Dietary isoflavones or isoflavone-rich food intake and breast cancer risk: A meta-analysis of prospective cohort studies.

BACKGROUND & AIMS: Previous studies implied that dietary isoflavone intake may reduce the risk of developing breast cancer, but some have shown ambiguous results. This study aimed to systematically evaluate and summarize available evidence on the effect dietary isoflavone intake has on the risk of developing breast cancer. METHODS: PubMed, Embase, and the Cochrane Library were searched for prospective cohort studies published through April 2017 that evaluated the effect of dietary isoflavone intake on the development of breast cancer. RESULTS: Sixteen prospective cohort studies, involving 11,169 breast cancer cases and 648,913 participants, were identified and included in our data analysis. The pooled relative risk (RR) of breast cancer was 0.99 for high versus low intake of isoflavones (95% confidence interval [CI], 0.91-1.09; P = 0.876) and 0.99 for moderate versus low intake of isoflavones (95%CI, 0.92-1.05; P = 0.653), with insignificant heterogeneity (P = 0.187 for high versus low, and P = 0.192 for moderate versus low). While a moderate consumption of soy-based foods did not significantly affect breast cancer risk, a high intake of soy-based foods associated with a lower risk of developing breast cancer. Considering specific foods, an increased the risk of developing breast cancer was seen with a moderate intake of formononetin, but no significant associations were found between breast cancer risk and other isoflavone-rich diets. CONCLUSIONS: The present meta-analysis indicates that women with a high dietary intake of soy foods may experience a statistically significant reduction in breast cancer risk. However, moderate formononetin consumption may increase the risk of developing breast cancer.

Downregulation of RASSF6 promotes breast cancer growth and chemoresistance through regulation of Hippo signaling.

This study aims to investigate the clinical significance and biological function of RASSF6 in human breast cancers. RASSF6 protein was found to be downregulated in 42 of 95 human breast cancer tissues by immunohistochemistry, which was associated with advanced TNM stage and nodal metastasis. The rate of RASSF6 downregulation was higher in Triple-negative breast cancer (TNBC). Downregulation of RASSF6 protein was also found in breast cancer cell lines, especially in TNBC cell lines. Overexpression RASSF6 inhibited cell growth rate and colony formation ability in MDA-MB-231 cell line. Depletion of RASSF6 promoted proliferation rate and colony formation ability in T47D cell line. Flow cytometry/PI staining demonstrated that RASSF6 inhibited cell cycle transition. AnnxinV/PI analysis showed that RASSF6 overexpression upregulated apoptosis induced by cisplatin (CDDP) while RASSF6 depletion inhibited apoptosis. JC-1 staining showed that RASSF6 overexpression inhibited mitochondrial membrane potential. Western blot analysis demonstrated that RASSF6 repressed cyclin D1, YAP while upregulated p21, cleaved caspase 3 and cytochrome c expression. In addition, RASSF6 activated Hippo signaling pathway by upregulating MST1/2 and LATS1 phosphorylation. Restoration of YAP inhibited cleaved caspase 3 and cytochrome c which were induced by RASSF6. Restoration of YAP also reduced the rate of CDDP induced apoptosis. In conclusion, this study provided evidence that RASSF6 functions as a potential tumor suppressor in human breast cancer through activation of Hippo pathway.

TRIM32 promotes proliferation and confers chemoresistance to breast cancer cells through activation of the NF-κB pathway.

Dysregulation of TRIM32 has been implicated in several human cancers, however, its clinical significance and biological function in breast cancer have not been investigated. Using immunohistochemistry, we found that TRIM32 expression is upregulated in breast cancer tissues and that it correlates with advanced stage and poor prognosis. TRIM32 is also overexpressed in 4/7 breast cancer cell lines. CCK8 and colony formation assays showed that TRIM32 depletion inhibited proliferation and colony formation in the T47D cell line, while TRIM32 overexpression promoted MCF-7 cell growth and colony formation. Cell viability and Annexin V/PI staining demonstrated that TRIM32 maintained breast cancer cell survival and reduced apoptosis rate when cells were treated with cisplatin. Western blot analysis demonstrated that TRIM32 overexpression resulted in an upregulation of p-IκB, p-p65, cIAP1, and cIAP2 and a downregulation of p21 and p27 in MCF-7 cells. TRIM32 depletion in T47D cells demonstrated the opposite results, suggesting that TRIM32 may activate the NF-κB pathway. The NF-κB inhibitor BAY 11-7082 blocked the effects of TRIM32 on cisplatin resistance and cIAP1/2 protein regulation. Taken together, the present study demonstrates that TRIM32 downregulates p21/p27 and upregulates IAP family proteins to facilitate breast cancer cell growth and inhibit drug-induced apoptosis, possibly through the NF-κB signaling pathway.

Prognostic significance of tumor deposits in gastric cancer patients who underwent radical surgery.

BACKGROUND: To investigate the prognostic significance of tumor deposits (TDs) in gastric cancers patients who underwent radical surgery. METHODS: Clinicopathologic and prognostic data from 2998 gastric cancer patients who underwent R0 surgery with D2/D3 lymphadenectomy were retrospectively reviewed. A TD was defined as discrete foci of tumor found in the perigastric fat or in adjacent ligament away from the leading edge of the tumor and showing no evidence of residual lymph node tissue, but within the lymph drainage area of the primary carcinoma. RESULTS: TDs were detected in 17.8% of patients. TDs were more frequently observed in cancers of larger size, of Borrmann type 4, with lymphovascular invasion, deeper in depth of invasion, and with extended lymph node metastasis. Multivariate analysis confirmed the presence of TDs as 1 of independent factors predicting a poorer outcome. When stratified by pN category, significant differences in survival were observed between patients with and without TDs for those in pN0/pT1-3, pN1/pT3, pN2/pT1-3 and pN3/pT2-3 category, but not for those in pT4a and pT4b category. Moreover, for cancers in each pN category, the prognosis for patients with TDs in pT1-4a category was similar with that of those without TDs in pT4a category, but significantly better than that of those with or without TDs in pT4b category. A revised pT category and a revised pTNM system were proposed, in which all the cancers with TDs in pT1-4a category were incorporated into those without TDs in pT4a category according to the pN category. Further analysis revealed the revised pT category and the revised pTNM system had better homogeneity, discriminatory ability, and monotonicity of gradients than the American Joint Committee on Cancer (AJCC) pT category and the AJCC pTNM system, respectively, representing optimum prognostic stratification. CONCLUSION: TDs significantly correlated with gastric cancer patients' survival. It might be more suitable for TDs to be treated as a form of serosal invasion. Consequently, en bloc resection of the primary carcinoma is crucially important, and adjuvant chemotherapy should always be considered if TDs have been detected.

Evaluation of the seventh edition of American Joint Committee on Cancer TNM staging system for gastric cancer: results from a Chinese monoinstitutional study.

BACKGROUND: To investigate the validity of the 7th edition of American Joint Committee on Cancer (AJCC) TNM staging system for gastric cancer with special attention paid to pT2/pT3, pN1/pN2, and pN3a/pN3b category. MATERIALS AND METHODS: Clinicopathologic data of 1998 patients underwent R0 surgery for histologically proven gastric cancers with >15 lymph nodes retrieved were retrospectively reviewed. RESULTS: Prognoses were significantly different between pT2 and pT3 categories, between pN1 and pN2 categories, or between pN3a and pN3b categories. Each stage in the 6th edition was divided into the 7th edition stage with different survival rates. Moreover, stage IIIA, IIIB, and IIIC in the 7th edition system was divided into the 6th edition stage with different survival rates. Prognoses for patients in 7th edition T4aN1M0/T3N2M0/T2N3aM0, T4bN0-1M0/T4aN2M0/T3N3aM0, and T4aN3aM0/T4bN2M0 were similar to that of patients in T1N3bM0, T2N3bM0, and T3N3bM0, respectively, but significantly better than that of patients in T2N3bM0, T3N3bM0, and T4aN3bM0, respectively. However, no significant difference could be observed among patients in T4bN3aM0, T4aN3bM0, T4bN3bM0, and stage IV. A revised TNM system was proposed, in which T1N3bM0 was incorporated into stage IIIA, T2N3bM0 into stage IIIB, T3N3bM0 into stage IIIC, T4bN3aM0/T4aN3bM0/T4bN3bM0 into stage IV. Further analyses revealed the revised TNM system had better homogeneity, discriminatory ability, and monotonicity of gradients than the 6th and the 7th edition system. CONCLUSIONS: It is reasonable to subclassify the 6th edition pT2 category and pN1 category into the 7th edition pT2/pT3 category and pN1/pN2 category, respectively. However, for better prognostic stratification, it might be more suitable for pN3a and pN3b categories to be considered individual determinants of the 7th edition TNM staging system.

Splenic hilar lymph node metastasis independently predicts poor survival for patients with gastric cancers in the upper and/or the middle third of the stomach.

BACKGROUND: Effectiveness of splenectomy for advanced gastric cancers occupying the upper and/or the middle third of the stomach is still in debate. The aim of the present study is to elucidate the impact of splenectomy on patient survival by investigating the pathological characteristics and prognostic significance of splenic hilar lymph node metastasis. METHODS: Clinicopathologic and prognostic data of 265 patients with gastric cancer in the upper and/or the middle third of the stomach who underwent the operation of en bloc resection of primary cancer and D2/D3 lymphadenectomy combined with splenectomy were retrospectively reviewed. RESULTS: Multivariate analysis revealed pT category, pN category, and distant lymph node metastasis independently correlated with the presence of splenic hilar lymph node metastasis. Prognoses of patients with positive splenic hilar lymph nodes were significantly poorer than that of patients with negative splenic hilar lymph nodes for the entire study population and for those who underwent R0 resection, but not for those who underwent R1-2 resection. There was no significant difference in survival between patients who underwent R0 resection with positive splenic hilar lymph nodes and those who underwent R1-2 resection. Splenic hilar lymph node metastasis was one of independent indicators predicting worse prognosis and the presence of distant metastasis after surgery. Subset analysis according to the TNM stage revealed there were significant differences in survival between patients with and without splenic hilar lymph node metastasis. CONCLUSIONS: Splenic hilar lymph node metastasis should be considered as one of incurable factors. Consequently, the efficiency of splenectomy aiming at prolonging survival for patients with high risk of splenic hilar lymph nodes metastasis should be questioned, although resection of invasive organs form gastric cancers has been recommended if R0 surgery could be achieved.

Log odds of positive lymph nodes: a novel prognostic indicator superior to the number-based and the ratio-based N category for gastric cancer patients with R0 resection.

BACKGROUND: Log odds of positive lymph nodes (LODDS) is defined as the log of the ratio between the probability of being a positive lymph nodes and the probability of being a negative lymph nodes when one lymph node is retrieved. The value of LODDS staging system on prognostic assessment for gastric cancer patients with R0 resection is still unclear. METHODS: Clinicopathologic and prognostic data of 2547 gastric cancer patients underwent D2 or D3 lymphadenectomy with R0 surgery were retrospectively studied. RESULTS: Multivariate analysis indentified LODDS stage was an independent prognostic factor, but not pN classification or rN classification. The scatter plots of the relationship between LODDS and the number, the ratio of nodes metastasis, suggested that the LODDS stage had power to divide patients with the same number or ratio of nodes metastasis into different groups. For patients in each of the pN or rN classifications, significant differences in survival could always be observed among patients in different LODDS stages. However, for patients in each LODDS stage, prognosis was highly homologous between those in different pN or rN classifications. A minimum number of 10, 15, 20, 25, and 10 nodes retrieved should be met for patients in the pN0, pN1, pN2, pN3, and rN0-3 classifications, respectively, unless the hazard risks of death would be underestimated or overestimated. However, LODDS stage could discriminate among 5 groups of patients with highly homologous prognosis, regardless how many nodes retrieved. CONCLUSIONS: The LODDS system is more reliable than the Union Internationale Contre le Cancer and American Joint Committee on cancer pN system and the rN system for prognostic assessment.

Advanced gastric cancer with early cancer macroscopic appearance: is it worthy of D2 lymphadenectomy?

BACKGROUND: Previous studies report that 5.9-22.2% of patients with preoperatively diagnosed early gastric cancers were eventually proven to have advanced gastric cancers by postoperative pathological examination. Such misdiagnosed cases commonly had cancers with macroscopic appearance like early gastric cancer and consequently can be recognized as a subgroup of cancer, namely advanced gastric cancer with early cancer macroscopic appearance (eAGC). Theoretically eAGCs might require D2 lymphadenectomy, but frequently undergo limited lymphadenectomy. However, the validity of the limited surgery is still unclear. METHODS: Clinicopathologic features of 134 patients with eAGC were retrospectively reviewed and compared with those of patients with early gastric cancers and advanced gastric cancers, respectively. RESULTS: Clinicopathologic features of eAGCs were similar to those of submucosa cancers, but significantly different from those of mucosa cancers and other muscularis propria cancers. Tumor size, lymphatic and/or blood vessels invasion (LBVI), and depth of invasion were identified as independent factors predicting lymph node metastasis; however, postoperative stage was not. All patients with eAGCs were proven to have lymph node metastasis restricted to the perigastric lymph nodes and lymph nodes at stations 7, 8a, and 9. Age, LBVI, and depth of invasion were independent prognostic factors for patients with preoperatively diagnosed early gastric cancers; however, the misdiagnosis of early cancer and the option of lymphadenectomy (D2 or not D2) had no impact on patient survival. The incidence of recurrence of eAGCs was similar to that of submucosa cancers, but significantly different from that of mucosa cancers and other muscularis propria cancers. CONCLUSIONS: Modified gastrectomy B (dissection of perigastric lymph nodes and nodes at stations 7, 8a, and 9) might be recommended for patients with eAGCs.

A novel subclassification of pT2 gastric cancers according to the depth of muscularis propria invasion: superficial muscularis propria versus deep muscularis propria/subserosa.

PURPOSE: To propose a novel subclassification of pT2 gastric cancers according to the depth of muscularis propria (MP) invasion (superficial MP vs. deep MP/subserosa [SS]) and to investigate its impact in prognostic assessment. SUMMARY BACKGROUND DATA: The major change in the sixth edition of the International Union Against Cancer (UICC)/American Joint Committee on Cancer (AJCC) TNM classification concerned the pT (primary tumor) category. Specifically, pT2 lesions were divided into pT2a (invading the MP) and pT2b (invading the SS) to discriminate these intramural locations. However, the value of the modification is still debated. METHODS: One thousand two hundred fifty-six patients with pT2 cancers classified according to the UICC/AJCC pT staging system were reviewed. Among them, 214 (17.0%) were classified as invasion of the superficial MP (sMP) or inner circular muscle, 163 (13.0%) as invasion of the deep MP (dMP) or outer longitudinal muscle, and 879 (70.0%) as invasion of SS. Clinicopathologic features were compared between patients with sMP, dMP, and SS invasion. Overall survival rates were compared between the pT2a and pT2b stage cancers, according to the UICC/AJCC and the novel pT2 system. Two-step multivariate analysis was performed to identify the significantly important prognostic factors. RESULTS: There was significant difference in most of the clinicopathologic features between sMP and SS cancers. Although, only 5 factors (tumor location, tumor size, Borrmann type, metastasis number, and metastasis ratio) were significantly different between dMP and SS cancers. In step 1 of the multivariate analysis, the UICC/AJCC pT2 system was an independent factor that correlated with prognosis, but was substituted by the novel pT2 system in step 2 of the multivariate analysis. With a certain metastasis ratio of lymph nodes, the novel pT2 system discriminated 2 subsets of patients with significantly different prognoses, whereas the UICC/AJCC pT2 system did not. CONCLUSIONS: The novel pT2 staging system, which was subclassified as sMP and dMP/SS cancers, had more potential to identify the different prognoses for patients with pT2 gastric cancers.