary nodes and the presence of perinodal infiltration at pretreatment MRI, higher clinical T stages, and use of a single tracer were independently associated with failed sentinel node identification after neoadjuvant chemotherapy in patients with breast cancer. © RSNA, 2020 See also the editorial by Imbriaco in this issue.

Background/objective: Neoadjuvant chemotherapy (NAC) is a standard treatment for locally advanced breast cancer, especially for HER2-positive or triple negative breast cancer which shows good response to chemotherapy. However, because a result of biomarkers is, occasionally, changed after NAC, the treatment strategy should be differently applied for patients with locally advanced breast cancer. We compared the results of biomarkers before and after NAC to evaluate the association with disease prognosis and oncologic results., Methods: Fifty-seven patients with locally advanced breast cancer underwent NAC and the immunohistochemical (IHC) staining results were compared between before and after NAC. And the association between oncologic outcomes and biomarkers was analyzed., Results: Negative status of estrogen receptor (ER) was associated with locoregional recurrence and distant metastasis both before and after NAC (p = 0.021, 0.019; p = 0.018, 0.036). And the negative status of progesterone receptor (PR) and triple negative status before neoadjuvant chemotherapy were also associated with death and distant metastasis, respectively. However, the changes of biomarkers after NAC in breast cancer were not directly associated with any oncologic outcomes., Conclusion: The absence of ER in breast cancer before and after NAC would be a significant prognostic factor for local recurrence and distant metastasis. Therefore, the absence of ER should be considered as important factor in determining the treatment strategy., (Copyright © 2019. Published by Elsevier Taiwan LLC.)

Emerging evidence suggests that the mammalian target of rapamcyin (mTOR) pathway is associated with radio-resistance in cancer treatment. We hypothesised that phosphorylated ribosomal S6 kinase 1 (p-S6K1), a major downstream regulator of the mTOR pathway, may play a role in predicting radio-resistance. Therefore, we evaluated the association of p-S6K1 expression with radio-resistance in breast cancer cell lines and patients. During median follow-up of 33 (range, 0.1-111) months for 1770 primary breast cancer patients who underwent surgery, patients expressing p-S6K1 showed worse 10-year loco-regional recurrence-free survival (LRFS) compared to that of p-S6K1-negative patients after radiotherapy (93.4% vs. 97.7%, p = 0.015). Multivariate analysis revealed p-S6K1 expression as a predictor of radio-resistance (hazard ratio 7.9, 95% confidence interval 1.1-58.5, p = 0.04). In vitro, CD44 high /CD24 low MCF7 cells with a radioresistant phenotype expressed higher levels of p-S6K1 than control MCF7 cells. Furthermore, the combination of radiation with treatment of everolimus, an mTOR-S6K1 pathway inhibitor, sensitised CD44 high /CD24 low MCF7 cells to a greater extent than MCF7 cells. This study provides in vivo and in vitro evidence for p-S6K1 expression status as an important marker for predicting the resistance to radiotherapy and as a possible target for radio-sensitization in breast cancer patients.

Background/aim: Multigene profiling assays provide strong evidence for predicting the prognosis of breast cancer. In this study, we aimed to evaluate the clinical validation of the BCT score with various prognostic factors., Materials and Methods: A total of 133 cases of hormone receptor-positive, cT1N0 breast cancers were analyzed. Risk stratification using the BCT score (Low, n=105; High, n=28) was analyzed with Ki67 index, p53 mutation, Immunohistochemistry 4 (IHC4) score, Nottingham Prognostic Index (NPI) and online PREDICT., Results: Ki67 index and NPI showed strong correlations with risk stratification based on BCT scores. Although the IHC4 score and online PREDICT were not associated with BCT score, there was a significant tendency of association with the online PREDICT results as the time of overall survival was increasing., Conclusion: Risk classification based on BCT scores might have a clinical significance as a prognostic marker in hormone receptor-positive, HER2-negative, early breast cancer., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objectives: The purpose of this study was to investigate which feature of the breast-specific gamma imaging (BSGI) uptake in women who were recently diagnosed with breast cancer was associated with malignancy., Methods: Data on 231 newly diagnosed breast cancer patients who underwent preoperative BSGI were retrospectively reviewed. Feature analysis was done by classifying BSGI uptake into mass, non-mass, or focus/foci. Descriptors for mass, non-mass, or focus/foci were shape, distribution, number, and intensity. BSGI features of known malignancies and lesions that were additionally found by BSGI were correlated with mammographic breast density, histology, hormonal status, and clinical follow-up data obtained over at least 2 years., Results: Among 372 breast lesions from 231 patients, 241 malignancies had been pathologically confirmed prior to BSGI and 131 additional lesions were found on BSGI. Irregular shape was more predictive of malignancy than oval shape (p=0.004) in mass uptake. Linear/ductal distribution was more predictive of malignancy than focal, regional, and segmental distribution (p<0.05) in non-mass uptake. Mammographic breast density was not associated with BSGI features. The lesion to normal ratio (LNR) was higher in the postmenopausal patients than that in the premenopausal patients (p=0.003)., Conclusions: The feature analysis of radiotracer uptake in BSGI is useful in predicting whether breast lesions are malignant or benign., Key Points: • The feature analysis of BSGI uptake is useful in predicting malignancy. • Irregular shape was predictive of malignancy in mass uptake. • Linear/ductal distribution was predictive of malignancy in non-mass uptake.

Purpose: The purpose of this study was to evaluate how the reference fat position influenced the calculation of the sonoelastographic strain ratio., Methods: Three hundred fifty-eight breast masses (256 benign lesions and 102 malignant lesions) in 300 women (mean age 47.4 years; age range 17-82 years) who had been scheduled for a percutaneous needle biopsy or surgical excision were examined using B-mode ultrasonography and elastography. The sonoelastographic strain ratio was calculated twice per lesion; once by dividing the strain value of the fat near the mass by that of the mass (FLR 1) and once by dividing the strain value of the subcutaneous fat by that of the mass (FLR 2)., Results: Most (91.9 %) showed a difference of less than 0.5 between FLR 1 and FLR 2 values. Regardless of the position of reference fat, there was no statistically significant difference between the FLR 1 and FLR 2 values (p value = 0.077 and 0.0825, respectively). According to the pathology of the lesion, a difference between FLR 1 and FLR 2 less than 0.5 occurred in 95.3 % of the benign lesions and 84 % of the malignant lesions (p < 0.001)., Conclusions: The sonoelastographic strain ratio was not significantly affected by the position of reference fat.

Function of cellular prion protein (PrP(c)) in cancer progression has not been elucidated yet. Ectopic expression of PrP(c) increases the invasion and migration of breast cancer cell line, MCF-7 cells. Overexpressed PrP(c) increases matrix metalloprotease-9 (MMP-9) expression by enhancing association of NF-κB in promoter of MMP-9 gene and ERK signaling in MCF-7 cells. Whereas, silencing of PrP(c) by siRNA suppresses ERK activation and MMP-9 expression resulting the down-regulation of MD-MB231 cell migration and invasion. Overall, these results suggest that PrP(c) contribute the breast cancer invasion and migration via MMP-9., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: Early diagnosis of breast cancer in very young women (<30 years) is challenging and the characteristic imaging findings are not yet fully understood. We evaluated the imaging findings of breast cancer in very young women (<30 years) and to correlate them with clinicopathological features., Material and Methods: A total of 50 surgically confirmed breast cancers were included in our retrospective study. The medical records were reviewed and the radiological features were analyzed according to the new 5th edition of the ACR BI-RADS lexicon., Results: The breast cancers in our study population most commonly presented as a self-detected mass (74%), T2-3 stage (58%), histological grade III (52.3%) and ER-positive (80%) subtype. The most common finding was an irregular (87.5%) hyperdense (66.7%) mass with indistinct margins (50%) on mammography and an irregular (75.6%) indistinct (57.8%) hypoechoic/heterogeneous (77.8%) mass without a posterior acoustic feature (60%) on ultrasonography. MRI revealed an irregular shape (63.3%), irregular margins (43.3%), and heterogeneous enhancement (60%) with washout kinetics (69.4%). Mammographically, microcalcifications were correlated with the HER2-enriched type, and mass-type lesions were correlated with triple-negative cancer (p=0.04). An oval/round mass on ultrasound (p=0.005), rim enhancement (p=0.004) and intralesional T2 high signal intensity (p=0.04) on MRI were associated with the triple-negative type., Conclusions: On all imaging modalities, breast cancer in very young women usually presented as an irregular mass, and certain radiological features could be used for predicting the specific tumor type., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: To evaluate the sonographic features of invasive apocrine carcinoma (IAC) of the breast., Materials and Methods: This study included five pathologically proven cases of IAC, and their sonographic features were retrospectively analyzed according to the Breast Imaging Reporting and Data System (BI-RADS) lexicon., Results: All five lesions involved the left breast and were seen as irregularly shaped masses. All lesions, except one, had a parallel orientation to the chest wall. All five lesions showed noncircumscribed margins and heterogeneous echotexture; however, they showed various posterior features. One lesion had edema as an associated feature. Sonographic assessments were classified as BI-RADS category 4 in all five cases., Conclusion: Invasive apocrine carcinoma sonographic findings are difficult to differentiate from those of invasive ductal carcinoma of no special type.

Background: Elastographpy is a newly developed noninvasive imaging technique that uses ultrasound (US) to evaluate tissue stiffness. The interpretation of the same elastographic images may be variable according to reviewers. Because breast lesions are usually reported according to American College of Radiology Breast Imaging and Data System (ACR BI-RADS) lexicons and final category, we tried to compare observer variability between lexicons and final categorization of US BI-RADS and the elasticity score of US elastography., Methods: From April 2009 to February 2010, 1356 breast lesions in 1330 patients underwent ultrasound-guided core biopsy. Among them, 63 breast lesions in 55 patients (mean age, 45.7 years; range, 21-79 years) underwent both conventional ultrasound and elastography and were included in this study. Two radiologists independently performed conventional ultrasound and elastography, and another three observers reviewed conventional ultrasound images and elastography videos. Observers independently recorded the elasticity score for a 5-point scoring system proposed by Itoh et al., BI-RADS lexicons and final category using ultrasound BI-RADS. The histopathologic results were obtained and used as the reference standard. Interobserver variability was evaluated., Results: Of the 63 lesions, 42 (66.7 %) were benign, and 21 (33.3 %) were malignant. The highest value of concordance among all variables was achieved for the elasticity score (k = 0.59), followed by shape (k = 0.54), final category (k = 0.48), posterior acoustic features (k = 0.44), echogenecity and orientation (k = 0.43). The least concordances were margin (k = 0.26), lesion boundary (k = 0.29) and calcification (k = 0.3)., Conclusion: Elasticity score showed a higher level of interobserver agreement for the diagnosis of breast lesions than BI-RADS lexicons and final category.

Purpose: The time from puberty to the first pregnancy is known to be important for a woman's life-time breast cancer risk. Recent studies suggest that epigenetic mechanisms may involve pubertal maturation processes, which can affect the risk of breast cancer in later life. Epigenetic alterations are related to lipotropes (methionine, choline, folate, and vitamin B12), which are methyl donors and cofactors. However, the effects of pubertal supplementation of lipotropes in breast cancer remain largely unknown., Methods: Twenty female Sprague-Dawley rats, aged 6 weeks, were divided into two groups and fed a normal control diet or a lipotrope-fortified diet formulated to provide five times basal levels of lipotropes during puberty. All rats were injected intraperitoneally with N-nitroso-N-methylurea at 50 days of age to induce mammary tumors., Results: Tumor multiplicity and tumor volume decreased significantly as a result of lipotrope supplementation. Interestingly, quantitative RT-PCR revealed significantly decreased expression of histone deacetylase 1 (Hdac1) and DNA methyltransferase 1 (Dnmt1) genes in tumor tissues of the rats supplemented with lipotrope-fortified diet, suggesting that reduced risk of breast cancer can be attributed, at least in part, to decreased expression of these two genes., Conclusions: This study demonstrates that supplementation of lipotrope-fortified diet during puberty suppresses tumor growth, potentially through down-regulating Hdac1 and Dnmt1 gene expression. Our findings suggest that pubertal methyl diet plays an important role in the etiology of breast cancer, and further studies are warranted to develop preventative strategies against breast cancer.

Metformin, the most widely prescribed drug for treatment of type 2 diabetes, has been shown to exert significant anticancer effects. Hyperthermia has been known to kill cancer cells and enhance the efficacy of various anti-cancer drugs and radiotherapy. We investigated the combined effects of metformin and hyperthermia against MCF-7 and MDA-MB-231 human breast cancer cell, and MIA PaCa-2 human pancreatic cancer cells. Incubation of breast cancer cells with 0.5-10 mM metformin for 48 h caused significant clonogenic cell death. Culturing breast cancer cells with 30 µM metformin, clinically relevant plasma concentration of metformin, significantly reduced the survival of cancer cells. Importantly, metformin was preferentially cytotoxic to CD44(high)/CD24(low) cells of MCF-7 cells and, CD44(high)/CD24(high) cells of MIA PaCa-2 cells, which are known to be cancer stem cells (CSCs) of MCF-7 cells and MIA PaCa-2 cells, respectively. Heating at 42°C for 1 h was slightly toxic to both cancer cells and CSCs, and it markedly enhanced the efficacy of metformin to kill cancer cells and CSCs. Metformin has been reported to activate AMPK, thereby suppressing mTOR, which plays an important role for protein synthesis, cell cycle progression, and cell survival. For the first time, we show that hyperthermia activates AMPK and inactivates mTOR and its downstream effector S6K. Furthermore, hyperthermia potentiated the effect of metformin to activate AMPK and inactivate mTOR and S6K. Cell proliferation was markedly suppressed by metformin or combination of metformin and hyperthermia, which could be attributed to activation of AMPK leading to inactivation of mTOR. It is conclude that the effects of metformin against cancer cells including CSCs can be markedly enhanced by hyperthermia.

Epigenetic alterations have emerged as an important mechanism involved in tumorigenesis. The epigenetic impact of DNA methylation in various types of human cancer is not completely understood. Previously, we observed melatonin-induced differential expression of miRNA and miRNA-related genes in human breast cancer cell lines that indicated an anticancer effect of melatonin. In this report, we further characterized epigenetic changes in melatonin-exposed MCF-7 cells through the analysis of DNA methylation profiles in breast cancer cells to provide new insights into the potential mechanisms of the anticancer effect of melatonin. Microarray-based DNA methylation and gene expression profiling were carried out using human breast cancer cell lines. We further identified a number of mRNAs whose expression levels show an inverse correlation with DNA methylation levels. The mRNA expression levels and methylation status of candidate genes in melatonin-exposed cells were confirmed by real-time quantitative PCR and bisulfite PCR. This approach led to the detection of cancer-related genes, which were oncogenic genes, including EGR3 and POU4F2/Brn-3b were down-regulated, while the tumor suppressor gene, GPC3, was up-regulated by 1 nm melatonin-treated MCF-7 cells. Our results provide detailed insights into the DNA methylation patterns induced by melatonin and suggest a potential mechanism of the anticancer effect of aberrant DNA methylation in melatonin-treated breast cancer cells., (© 2012 John Wiley & Sons A/S.)

MicroRNAs (miRNAs) are small, noncoding RNAs that play a crucial role in regulation of gene expression. Recent studies have shown that miRNAs implicated in initiation and progression of various human cancers, including breast cancer and also analysis of miRNA expression profiles in cancer provide new insights into potential mechanisms of carcinogenesis. Melatonin, N-acetyl-5-methoxytryptamine, is synthesized by the pineal gland in response to the dark/light cycle and has been known to act as a synchronizer of the biological clock. Melatonin has a variety of therapeutic effects, such as immunomodulatory actions, anti-inflammatory effects, and antioxidant actions. Furthermore, melatonin is reported to have an anticancer function including suppression of the metabolism of tumor cells and induction of tumor suppressor genes in cancer cells, including breast cancer cells. In this study, we determined whether miRNAs play a role in regulation of various gene expression responses to melatonin in MCF-7 human breast cancer cells. We examined whole-genome miRNA and mRNA expression and found that 22 miRNAs were differentially expressed in melatonin-treated MCF-7 cells. We further identified a number of mRNAs whose expression level shows a high inverse correlation with miRNA expression. The Gene Ontology (GO) enrichment analysis and pathways analysis were performed for identification of the signaling pathways and biological processes affected by differential expression of miRNA and miRNA-related genes. Our findings suggested that melatonin may modulate miRNA and gene expression as an anticancer mechanism in human breast cancer cells., (© 2011 John Wiley & Sons A/S.)

Purpose: The aim of this study was to evaluate the imaging findings of invasive lobular carcinoma (ILC) compared to those of invasive ductal carcinoma (IDC)., Materials and Methods: The study included ILCs (n = 27) and IDCs (n = 85). Imaging findings were retrospectively evaluated, according to the BI-RADS lexicon. We compared the imaging findings, multiplicity, and magnetic resonance imaging (MRI) detection accuracy of ILC with those of IDC., Results: At mammography, normal findings and mass lesions were more frequent with ILCs (14.8% and 59.2%, respectively) than with IDCs (1.2% and 44.7%, respectively) (P = 0.009). With ultrasonography (US), posterior acoustic shadowing was more frequently seen in ILCs (59.2%) than in IDCs (15.8%) (P < 0.001). With MRI, both ILCs and IDCs most commonly appeared as a heterogeneously enhancing, irregular mass with a spiculated border. Multifocality was more frequently associated with ILCs (40.7%) than with IDCs (14.1% 1% 0.002). However, multicentricity and bilaterality were not different between the two groups. The sensitivity and specificity of MRI for the detection of multiplicity were 91.6% and 73.3%, respectively, for ILCs and 83.3% and 80.3%, respectively, for IDCs., Conclusion: Normal findings, mass lesions on mammography, and posterior acoustic shadowing on US were more frequently associated with ILCs than with IDCs. Multifocality was more prevalent with ILCs than with IDCs.

Aim: To estimate the acceptable compression ratio of full-field digital mammography (FFDM) using the Joint Photographic Experts Group (JPEG) 2000 compression algorithm., Materials and Methods: Eighty cases that included images of 40 masses (20 benign, 20 malignant) and 40 microcalcifications (20 benign, 20 malignant) were collected. The images were compressed to five different lossy ratios: 20:1, 40:1, 60:1, 80:1, and 100:1, and four radiologists independently determined whether the compressed group was distinguishable from the control group. The ratio of the compressed group that was rated indistinguishable from the control group was compared for each reviewer, and the results were analysed for agreements of three or more reviewers., Results: The ability to distinguish the compressed image from the control group is given as a range across the four reviewers: 0-1.3% (0/80 to 1/80) of the 20:1, 0-2.5% (0/80 to 2/80) of the 40:1, 5-7.5% (4/80 to 6/80) of the 60:1, 10-37.5% (8/80 to 30/80) of the 80:1, and 30-87.5% (24/80 to 70/80) of the 100:1. For three compression groups (20:1, 40:1, and 60:1), three or more reviewers agreed that there was a distinguishable difference for 0/80, 0/80, and 3/80 images, respectively. Thus, the compressed images do not differ significantly from the control group (p>0.05). However, the 80:1 and 100:1 compressed images were different for 9/80 and 29/80 images, respectively, which is significantly different from the control group (p<0.05)., Conclusion: The lossy 60:1 compression ratio for FFDM is visually identical to the control image and, therefore, potentially acceptable for primary interpretation., (Copyright © 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Dihydroavenanthramide D (DHAvD) is a synthetic analog to naturally occurring avenanthramide, which is the active component of oat. Previous study demonstrates that DHAvD strongly inhibits activation of nuclear factor-kappa B (NF-κB), which is a major component in cancer cell invasion. The present study investigated whether DHAvD can modulate MMP-9 expression and cell invasion in MCF-7 human breast cancer cells. MMP-9 expression and cell invasion in response to 12-O-tetradecanoylphorbol-13-acetate (TPA) was increased, whereas these inductions were muted by DHAvD. DHAvD also suppressed activation of mitogen-activated protein kinase (MAPK), and MAPK-mediated nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1) activations in TPA-treated MCF-7 cells. The results indicate that DHAvD-mediated inhibition of TPA-induced MMP-9 expression and cell invasion involves the suppression of the MAPK/NF-κB and MAPK/AP-1 pathways in MCF-7 cells. DHAvD may have potential value in breast cancer metastasis., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to develop and implement the Hospice Smart Patient Program and to evaluate its effectiveness., Methods: It was quasi-experimental non-equivalent pre-post study. Breast cancer patients who underwent surgery, chemotherapy or radiotherapy, or who needed palliative care, participated in the study. Participants were divided into two groups, experimental and control groups based on their preferences. The program was developed after literature review and discussion among experts on hospice and palliative care. Participants who were in the experimental group received either face-to-face or phone "Hospice Smart Patient" Service at least once a week for 5 months., Results: There was a significant difference in quality of life and communication skill between the two groups after the service was provided. In addition, participants in experimental group showed improved decision making skills, mastery sense, and understanding of hospice and palliative care, which would be beneficial in improving their quality of life., Conclusion: We have concluded that the "Hospice Smart Patient" Program is useful for cancer patients in decision making, improving self-control and choosing hospice care to improve their quality of life.

Purpose: The purpose was to evaluate the mammographic and sonographic (US) features of lobular carcinoma in situ (LCIS). Methods. Mammographic and US findings of nine lesions diagnosed pathologically as pure LCIS were analyzed retrospectively according to the American College of Radiology breast imaging reporting and data system (BI-RADS) lexicon., Results: With regards to mammographic findings of LCIS, there were no lesions demonstrated in six cases and a mass in three cases, two of which contained microcalcifications. The most common US findings of LCIS were irregular shape (five cases), ill-defined margins (eight cases), and hypoechogenicity (seven cases). All cases had an elongated shape parallel to the skin or were round (no lesion had a taller-than-wide shape). Two cases were associated with microcalcifications. The final BI-RADS categories were category 3 (probably benign finding) in one case, category 4A (low suspicion of malignancy) in two cases, and category 4B (intermediate suspicion of malignancy) in six cases., Conclusions: LCIS is frequently mammographically occult, and an incidental finding on routine screening mammograms, usually because of microcalcifications. LCIS, a high-risk lesion, can mimic invasive carcinoma on US., (Copyright © 2010 Wiley Periodicals, Inc.)

Certain fatty acids in canola oil (CAN) have been associated with a reduced risk of breast cancer. This study assessed the effects of CAN on proliferation and death of human breast cancer cells in vitro and in vivo in chemically induced mammary carcinogenesis. We hypothesize that CAN reduces breast cancer cell growth by inducing cell death. In a series of in vitro experiments, human breast cancer T47D and MCF-7 cells were cultured and treated with CAN and two chemotherapeutic drugs, tamoxifen and cerulenin. Cell proliferation and caspase-3 and p53 activities were measured. Reduced cancer cell growth and increased expression of caspase-3 and p53 were seen in T47D and MCF-7 cells treated with CAN. Moreover, CAN showed synergistic cancer cell growth inhibition effects with tamoxifen and cerulenin. In a subsequent live animal experiment, 42 female Sprague-Dawley rats were randomly assigned to corn oil (CORN) or CAN diets, and mammary tumors were chemically induced by N-nitroso-N-methylurea. CAN-dieted rats had reduced tumor volumes and showed an increased survival rate as compared to CORN-dieted rats. We demonstrated that CAN has suppressive effects on cancer growth, and reduces tumor volumes. The results suggest that CAN may have inhibitory effects on breast cancer cell growth, and warrants further investigation of the synergistic effects of CAN with anti-cancer drugs.

Purpose: The aims of this study are to demonstrate the clinical characteristics and various imaging findings of breast cancers in patients with interstitial mammoplasty., Methods: A total of six patients, who had breast cancer and had received liquid silicone or paraffin injection for augmentation, were included in this study. Mammography, ultrasonography, dynamic breast MRI, and PET/CT were performed for 5, 3, 6, and 2 patients, respectively. The clinical course was reviewed, and the imaging findings were retrospectively evaluated according to the ACR BI-RADS atlas., Results: The mean maximal diameter of the detected breast cancers on enhanced breast MRI was 5.5 cm (range 4.8-7.1 cm). Although the breast cancers were all of a large size, subjective breast symptoms exhibited in only four of six patients. Mammographic examinations exhibited variable associate findings such as skin thickening, ipsilateral volume increase, and increase densities, but could not demonstrate main breast masses. A few sonographic examinations exhibited masses with associate findings such as skin thickening. On breast MRI, enhancing breast cancers with associate findings were detected in all the patients. On PET-CT, breast cancers and distant metastases were detected., Conclusions: Breast cancers in these patients were detected at the advanced stage. Dynamic breast MRI was useful for detecting breast cancer in these patients. Mammography failed to demonstrate the breast cancer, but cancer detection was facilitated by associated findings: skin thickening, asymmetric volume increase, and increased density.

Lipotropes (methyl group containing nutrients, including methionine, choline, folate, and vitamin B(12)) are dietary methyl donors and cofactors that are involved in one-carbon metabolism, which is important for genomic DNA methylation reactions and nucleic acid synthesis. One-carbon metabolism provides methyl groups for all biological methylation pathways and is highly dependent on dietary supplementation of methyl nutrients. Nutrition is an important determinant of breast cancer risk and tumor behavior, and dietary intervention may be an effective approach to prevent breast cancer. Apoptosis is important for the regulation of homeostasis and tumorigenesis. The anti-apoptotic protein Bcl-2 may be a regulatory target in cancer therapy; controlling or modulating its expression may be a therapeutic strategy against breast cancer. In this study, the effects of lipotrope supplementation on the growth and death of human breast cancer cell lines T47D and MCF-7 were examined and found to inhibit growth of both T47D and MCF-7 cells. Furthermore, the ratios of apoptotic cells to the total number of cells were approximately 44% and 34% higher in the lipotrope-supplemented treatments of T47D and MCF-7 cancer cells, respectively, compared with the control treatments. More importantly, Bcl-2 protein expression was decreased by approximately 25% from lipotrope supplementation in T47D cells, suggesting that lipotropes can induce breast cancer cell death by direct downregulation of Bcl-2 protein expression. Cancer treatment failure is often correlated with Bcl-2 protein upregulation. These data may be useful in the development of effective nutritional strategies to prevent and reduce breast cancer in humans.

Objective: This study aims to evaluate the degree of inter- and intraobserver agreement when characterizing breast abnormalities using the Breast Imaging Reporting and Data System (BI-RADS)-ultrasound (US) lexicon, as defined by the American College of Radiology (ACR)., Materials and Methods: Two hundred ninety three female patients with 314 lesions underwent US-guided biopsies at one facility during a two-year period. Static sonographic images of each breast lesion were acquired and reviewed by four radiologists with expertise in breast imaging. Each radiologist independently evaluated all cases and described the mass according to BI-RADS-US. To assess intraobserver variability, one of the four radiologists reassessed all of the cases one month after the initial evaluation. Inter- and intraobserver variabilities were determined using Cohen's kappa (k) statistics., Results: The greatest degree of reliability for a descriptor was found for mass orientation (k = 0.61) and the least concordance of fair was found for the mass margin (k = 0.32) and echo pattern (k = 0.36). Others descriptive terms: shape, lesion boundary and posterior features (k = 0.42, k = 0.55 and k = 0.53, respectively) and the final assessment (k = 0.51) demonstrated only moderate levels of agreement. A substantial degree of intraobserver agreement was found when classifying all morphologic features: shape, orientation, margin, lesion boundary, echo pattern and posterior feature (k = 0.73, k = 0.68, k = 0.64, 0.68, k = 0.65 and k = 0.64, respectively) and rendering final assessments (k = 0.65)., Conclusion: Although BI-RADS-US was created to achieve a consensus among radiologists when describing breast abnormalities, our study shows substantial intraobserver agreement but only moderate interobserver agreement in the mass description and final assessment of breast abnormalities according to its use. A better agreement will ultimately require specialized education, as well as self-auditing practice tests.

The purpose of this study was to evaluate cyclooxygenase-2 (COX-2) expression in the successive steps of breast carcinogenesis and to determine its correlation with HER-2/neu and p53 expression in invasive ductal carcinomas of the breast. Immunohistochemical staining with anti-COX-2 antibody was performed in normal breast tissue, usual hyperplasia, ductal carcinoma in situ, and invasive ductal carcinoma. Expression of COX-2 in invasive ductal carcinoma was correlated with immunohistochemical expression of HER-2/neu and p53 protein. COX-2 expression was found to be progressively elevated along the continuum from normal breast tissue to invasive ductal carcinoma (P<0.001). COX-2 expression significantly correlated with p53 and HER-2/neu protein expression (P<0.05 and P<0.001). On multivariate analysis, only TNM stage and elevated COX-2 expression correlated with survival. Our results suggest that COX-2 may be involved in the carcinogenesis of the breast and may be an independent prognostic indicator in patients with invasive ductal carcinoma. HER-2/neu and p53 are likely to be involved in the regulation of COX-2 expression in invasive ductal carcinomas of the breast.

Loss of PTEN expression has been associated with advanced stages of tumor. Tumor angiogenesis is involved in tumor progression. In breast cancer, a high frequency of mutations of the PTEN locus has been reported. However, the prognostic importance of PTEN expression and its correlation with angiogenesis in breast cancer have not been well established. Formalin-fixed, paraffin-embedded tissues from 99 women with a primary diagnosis of invasive ductal carcinoma were evaluated for PTEN expression by immunohistochemical methods. The microvessel density (MVD) was also studied by immunohistochemical labeling of endothelial cells with CD34 antibody. Computerized image analysis was used to evaluate MVD. Reduced PTEN expression was seen in 27.3% of invasive ductal carcinoma. The MVD ranged from 22.0 to 197.0, with a median value of 58.5 (65.4 +/- 27.9). Reduced PTEN expression correlated with lymph node status (P < 0.01), tumor grade (P < 0.05), and tumor-node-metastasis (TNM) stage (P < 0.05). There was a statistically significant correlation between reduced PTEN expression and increased MVD (P < 0.05). The mean MVD was higher in reduced PTEN-expressive tumors, irrespective of stage, compared with normal PTEN-expressive tumors with the same stage. On multivariate analysis, only TNM stage and reduced PTEN expression correlated with survival. Our results suggest that reduced PTEN expression may be an independent prognostic indicator in patients with invasive ductal carcinoma. PTEN loss may be associated with increased tumor angiogenesis.

Among the first nutrients to be linked to cancer were methyl group containing nutrients including methionine. Methionine and its metabolic derivatives are essential components in several indispensable biological reactions including protein synthesis, polyamine synthesis, and many transmethylation reactions. The purpose of this study was to determine the extent to which methionine excess affects the proliferation and gene expression of the human breast cancer cell line MCF-7. Cells were first grown in control medium; the medium was then replaced with either control or methionine-supplemented treatment media. We found that 5 and 10 g/L methionine significantly suppressed cell growth on day 1, and no further growth was detected after 3 d of treatment. Cell proliferation in the methionine treated group was significantly lower than that of the control group. Northern analysis revealed that expression of p53 in methionine-treated MCF-7 cells was approximately 70% lower than that of control cells. p53 is a key cell cycle regulatory protein that has been implicated in tumorigenesis and cancer progression. Alteration of the p53 tumor suppressor gene is the most common genetic change found in a wide variety of malignancies, including cancer. This study shows that excess methionine (5 g/L) inhibited proliferation of MCF-7 breast cancer cells, and down regulation of p53 is correlated with this inhibition. These findings may aid in the development of nutritional strategies for breast cancer therapy.

The vascular endothelial growth factor (VEGF) appears to play an important role in tumor angiogenesis. The p53 and HER-2/neu genes have been thought to regulate VEGF expression. Although the most common genetic alterations described in human breast cancer are p53 gene mutations and HER-2/neu gene amplification, there is a paucity of reports concerning a possible association between VEGF expression and p53 and HER-2/neu expression. Ninety-nine invasive ductal carcinoma cases were examined by immunohistochemical studies with anti-VEGF, anti-p53, anti-HER-2/neu, and anti-CD34 antibodies. Computerized image analysis was used to evaluate the microvessel density (MVD). Eighty-eight tumors (88.9%) were classified as being VEGF positive. Twenty-five tumors (25.3%) showed p53 protein expression, while 36 tumors (35.4%) expressed the HER-2/neu protein. The MVD ranged from 22.0 to 197.0, with a median value of 58.5 (65.4 +/- 27.9). The tumors expressing VEGF had a significantly higher MVD than those that did not (P < 0.05). VEGF expression was significantly associated with p53 protein expression (P < 0.01). In double VEGF and p53 immunohistochemical stained sections, the two markers were generally expressed in the same tumor cells. The cancer stage was the only independent prognostic factor of disease-free and overall survival. The authors' results suggest that VEGF expression plays a role in promoting angiogenesis in invasive ductal carcinoma of the breast, and p53 is likely to be involved in regulating VEGF expression.

Lipotropes, a methyl group containing nutrients, including choline, methionine, folic acid, and vitamin B(12), are essential nutrients for humans. They are important methyl donors that interact in the metabolism of one-carbon units and are essential for the synthesis and methylation of deoxyribonucleic acid. The purpose of this study was to examine the effects of excess lipotropes on the growth of a human breast cancer cell line, MCF-7, and normal mammary cells, MCF-10A, in culture. Both cell lines were grown in basal culture medium for 24 h and then switched to medium supplemented with 50 times the amount of each lipotrope as basal culture medium (control). Although there were no significant differences in growth between treatments in either cell line, gene array and Northern analysis revealed that expression of bcl-2 was decreased in lipotrope-treated MCF-7 cells. The ability to induce tumor cell death could have many uses in the prevention and treatment of cancer. Bcl-2 regulates apoptosis and has been shown to directly affect the sensitivity of cancer cells to chemotherapy agents, and it is suggested that strategies designed to block Bcl-2 might prove useful in sensitizing tumor cells to chemotherapy-induced apoptosis. This study shows that although excess lipotropes do not inhibit the growth of breast cancer cells, they can down-regulate the bcl-2 gene, suggesting that lipotropes may increase the susceptibility of breast cancer cells to anticancer drugs.

Objective: To investigate the relationship between angiogenesis, apoptosis and cell proliferation in invasive ductal carcinoma of the breast and their relation to tumor behavior., Study Design: Microvessels were immunohistochemically labeled with antibody to CD34 in sections from 82 cases of invasive ductal carcinoma. Computerized image analysis was used to evaluate microvessel density (MVD). The authors measured the apoptotic index (AI) using the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling technique and proliferating cell nuclear antigen labeling index (PCNA LI) by PCNA immunohistochemistry on serial sections., Results: Statistical analysis revealed a significant inverse correlation between MVD and AI (r = -.313, P = .004) and failed to find a significant correlation between MVD and PCNA LI. There was a significant positive correlation between AI and PCNA LI (r = .393, P = .000). Significant differences in AI between high MVD (> or = 59.9%) and low MVD (< 59.9%) were seen (P < .001), with no appreciable differences in PCNA LI between the two groups. Histologic grade and stage were the only independent prognostic factors in both disease-free and overall survival., Conclusion: Angiogenesis in breast cancer may be related to the ability of tumor cells to survive rather than to their proliferative activity. Apoptosis is related to cell proliferation in breast cancer.

To determine the effects of lipotrope modification on breast cancer cell growth and cell death, the human breast cancer cell line MCF-7 was assigned to grow in one of three lipotrope treatment media for four days. The treatment media included lipotrope-control medium (LCM), containing all required lipotropes; lipotrope-deficient medium (LDM), lacking all lipotropes but supplying homocysteine instead; and lipotrope-additive medium (LAM), containing twice as much of each lipotrope as LCM. Cell count and [3H]thymidine incorporation into DNA revealed that LDM slowed cell growth and inhibited cell proliferation in the MCF-7 cell line. Gel electrophoresis showed significant DNA degradation with the appearance of fragments in LDM-treated cells, whereas the DNA in LCM and LAM cells was largely intact. The LDM group displayed more apoptotic bodies as detected by in situ immunohistochemistry. The gene expression level of bcl-2 was lower in cells treated with LDM than in those treated with LCM and LAM, whereas p53 gene expression did not appear different among the three treatment groups. It is concluded that lipotrope deficiency inhibits cell growth and induces programmed cell death in the human breast cancer cell line MCF-7.