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Background: The contradictory role of CD8 + CD28- T cells in tumour immunity has been reported, while their biological and clinical significance in HER2-positive metastatic breast cancer (MBC) is still unknown., Methods: HER2-positive MBC patients with no prior therapy in the metastatic setting were retrospectively recruited at two medical centres. Peripheral CD8 + CD28- T cells (pT CD8+CD28- ) were detected at baseline and following therapeutic intervals. Progression-free survival (PFS) was compared according to pT CD8+CD28- levels. The molecular features of pT CD8+CD28- and its correlation with tumour immunity were also investigated., Results: A total of 252 patients were enrolled, and the median follow-up time was 29.6 months. pT CD8+CD28- high at baseline has prolonged PFS compared to pT CD8+CD28- low (P = 0.001). Patients who maintained pT CD8+CD28- high had a longer PFS than those who kept pT CD8+CD28- low (P < 0.001). The enhanced pT CD8+CD28- level also indicates a longer PFS compared to pT CD8+CD28- low (P = 0.025). Here, pT CD8+CD28- was demonstrated as an antigen-experienced effector T cell. Higher IL-2 level (P = 0.034) and lower TGF-β level (P = 0.016) in the serum and highly infiltrated CD8 + CD28- T cells (P = 0.037) were also connected to pT CD8+CD28- high., Conclusions: High pT CD8+CD28- level is associated with a favourable tumour immunity and a better PFS of HER2-targeting therapy in MBC patients., (© 2024. The Author(s).)

Breast and lung cancers are the leading causes of mortality and most frequently diagnosed cancers in women and men, respectively, worldwide. Although the antitumor activity of chalcones has been extensively studied, the molecular mechanisms of isoliquiritigenin analog 2', 4', 4-trihydroxychalcone (metochalcone; TEC) against carcinomas remain less well understood. In this study, we found that TEC inhibited cell proliferation of breast cancer BT549 cells and lung cancer A549 cells in a concentration-dependent manner. TEC induced cell cycle arrest in the S-phase, cell migration inhibition in vitro , and reduced tumor growth in vivo . Moreover, transcriptomic analysis revealed that TEC modulated the activity of the JAK2/STAT3 and P53 pathways. TEC triggered the senescence-associated secretory phenotype (SASP) by repressing the JAK2/STAT3 axis. The mechanism of metochalcone against breast cancer depended on the induction of SASP via deactivation of the JAK2/STAT3 pathway, highlighting the potential of chalcone in senescence-inducing therapy against carcinomas., Competing Interests: The authors declared no conflicts of interest., (© 2024 Zhou et al.)

Importance: Breast cancer in young women has a less favorable prognosis compared with older women. Yet, comprehensive data on recent trends and how period and cohort effects may affect these trends among young women are not well-known., Objective: To evaluate breast cancer incidence among young women in the US over a 20-year period by race and ethnicity, hormone receptor status (estrogen receptor [ER] and progesterone receptor [PR]), tumor stage, and age at diagnosis, as well as how period and cohort effects may affect these trends., Design, Setting, and Participants: This cross-sectional study used data from Surveillance, Epidemiology, and End Results 17 registries (2000-2019). Women aged 20 to 49 years with a primary invasive breast cancer were included. Data were analyzed between February and June 2023., Main Outcomes and Measures: Age-standardized incidence rates (ASIR), incidence rate ratios (IRR), and average annual percent changes (AAPC) stratified by race and ethnicity, hormone receptor status, tumor stage, and age at diagnosis., Results: Out of 217 815 eligible women (1485 American Indian or Alaska Native [0.7%], 25 210 Asian or Pacific Islander [11.6%], 27 112 non-Hispanic Black [12.4%], 37 048 Hispanic [17.0%], 126 960 non-Hispanic White [58.3%]), the majority were diagnosed with an ER+/PR+ tumor (134 024 [61.5%]) and were diagnosed with a stage I tumor (81 793 [37.6%]). Overall, invasive breast cancer incidence increased (AAPC, 0.79; 95% CI, 0.42 to 1.15), with increasing trends across almost all racial and ethnic groups. ASIR increased for ER+/PR+ (AAPC, 2.72; 95% CI, 2.34 to 3.12) and ER+/PR- tumors (AAPC, 1.43; 95% CI, 1.00 to 1.87), and decreased for ER-/PR+ (AAPC, -3.25; 95% CI, -4.41 to -2.07) and ER-/PR- tumors (AAPC, -0.55; 95% CI, -1.68 to 0.60). For women aged 20 to 29 and 30 to 39 years, ASIRs were highest among non-Hispanic Black women (age 20-29 years: IRR, 1.53; 95% CI, 1.43 to 1.65; age 30-39 years: IRR, 1.15; 95% CI, 1.12 to 1.18). For women aged 40 to 49 years, ASIR was lower for non-Hispanic Black women (IRR, 0.96; 95% CI, 0.94 to 0.97) compared with non-Hispanic White women. Incidence rates increased for stages I and IV tumors but decreased for stage II and III tumors. Age-period-cohort analysis demonstrated both cohort and period effects on breast cancer incidence (P < .001)., Conclusions and Relevance: In this population-based cross-sectional analysis, an increase in breast cancer incidence rates among young US women and age-related crossover between non-Hispanic White and Black women were observed. Prevention efforts in young women need to adopt a targeted approach to address racial disparities in incidence rates observed at different age phases.

Multiple new subtypes of breast cancer (BRCA) are identified in women each year, rendering BRCA the most common and rapidly expanding form of cancer in females globally. NUF2 has been identified as a prognostic factor in various human cancers, regulating cell apoptosis and proliferation. However, its role in BRCA prognosis has not been clarified. This study explored the role of NUF2 in breast cancer development and prognosis using informatic analysis combined with in vivo intracellular studies. Through the online website TIMER, we evaluated the transcription profile of NUF2 across a variety of different cancer types and found that NUF2 mRNA was highly expressed in BRCA patients. Its transcription level was found to be related to the subtype, pathological stage, and prognosis of BRCA. The R program analysis showed a correlation of NUF2 with cell proliferation and tumor stemness in the BRCA patient samples. Subsequently, the association between the NUF2 expression level and immune cell infiltration was analyzed using the XIANTAO and TIMER tools. The results revealed that NUF2 expression was correlated with the responses of multiple immune cells. Furthermore, we observed the effect of NUF2 expression on tumor stemness in BRCA cell lines in vivo. The experimental results illuminated that the overexpression of NUF2 statistically upregulated the proliferation and tumor stemness ability of the BRCA cell lines MCF-7 and Hs-578T. Meanwhile, the knockdown of NUF2 inhibited the abilities of both cell lines, a finding which was verified by analyzing the subcutaneous tumorigenic ability in nude mice. In summary, this study suggests that NUF2 may play a key role in the development and progression of BRCA by affecting tumor stemness. As a stemness indicator, it has the potential to be one of the markers for the diagnosis of BRCA.

Invasive breast cancer (IBC) is a kind of malignant tumor in which cancer cells have broken through the basement membrane of breast ducts or lobular acini and invaded the stroma. Although ultrasound elastography score (UES) has shown unique advantages in the diagnosis of IBC, its value in the prognosis is not clear. Here, we explored the correlation of UES with IBC and biological prognostic factors. The datum of 86 patients with suspected IBC from January 2018 to December 2021 was collected. UE was applied in the examination of all patients. The lesion tissue of the malignant group was punctured to detect and analyze the expression of biological prognostic factors, including estrogen receptor (E receptor), progesterone receptor (P receptor), and human epidermal growth factor 2 (HER factor 2) and Ki67. The differences in UES under different biological prognostic factors were compared. The receiver operating characteristic (ROC) curve was applied to analyze the diagnostic value of UES of IBC and the expression of biological prognostic factors. Based on the pathological diagnosis results, the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of UES in the diagnosis of IBC were analyzed. The correlation of UES with IBC and biological prognostic factors was analyzed by multiple linear regression and Spearman method. ROC analysis showed that the area under the curve of UES for diagnosing IBC and evaluating the expression of P receptor, HER factor 2, and Ki67 were 0.877, 0.704, 0.763, and 0.820, respectively ( P ＜0.05). The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of UES when diagnosing IBC were 92.42%, 90.00%, 91.86%, 96.83%, and 78.26%, respectively. The UES of E receptor expression (positive and negative group) showed no obvious variance ( P  > 0.05). The UES of P receptors (positive and negative), HER factor 2 (positive and negative), and Ki67 (high and low expression) showed obvious differences ( P  < 0.05). Multiple linear regression and Spearman indicated UES was significantly correlated with the expression of P receptor, HER factor 2, and Ki67 ( P ＜0.05). UES has a certain diagnostic value for IBC and is significantly correlated to the expression of P receptor, HER factor 2, and Ki67, which is helpful for evaluating the prognosis of patients with IBC., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2022 Q. Fu et al.)

Dysregulation of the Hippo signaling pathway seen in many types of cancer is usually associated with a poor prognosis. Paris saponin VII (PSVII) is a steroid saponin isolated from traditional Chinese herbs with therapeutic action against various human cancers. In this study we investigated the effects of PSVII on human breast cancer (BC) cells and its anticancer mechanisms. We showed that PSVII concentration-dependently inhibited the proliferation of MDA-MB-231, MDA-MB-436 and MCF-7 BC cell lines with IC 50 values of 3.16, 3.45, and 2.86 μM, respectively, and suppressed their colony formation. PSVII (1.2-1.8 μM) induced caspase-dependent apoptosis in the BC cell lines. PSVII treatment also induced autophagy and promoted autophagic flux in the BC cell lines. PSVII treatment decreased the expression and nuclear translocation of Yes-associated protein (YAP), a downstream transcriptional effector in the Hippo signaling pathway; overexpression of YAP markedly attenuated PSVII-induced autophagy. PSVII-induced, YAP-mediated autophagy was associated with increased active form of LATS1, an upstream effector of YAP. The activation of LATS1 was involved the participation of multiple proteins (including MST2, MOB1, and LATS1 itself) in an MST2-dependent sequential activation cascade. We further revealed that PSVII promoted the binding of LATS1 with MST2 and MOB1, and activated LATS1 in the BC cell lines. Molecular docking showed that PSVII directly bound to the MST2-MOB1-LATS1 ternary complex. Microscale thermophoresis analysis and drug affinity responsive targeting stability assay confirmed the high affinity between PSVII and the MST2-MOB1-LATS1 ternary complex. In mice bearing MDA-MB-231 cell xenograft, administration of PSVII (1.5 mg/kg, ip, 4 times/week, for 4 weeks) significantly suppressed the tumor growth with increased pLATS1, LC3-II and Beclin 1 levels and decreased YAP, p62 and Ki67 levels in the tumor tissue. Overall, this study demonstrates that PSVII is a novel and direct Hippo activator that has great potential in the treatment of BC., (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)

This study explored the role of MTDH in regulating the sensitivity of breast cancer cell lines to gemcitabine (Gem) and the potential miRNAs targeting MTDH. The expression of MTDH in cancer tissues and cells was detected by immunohistochemical staining or qRT-PCR. The target genes for MTDH were predicted by bioinformatics and further confirmed by dual-luciferase reporter assay and qRT-PCR. Cancer cells were transfected with siMTDH, MTDH, miR-9-3p inhibitor, or mimics and treated by Gem, then CCK-8, colony formation assay, tube formation assay, flow cytometry, wound healing assay, and Transwell were performed to explore the effects of MTDH, miR-9-3p, and Gem on cancer cell growth, apoptosis, migration, and invasion. Expressions of VEGF, p53, cleaved caspase-3, MMP-2, MMP-9, E-Cadherin, N-Cadherin, and Vimentin were determined by Western blot. MTDH was high-expressed in cancer tissues and cells, and the cells with high-expressed MTDH were less sensitive to Gem, while silencing MTDH expression significantly promoted the effect of Gem on inducing apoptosis, inhibiting cell migration, invasion, and growth, and on regulating protein expressions of cancer cells. Moreover, miR-9-3p had a targeted binding relationship with MTDH, and overexpressed miR-9-3p greatly promoted the toxic effects of Gem on cancer cells and expressions of apoptosis-related proteins, whereas overexpressed MTDH partially reversed such effects of overexpressed miR-9-3p. The study proved that miR-9-3p regulates biological functions, drug resistance, and the growth of Gem-treated breast cancer cells through targeting MTDH., (© 2021. The Author(s).)

Background: Women at high lifetime breast cancer risk may benefit from supplemental breast magnetic resonance imaging (MRI) screening, in addition to routine mammography screening for earlier cancer detection., Materials and Methods: We performed a cross-sectional study of 422,406 women undergoing routine mammography screening across 86 Breast Cancer Surveillance Consortium (BCSC) facilities during calendar year 2012. We determined availability and use of on-site screening breast MRI services based on woman-level characteristics, including >20% lifetime absolute risk using the National Cancer Institute risk assessment tool. Multivariate analyses were performed to determine sociodemographic characteristics associated with on-site screening MRI use., Results: Overall, 43.9% (2403/5468) of women at high lifetime risk attended a facility with on-site breast MRI screening availability. However, only 6.6% (158/2403) of high-risk women obtained breast MRI screening within a 2-year window of their screening mammogram. Patient factors associated with on-site MRI screening use included younger (<40 years) age (odds ratio [OR] = 2.39, 95% confidence interval [CI]: 1.34-4.21), family history (OR = 1.72, 95% CI: 1.13-2.63), prior breast biopsy (OR = 2.09, 95% CI: 1.22-3.58), and postsecondary education (OR = 2.22, 95% CI: 1.04-4.74)., Conclusions: While nearly half of women at high lifetime breast cancer risk undergo routine screening mammography at a facility with on-site breast MRI availability, supplemental breast MRI remains widely underutilized among those who may benefit from earlier cancer detection. Future studies should evaluate whether other enabling factors such as formal risk assessment and patient awareness of high lifetime breast cancer risk can mitigate the underutilization of supplemental screening breast MRI.

Objective The aim of the present study was to determine how many sentinel lymph nodes (SLNs) are appropriate for predicting non-SLN metastasis in breast cancer. Methods The association between clinicopathological features and non-SLN metastasis was retrospectively analyzed in 472 patients who underwent axillary lymph node dissection (ALND) following SLN biopsy. Another 251 patients who underwent only SLN biopsy without ALND were analyzed and followed up for 2 years. Results A large tumor size, positive SLN, and HER-2 positivity were independent predictors of non-SLN metastasis. There were significant differences in non-SLN metastasis between patients with one negative SLN and patients with an absence of negative SLNs. There was no significant difference in non-SLN metastasis between patients with one negative SLN and two or more negative SLNs. The recurrence-free survival rate for patients who did not undergo ALND was 99.6% (245/246). Conclusion Surgeons should ensure that the number of SLNs obtained is appropriate. The presence of one negative SLN is enough in SLN biopsy. Considering the invasiveness of the surgery, two or more negative SLNs may be unnecessary.

BACKGROUND Breast cancer is one of the most common malignancies in women. In a previous study, we found that for two patients who had a high risk of lymphatic metastasis, lymphatic metastasis did not occur; whereas, for two patients who had a low risk of lymphatic metastasis, lymphatic metastasis did occur. MATERIAL AND METHODS We analyzed the differential gene expressions of these four patients by RNA-sequence. The data (HRNM&#95;T versus HRNM&#95;N, LRYM&#95;T versus LRYM&#95;N, and HRNM&#95;T versus LRYM&#95;T) was then processed using differentially expressed genes (DEGs) analysis, functional analysis for DEGs, and PPI network construct. RESULTS For HRNM&#95;T versus HRNM&#95;N, there were 224 DEGs. There were 504 DEGs for LRYM&#95;T versus LRYM&#95;N, and 88 DEGs for LRYM&#95;T versus LRYM&#95;N. For HRNM&#95;T versus HRNM&#95;N, DEGs were up-regulated mainly in the cell cycle, the IL-17 signaling pathway, and the progesterone-mediated oocyte maturation; DEGs were down-regulated mainly in the IL-17 signaling pathway. For LRYM&#95;T versus LRYM&#95;N, DEGs were up-regulated mainly in protein digestion and absorption, and cytokine-cytokine receptor interaction; DEGs were down-regulated mainly in ECM-receptor interaction. For HRNM&#95;T versus LRYM&#95;T, DEGs were up-regulated mainly in the PPAR signaling pathway; DEGs were downregulated mainly in the adipocytokine signaling pathway. The DEGs were screened to construct PPI networks. CONCLUSIONS The GO and KEGG functional enrichments of HRNM&#95;T versus HRNM&#95;N, and LRYM&#95;T versus LRYM&#95;N were consistent with earlier studies. For HRNM&#95;T versus LRYM&#95;T, DEGs were up-regulated mainly in PPAR signaling; DEGs were down-regulated mainly in the adipocytokine pathway.

Objective: To detect the proportion of lymphocyte subsets in peripheral blood of the advanced breast cancer patients before and after chemotherapy with docetaxel and thiotepa, as well as the association between the proportion of peripheral blood lymphocyte subsets with the response rate and prognosis., Methods: The proportions of lymphocyte subsets (CD3+ T cell, CD3+/CD4+ T cell, CD3+/CD8+ T cell, CD3-/CD16+56+ NK cell, CD3+/CD16+56+ T cell, CD19+ B cell, CD4+/CD25+ T cell, CD8+/CD28- T cell, CD8+/CD28+ T cell) in the peripheral blood of 86 patients were analyzed with flowcytometry before and after chemotherapy. The result was analyzed in combination with clinicopathological data., Results: The proportion of regulatory T cells (Treg) after chemotherapy in the disease control patients decreased significantly compared with that of the progressive patients (P=0.034). The difference of the proportions of Treg before and after chemotherapy affected significantly the overall survival (OS). The OS of the patients with decreased proportion of Treg was significantly longer than that of the patients with increased proportion of Treg, which was 23.5 and 9.4 months respectively (P<0.05)., Conclusion: The patients with decreased proportion of Treg after chemotherapy had higher response rate and better survival benefit.

Objective: Different chemotherapy regimens may contribute differently to the development of Premature Ovarian Failure (POF) in women of reproductive age with breast cancer. Here we evaluated how two different chemotherapy regimens, CAF (tegafur + pirarubicin + ifosfamide) and DTC (docetaxel + pirarubicin + ifosfamide), affect the development of POF., Patients and Methods: We enrolled 164 women of reproductive age with breast cancer (mean ± SD age of 34.56 ± 9.48 years). The patients were divided into two groups, which were respectively treated with CAF (n = 89) or DTC (n = 75) chemotherapy regimen. Both study groups were comparable in all analyzed characteristics at baseline. Patients were treated with respective chemotherapy regimen for 6 months and followed up for over 12 months after completion of chemotherapy. Study outcomes were occurrence rates of POF, menstrual status and recovery after completion of chemotherapy, and serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), and oestradiol (E2)., Results: At 6 months after completion of chemotherapy, POF incidence rates were significantly lower in the CAF group. Furthermore, the proportion of patients with eumenorrhea, menstrual disorders or chemotherapy-induced amenorrhea in this study group was also significantly different from the DTC group. Similarly, adverse changes of serum levels of FSH, LH and E2 were less pronounced in the CAF group., Conclusions: Both tested chemotherapy regimens can cause POF; however, adverse effects of DCT chemotherapy regimen on ovarian function are more pronounced than those by CAF chemotherapy regimen.

Importance: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists., Objective: To identify mutation-specific cancer risks for carriers of BRCA1/2., Design, Setting, and Participants: Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk., Exposures: Mutations of BRCA1 or BRCA2., Main Outcomes and Measures: Breast and ovarian cancer risks., Results: Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers., Conclusions and Relevance: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.

Taurine (Tau), the most abundant free amino acid in humans has numerous potential health benefits through its antioxidant and anti-inflammatory properties. However, limited studies have assessed its effect on tumors and the antitumor mechanism remains unknown. The present study investigated the cellular and molecular changes induced by Tau, leading to the induction of apoptosis in human breast cancer cell lines MCF-7 and MDA-MB-231. MCF-7 is p53 proficient (p53+/+) and MDA-MB-231 is a p53 null mutant (p53-/-). Cell proliferation and viability were assessed by MTT. Flow cytometry and hoechst33342 fluorescent staining were employed to detect apoptosis. Spectrophotometry was used to detect caspase-3 activity. Reverse transcription-polymerase chain reaction and western blot analysis were used to detect the levels of mRNA and proteins of p53-upregulated modulator of apoptosis (PUMA), Bax and Bcl-2. Finally, the affect of Tau on the growth of MDA-MB-231-cell-nude mice xenografts was examined. In the study, Tau inhibited growth and induced apoptosis of the two cell lines in a concentration- and time-dependent manner. Notably, the inhibitory effect of Tau on p53-/- cancer cells was clearly significant compared to the p53+/+ cancer cells. Further studies showed that Tau promoted apoptosis in human breast cancer cells and inhibited the growth of tumor in nude mice by inducing the expression of PUMA, which further up- and downregulated the expression of Bax and Bcl-2 protein, giving rise to increased activation of caspase-3. Collectively, these results indicate that Tau is a potent candidate for the chemotherapy of breast cancer through increasing the PUMA expression independent of p53 status.

Secondary lymphoid tissue chemokine (SLC/CCL21) and its receptor CCR7 have been implicated in lymph node metastasis, whereas the mechanism of which remains unclear. Epithelial-mesenchymal transition (EMT) plays an important role in invasion and migration of cancer cells. We presumed that CCL21/CCR7 axis activates EMT process to induce cancer cell invasion and metastasis. Firstly, the expressions of CCR7 and EMT markers were examined by immunohistochemical staining in the primary breast carcinoma tissues from 60 patients who underwent radical mastectomy. Then, we investigated whether CCL21/CCR7 induces EMT process during mediating cancer cell invasion or migration in vitro. By immunohistolochemistry, high expressions of CCR7, Slug and N-cadherin were seen in 60, 65, and 76.67 % of tumors, respectively, and significantly associated with lymph node metastases as well as clinical pathological stage. Furthermore, the CCR7 expression was significantly correlated to Slug and N-cadherin. In vitro, stimulating breast cancer cell lines 1428, MCF-7 and MDA-MB-231 with CCL21, the invasion and migration of tumor cells were promoted, and simultaneously, EMT phenotype of tumor cells was enhanced, including down-regulation of E-cadherin, up-regulation of Slug, Vimentin and N-cadherin at both protein and mRNA levels. Inversely, knockdown of CCR7 by shRNA suppressed tumor cell invasion, migration and EMT phenotype induced by CCL21. These results indicated that CCL21/CCR7 axis could activate EMT process during chemotaxis of breast carcinoma cells.

Background: This systemic analysis was conducted to evaluate the efficacy and safety of pemetrexed based chemotherapy in treating patients with metastatic breast cancer as first or second line chemotherapy., Methods: Clinical studies evaluating the efficacy and safety of pemetrexed based regimens on response and safety for patients with breast cancer were identified using a predefined search strategy. Pooled response rate (RR) of treatment were calculated., Results: In first line pemetrexed based regimens, 10 clinical studies which including 513 patients with advanced breast cancer were considered eligible for inclusion. For second line pemetrexed based chemotherapy, 5 clinical studies which including 281 patients with advanced breast cancer were considered eligible. Systemic analysis suggested that, in all patients, pooled RR was 32.6% (167/513) in pemetrexed based first line regimens, and 13.9 % (39/281) in pemetrexed based second line regimens. Major adverse effects were neutropenia, leukopenia, fatigue, and anemia in pemetrexed based first line treatment; and lymphopenia, neutropenia, leukopenia, as well as anemia in second line chemotherapy. One treatment related death occurred with pemetrexed based second line treatment., Conclusion: This systemic analysis suggests that pemetrexed based first line regimens are associated with a reasonable response rate and acceptable toxicity, however with low response rate for treating patients with metastatic breast cancer when is used in the second line.

Background: We hypothesized that combination of dendritic cell (DC) with autologous cytokine-induced killer (CIK) immunotherapy in setting of high-dose chemotherapy (HDC) would be effective for selected metastatic breast cancer (MBC) patients., Patients and Methods: Our previous work showed thiotepa could eradicate breast cancer stem cells. From 2004 to 2009, 79 patients received standard dose chemotherapy (SDC) of 75 mg/m(2) docetaxel and 75 mg/m(2) thiotepa versus 87 patients of HDC + DC/CIK: 120 mg/m(2) docetaxel to mobilize peripheral CD34(+) progenitor cells, a sequence of HDC (120 mg/m(2) docetaxel, plus 175 mg/m(2) thiotepa) + DC/CIK, with or without 400 mg/m(2) carboplatin depending upon bone marrow function. The endpoints were response rates (RR), progression-free survival (PFS), and overall survival (OS)., Results: Compared with SDC, PFS and OS were improved in HDC + DC/CIK (median PFS 10.2 vs. 3.7 months, P < 0.001; median OS 33.1 vs. 15.2 months, P < 0.001). Patients of pre-menopausal, HDC as first-line treatment after metastasis, or with visceral metastasis showed prolonged PFS and OS. SDC group also achieved the similar response as previous reports., Conclusion: Our study demonstrated the novel combination of HDC with DC/CIK to be an effective choice for the selected MBC population, in which choosing appropriate chemo regimens played important roles, and also specific HDC regimen plus DC/CIK immunotherapy showed the clinical benefits compared with chemotherapy alone.

Objectives: To investigate relationships between several protein biomarkers and clinical responses to neoadjuvant chemotherapy (NAC) in breast cancer., Methods: Tumour tissue samples from female patients with locally advanced breast carcinoma (stages IIA to IIIC), treated with NAC regimens (including 5-fluorouracil, epirubicin, cyclophosphamide and docetaxel, epirubicin, cyclophosphamide) were analysed retrospectively. Immunohistochemical analysis was used to test for protein levels of oestrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor (HER)-2, protein 53 (p53) and γ-synuclein. Relationships between protein biomarkers and responses to NAC were analysed by multivariate logistic regression analysis., Results: Data from 154 patients (median age, 51 years; range 27-75 years) were included. Multivariate logistic regression analysis showed that γ-synuclein was an independent predictor of NAC objective response rate, and a statistically significant relationship was observed between NAC regimen, γ-synuclein levels and pathological complete response rate., Conclusions: These study findings suggest that γ-synuclein - in combination with other markers such as ER, PR and HER-2 - may serve as a biomarker for response to NAC in breast cancer and warrants further study.

Purpose: Suppression of cellular immunity resulting from tumorigenesis and/or therapy might promote cancer cells' growth, progression and invasion. Here, we explored whether T lymphocyte subtypes from peripheral blood of metastatic breast cancer (MBC) female patients could be used as alternative surrogate markers for cancer progress. Additionally, plasma levels of interleukin (IL)-2, IL-4, IL-6, IL-10, IFN-γ, and transforming growth factor-β1 were quantitated from MBC and healthy volunteers., Experimental Design: This study included 89 female MBC patients during the post-salvage chemotherapy follow-up and 50 age- and sex-matched healthy volunteers as control. The percentages of T lymphocyte subpopulations from peripheral blood and plasma levels of cytokines were measured., Results: Both CD8(+)CD28(-) and CD4(+)CD25(+) were elevated in MBC patients compared to the control cohort (P < 0.05). In contrast, CD3(+) and CD8(+)CD28(+)cells were significantly lower in MBC patients (P < 0.0001, P = 0.045, respectively). MBC patients had elevated levels of immunosuppressive cytokines IL-6 and IL-10. Patients with elevated CD8(+)CD28(-) and CD4(+)CD25(+) cells showed increased levels of IL-6, and only patients with elevated CD8(+)CD28(-) had decreased interferon-γ. Univariate analysis indicated increased CD3(+)CD4(+) or CD8(+)CD28(+)correlated with prolonged progression-free survival (PFS), while elevated CD8(+)CD28(-)associated with shorten PFS. The percent of CD8(+)CD28(-) T lymphocytes is an independent predictor for PFS through multivariate analysis., Conclusions: This study suggests that progressive elevated levels of CD8(+)CD28(-) suppressor T lymphocytes represent a novel independent predictor of PFS during post-chemotherapy follow-up.

Objective: To investigate the risk factors on female breast cancer in Zhejiang province., Methods: A case-control study was conducted in 200 cases of female breast cancer with histopathological diagnosis and 200 matched controls from Zhejiang province., Results: Univariate conditional logistic regression showed that family history of malignant tumor and breast cancer, housing decoration in last 10 years, mammary hyperplasia, adverse life events, bra with steel rings, sleeping with bra, high fat and pickle intake, poor sleep were positively related to breast cancer; whereas environmental friendly decoration materials, long decoration time interval, workplace condition, more lactation and parity, high fruits intake, sufficient sleep were negatively related to breast cancer. Multivariate conditional logistic regression analysis showed that the risk factors included family history of other tumors [odds ratio (OR)= 1.571,95% confidence interval(CI):1.029-2.396],mammary hyperplasia (OR=3.066,95%CI:1.834-5.126), job-related life events (OR=4.575,95%CI:1.690-12.390),the death of a loved one (OR=2.555,95%CI:1.475-4.424), wearing bra at night (OR=1.902,95%CI:1.177-3.072),high fat intake (OR=2.709,95%CI:1.546-4.749) and salted food (OR=2.460,95%CI:1.300-4.653). Factors as environmental friendly decoration materials (OR=0.517,95%CI:0.339-0.789),workplaces condition (OR=0.430,95%CI:0.243-0.762),more lactation (OR=0.109,95%CI:0.013-0.896),enough sleep (OR=0.424,95%CI:0.205-0.880) were protective factors., Conclusion: Hereditary,psychological factors,lifestyle,environment and diet related factors are significantly associated with risk of breast cancer.

Objective: To investigate the effect of Evn-50 extracted from Vitex negundo on human breast cancer cell line MCF-7 and MCF-7/TAM-R cells in vitro., Methods: MCF-7 and tamoxifen-resistant MCF-7/TAM-R cells were treated with Evn-50,tamoxifen or combination of Evn-50 and tamoxifen. Cell proliferation inhibition rates were determined by MTT assay. The apoptosis rate and the change of cell cycle were detected by PI staining flow cytometry. Protein expression of phospho-MAPK 44/42 (Thr202/Tyr204),MAPK P44/42, phospho-AKT (Ser473) and AKT were detected with Western blotting., Results: The viability of MCF-7 cells was decreased in combination group [(28.65 ±11.43)%] and Evn-50 group [(53.02 ±15.14)%] compared with TAM group (P<0.01). The cell viability of MCF-7/TAM-R in combination group [(42.11 ±14.30)%] was significantly lower than that in TAM group [(92.18 ±13.16)%] (P<0.01). The cell apoptosis rate was dependent on the time of treatment in all groups,the effects on apoptosis and G2/M phase cells were most prominent at 72 h (P<0.01). Western blotting revealed that protein levels of phosphorylated AKT and p-MAPK44/42 decreased,while the expression of total AKT and MAPK44/42 was stable. In MCF-7/TAM-R cells,the expression of phosphorylation of AKT and MAPK44/42 protein was not changed in Evn-50 or TAM alone group,but significantly inhibited in the combination group at 72 h., Conclusion: Evn-50 can inhibit cell growth and induce apoptosis in MCF-7 and MCF-7/TAM-R cells,it can reverse tamoxifen-resistance of MCF-7/TAM-R cells.The mechanisms may be related to the down-regulation of phosphorylated ERK1/2 in MAPK signal pathway and phosphorylated AKT in AKT signal pathway.

Inherited BRCA1 mutations confer elevated cancer risk. Recent studies have identified genes that encode proteins that interact with BRCA1 as modifiers of BRCA1-associated breast cancer. We evaluated a comprehensive set of genes that encode most known BRCA1 interactors to evaluate the role of these genes as modifiers of cancer risk. A cohort of 2,825 BRCA1 mutation carriers was used to evaluate the association of haplotypes at ATM, BRCC36, BRCC45 (BRE), BRIP1 (BACH1/FANCJ), CTIP, ABRA1 (FAM175A), MERIT40, MRE11A, NBS1, PALB2 (FANCN), RAD50, RAD51, RAP80, and TOPBP1, and was associated with time to breast and ovarian cancer diagnosis. Statistically significant false discovery rate (FDR) adjusted P values for overall association of haplotypes (P(FDR)) with breast cancer were identified at ATM (P(FDR) = 0.029), BRCC45 (P(FDR) = 0.019), BRIP1 (P(FDR) = 0.008), CTIP (P(FDR) = 0.017), MERIT40 (P(FDR) = 0.019), NBS1 (P(FDR) = 0.003), RAD50 (P(FDR) = 0.014), and TOPBP1 (P(FDR) = 0.011). Haplotypes at ABRA1 (P(FDR) = 0.007), BRCC45 (P(FDR) = 0.016 and P(FDR) = 0.005 in two haplotype blocks), and RAP80 (P(FDR) < 0.001) were associated with ovarian cancer risk. Overall, the data suggest that genomic variation at multiple loci that encode proteins that interact biologically with BRCA1 are associated with modified breast cancer and ovarian cancer risk in women who carry BRCA1 mutations., (©2011 AACR.)

Currently, there are no applied molecular markers to aid in predicting risk of carcinoma in situ (CIS) progression to invasive cancer, and therefore, all women diagnosed with CIS undergo surgery. Standard assessment of protein expression in fixed tissue by immunohistochemistry (IHC) is not quantitative and hence is not well suited for measuring biomarkers. In this study, we developed an original analytical method for IHC quantification. Using our novel image-based uniplex (IBU) method, quantitative protein profiling was performed on 90 samples of the breast (17 histologically normal tissues, 16 benign lesions, 15 CIS, and 42 invasive carcinomas). Differences between groups were assessed using analysis of variance (ANOVA) and mixed effects models. Measuring protein expression on a continuous scale revealed a significant increase in Ras-related protein 1 (Rap1) and the insulin-like growth factor type I receptor (IGF-IR) in conjunction with the presence of cancer invasion. Women with invasive cancers were four times more likely to have increased levels of Rap1 [odds ratio (OR) = 3.91; P = 0.0002] and IGF-IR (OR=4.33; P<0.0001) than women with non-invasive lesions. Furthermore, expression of both proteins was also increased significantly in CIS adjacent to invasive tumors compared with non-cancerous tissue. These novel findings of a significant up-regulation of Rap1 and IGF-IR in CIS progressing to invasive cancers warrant further investigation of Rap1 and IGF-IR together as a dual biomarker to aid in predicting risk of progression and ultimately providing non-surgical treatment options to those at lower risk.

Background: Inherited BRCA1 and BRCA2 (BRCA1/2) mutations confer elevated breast cancer risk. Knowledge of factors that can improve breast cancer risk assessment in BRCA1/2 mutation carriers may improve personalized cancer prevention strategies., Methods: A cohort of 5,546 BRCA1 and 2,865 BRCA2 mutation carriers was used to evaluate risk of breast cancer associated with BARD1 Cys557Ser. In a second nonindependent cohort of 1,537 of BRCA1 and 839 BRCA2 mutation carriers, BARD1 haplotypes were also evaluated., Results: The BARD1 Cys557Ser variant was not significantly associated with risk of breast cancer from single SNP analysis, with a pooled effect estimate of 0.90 (95% CI: 0.71-1.15) in BRCA1 carriers and 0.87 (95% CI: 0.59-1.29) in BRCA2 carriers. Further analysis of haplotypes at BARD1 also revealed no evidence that additional common genetic variation not captured by Cys557Ser was associated with breast cancer risk., Conclusion: Evidence to date does not support a role for BARD1 variation, including the Cy557Ser variant, as a modifier of risk in BRCA1/2 mutation carriers., Impact: Interactors of BRCA1/2 have been implicated as modifiers of BRCA1/2-associated cancer risk. Our finding that BARD1 does not contribute to this risk modification may focus research on other genes that do modify BRCA1/2-associated cancer risk., (©2011 AACR.)

Human leucocyte antigen class I (HLA-I), which includes HLA-A, -B and -C, is an essential immune factor participating in the antitumour immune response. The changes in HLA-I expression in peripheral blood T lymphocytes in cancer patients have yet to be defined. This study examined the expression of HLA-I on CD4(+) and CD8(+) T lymphocytes in female patients with stage I - IV breast infiltrating ductal carcinoma, benign breast tumour diseases (mammary intraductal papilloma or breast fibroadenoma), and in healthy controls. HLA-I was down-regulated on CD4(+) T lymphocytes from patients with stage III and IV cancer, and on CD8(+) T lymphocytes in patients with stage I - IV cancer compared with healthy controls. HLA-I expression in T lymphocytes may contribute towards immune-balance disorders in tumour patients.