Increased androgen receptor expression in estrogen receptor-positive/progesterone receptor-negative breast cancer.

PURPOSE: Expression of estrogen receptor alpha (ER) and/or progesterone receptor (PR) defines luminal breast cancer. Even though androgen (AR) and glucocorticoid receptors (GR) are highly expressed in luminal breast cancers, prognostic value remains uncertain and concomitant expression of these four hormone receptors is still unexplored. METHODS: Here, we evaluated ER, PR, AR, and GR expression, using immunohistochemistry, in a cohort of 169 breast cancer patients and correlated these findings with clinical and pathological parameters. RESULTS: We found that AR is more frequently expressed and at higher levels in the ER+PR- subset compared to ER+PR+ tumors. There were no significant differences in GR expression between tumor subsets. Moreover, most luminal tumors also expressed either AR or GR and most basal tumors were also negative for AR and GR. CONCLUSION: These data suggest that targeting AR in ER+PR- tumors may represent a promising therapeutic alternative in hormonal refractory tumors.

Characterizing the Relapse Potential in Different Luminal Subtypes of Breast Cancers with Functional Proteomics.

Poor prognosis due to the high relapse and metastasis rates of breast cancer has been particularly linked to the luminal B subtype. The current study utilized MCF-7 and ZR-75-1 to investigate various luminal subtypes of breast cancers that have discrepant expressions in the estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2). Understanding of the differential protein profiles and the associated pathways could help alleviate the malignance and promote the long-term survival rate of breast cancer patients. Functional proteome tools were applied to comprehensively delineate the global protein alterations that reflect the varieties of biological features between the two subtypes. In this study, a total of 11 proteins with significant and meaningful changes were identified. These protein targets including PRX2, CK19, nucleophosmin and cathepsin D were mostly involved in cell differentiation or proliferation. Particularly, cathepsin D was highly expressed in the luminal B subtype. Moreover, the level of cathepsin-D was also upregulated in the clinical metastatic tissues. Accordingly, the RNA interference-mediated silencing of cathepsin D stimulated ER expression but suppressed the level of HER2. The knockdown of cathepsin D enhanced the level of ZO-1 and a remarkable decrease in N-cadherin was also detected. Again, the matrix metalloproteinases (MMP) activity was impaired under the cathepsin D abolishment. Collectively, this study represented a modality to explore novel relationships in a proteome complex and highlighted the functional roles of cathepsin D in treatment options for different subtypes of breast cancer.

Polymorphic variants of the hOGG1, APEX1, XPD, SOD2, and CAT genes involved in DNA repair processes and antioxidant defense and their association with breast cancer risk.

Breast cancer is one of the leading causes of mortality among women. The most frequently encountered tumors are luminal tumors. Associations of polymorphisms in the hOGG1 (rs1052133), APEX1 (rs1130409), XPD (rs13181), SOD2 (rs4880), and CAT (rs1001179) genes were studied in 313 nonsmoking postmenopausal patients with luminal B subtype breast cancer. The control group consisted of 233 healthy nonsmoking postmenopausal women. Statistically significant associations of the XPD and APEX1 gene polymorphisms with the risk of developing luminal B Her2-negative subtype of breast cancer were observed in a log-additive inheritance model, while the CAT gene polymorphism showed an association in a dominant inheritance model (OR = 1.41; CI 95 %: 1.08-1.85; Padj.= 0.011; OR = 1.39; CI 95 %: 1.07-1.81; Padj = 0.013 и OR = 1.70; CI 95 %: 1.19-2.43; Padj = 0.004, respectively). In the group of elderly women (aged 60-74 years), an association of the CAT gene polymorphism with the risk of developing luminal B subtype of breast cancer was found in a log-additive inheritance model (OR = 1.87; 95 % CI: 1.22-2.85; Padj = 0.0024). Using MDR analysis, the most optimal statistically significant 3-locus model of gene-gene interactions in the development of luminal B Her2-negative subtype breast cancer was found. MDR analysis also showed a close interaction and mutual enhancement of effects between the APEX1 and SOD2 loci and the independence of the effects of these loci from the CAT locus in the formation of luminal B subtype breast cancer.

EARS2 significantly coexpresses with PALB2 in breast and pancreatic cancer.

BACKGROUND: PALB2 (BRCA2 partner and localizer) is a BRCA2-interacting protein that is required for BRCA2 genome caretaker tasks and interacts with BRCA1. Women with PALB2 mutation have a 40% to 60% higher risk of breast cancer, almost equivalent to women who have BRCA mutations. PALB2 mutation may also increase the risk of pancreatic cancer. New guidelines for PALB2 mutation in breast cancer advise pancreatic cancer screening, which includes M.R.I.s of the pancreas as well as endoscopic ultrasonography, for women who have a family history of pancreatic cancer. Using the Cancer Genome Atlas (TCGA) and The Human Protein Atlas we examined genes that co-express with PALB2 in breast and pancreatic cancer. METHODS: We used cBioPortal for Cancer Genomics to analyze data in TCGA. cBioPortal provides visualization, analysis and download of large-scale cancer genomics data sets. We used the UCSC Xena Browser to additionally analyze gene expression in TCGA. RESULTS: Six genes, EARS2, ARL6IP1, DNAJA3, KNOP1, RPUSD1, and TMEM186, significantly coexpressed with PALB2 in both breast and pancreatic cancer. Glutamyl-tRNA synthetase 2 (EARS2) was the only gene coexpressing with PALB2 in the breast and pancreatic cancer subjects that was significantly related to pancreatic cancer survival. Elevated PALB2 and EARS2 gene expression are both significantly associated with the PAM50 Luminal B subtype and high risk of recurrence, suggesting why these women may need active intervention, such as prophylactic mastectomy. CONCLUSIONS: EARS2 expression might be a risk factor for pancreatic cancer in breast cancer patients with PALB2 mutations. By assessing EARS2 expression in breast tumors, the clinician might obtain a second piece of information that, with family history of pancreatic cancer, could inform the decision to perform pancreatic cancer screening.

Jolkinolide B inhibits proliferation or migration and promotes apoptosis of MCF-7 or BT-474 breast cancer cells by downregulating the PI3K-Akt pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The diterpenoids extracted from Euphorbia kansui S.L. Liou ex S.B.Ho, Euphorbia fischeriana Steud. have good antitumor effects. Jolkinolide B has anti-breast cancer effect, but it is unclear whether it has different therapeutic effects between luminal A subtype and luminal B subtype breast cancer. AIM OF THE STUDY: This study investigated the Jolkinolide B has different therapeutic, important targets and pathways effects between luminal A subtype and luminal B subtype breast cancer. MATERIALS AND METHODS: We used bioinformatics to predict the biological process and molecular mechanism of Jolkinolide B in treating two types of breast cancer. Then, in vitro, cultured MCF-7 cells and BT-474 cells were divided into control group, PI3K inhibitor + control group, Jolkinolide B group and PI3K inhibitor + Jolkinolide B group. The CCK-8 assay, Flow cytometric analysis and Transwell cell migration assay was used to detect the cell proliferation, apoptosis, and migration in each group, respectively. ELISA was used to measure the content of Akt and phosphorylated Akt (p-Akt) in cell lysis buffer. RESULTS: Compared to luminal A breast cancer, Jolkinolide B had more targets, proliferation, migration processes and KEGG pathways when treating luminal B subtype breast cancer. Jolkinolide B significantly prolonged the survival time of luminal B subtype breast cancer patients. Compared to the control group, the cell proliferation absorbance value (A value) and migration number of the two kinds of breast cancer cells in the Jolkinolide B group were decreased (P < 0.01, n = 6), and the number of apoptotic cells was increased (P < 0.01, n = 6). Compared to the Jolkinolide B group, the A value and migration number of the two types of breast cancer cells were significantly decreased in the PI3K inhibitor + Jolkinolide B group (P < 0.01, n = 6), and the number of apoptotic cells was significantly increased (P < 0.01, n = 6). In addition, compared to MCF-7 cells, the A value and migration number of BT-474 cells stimulated with Jolkinolide B were significantly decreased (P < 0.01, n = 6), and the number of apoptotic cells was significantly increased (P < 0.01, n = 6). Akt and p-Akt protein levels in the two breast cancer cell lines in the Jolkinolide B group were all decreased (P < 0.01, n = 6), especially in BT-474 cells stimulated by Jolkinolide B. CONCLUSION: Jolkinolide B regulates the luminal A and luminal B subtypes of breast cancer through PI3K-Akt, EGFR and other pathways. Jolkinolide B has more significant therapeutic effect on luminal B subtype breast cancer. In vitro, experiments verified that Jolkinolide B significantly inhibited the proliferation and migration activity of BT-474 breast cancer cells by downregulating the PI3K-Akt pathway.

Negative progesterone receptor status correlates with increased risk of breast cancer recurrence in luminal B HER2-positive and -negative subtypes.

OBJECTIVES: The prognostic significance of the progesterone receptor (PR) has been widely investigated in luminal A and luminal B [human epidermal growth factor receptor 2 (HER2)-] breast cancer subtypes, both of which are estrogen receptor (ER)-positive and HER2-negative. In contrast, few studies have focused on PR status in luminal B (HER2+) tumors. The aim of this study was to evaluate the impact of positive PR status on outcomes in patients with luminal B (HER2-) or luminal B (HER2+) breast cancer. METHODS: Survival analysis was performed to estimate the likelihood of distant recurrence and death in 469 breast cancer patients with the luminal B (HER2-) or luminal B (HER2+) subtype. The relationship between PR and HER2 status was also assessed. RESULTS: Of 387 luminal B (HER2-) and 82 luminal B (HER2+) cancers, PR+ was significantly more frequent in the former than the latter (86.3% vs. 61.0%, respectively; P<0.001). In univariate analysis, PR was identified as a significant favorable prognostic factor for distant disease-free survival and overall survival in both subtypes, but in multivariate analysis PR was not an independent prognostic factor. CONCLUSIONS: After patients with luminal B subtype were divided into two subgroups according to HER2 status, there was evidence of a relatively good prognosis in the PR+ subgroup. Further studies with a larger number of patients are recommended to validate these findings.

Dysregulation of TLR2 Serves as a Prognostic Biomarker in Breast Cancer and Predicts Resistance to Endocrine Therapy in the Luminal B Subtype.

Background: Breast cancer (BCa) is a serious global health burden among females, and the development of resistance represents an important challenge to BCa treatment. Here, we examined the expression of toll-like receptor 2 (TLR2) in BCa patients and the prognostic value of TLR2 for predicting endocrine resistance. Methods: The study included 150 BCa patients, of which 82 underwent endocrine therapy. TLR2 mRNA expression was measured by quantitative Real-Time PCR, and its prognostic value was determined by Kaplan-Meier survival analysis. Changes in the expression of TLR2 in BCa patients with endocrine resistance were assessed, and the value of TLR2 for predicting endocrine resistance was evaluated using the receiver operating characteristic curve analysis. Results: TLR2 expression was higher in BCa tissue than in normal tissue and associated with tumor size, HER2 status, tumor subtype, and TNM stage. TLR2 upregulation was associated with poor prognosis in patients with BCa, as well as endocrine resistance, and TLR2 upregulation was more prevalent among HER2-positive BCa cases. The predictive performance of TLR2 for endocrine resistance was higher in HER2-positive BCa than in other hormone receptor-positive BCa cases. Conclusion: TLR2 upregulation is a promising biomarker for prognosis and predicting resistance to endocrine therapy. The relationship between TLR2 and HER2 indicates that TLR2 may be involved in endocrine resistance through the HER2 signaling pathway in BCa.

Correlation of FANCM expression with clinical factors in luminal B breast cancer.

BACKGROUND: The genotype of Fanconi Anemia complementation group M (FANCM) was previously found to be associated with breast cancer risk in several populations. Here, we studied the expression of FANCM and its correlation with clinical characteristics in Chinese patients with breast cancer. METHODS: We performed an immunohistochemical study of FANCM protein in clinical breast cancer tissues from 310 patients along with 44 adjacent tissues. RESULTS: FANCM protein level is lower in triple-negative breast cancer tissues than in other subtypes (P = 0.008). In addition, high FANCM expression correlated with pathology type IDC (P = 0.040), estrogen receptor positive (P < 0.001), progesterone receptor positive (P = 0.001), and low Ki-67 status (P = 0.003). Multivariate analysis revealed that FANCM status was an independent prognostic factor for overall survival (P = 0.017) in luminal B breast cancer. CONCLUSIONS: FANCM levels are significantly associated with different subtypes of human breast cancer. Specifically, FANCM could play a role in the progression of luminal B breast cancer.

High collagen density augments mTOR-dependent cancer stem cells in ERα+ mammary carcinomas, and increases mTOR-independent lung metastases.

Metastatic estrogen receptor alpha positive (ERα+) cancers account for most breast cancer mortality. Cancer stem cells (CSCs) and dense/stiff extracellular matrices are implicated in aggression and therapy resistance. We examined this interplay and response to mTOR inhibition using ERα+ adenocarcinomas from NRL-PRL females in combination with Col1a1tmJae/+ (mCol1a1) mice, which accumulate collagen-I around growing tumors. Orthotopic transplantation of tumor cells to mCol1a1 but not wildtype hosts resulted in striking desmoplasia. Mammary tumors in mCol1a1 recipients displayed higher CSC activity and enhanced AKT-mTOR and YAP activation, and these animals developed more and larger lung metastases. Treatment with the mTOR inhibitor, rapamycin, with or without the anti-estrogen, ICI182780, rapidly diminished mammary tumors, which rapidly reversed when treatment ceased. In contrast, lung metastases, which exhibited lower proliferation and pS6RP, indicating lower mTOR activity, were unresponsive, and mCol1a1 hosts continued to sustain greater metastatic burdens. These findings shed light on the influence of desmoplastic tumor microenvironments on the CSC niche and metastatic behavior in ERα+ breast cancer. The differential mTOR dependence of local mammary tumors and pulmonary lesions has implications for success of mTOR inhibitors in advanced ERα+ disease.

RNA-seq data of invasive ductal carcinoma and adjacent normal tissues from a Korean patient with breast cancer.

Invasive ductal carcinoma is the most common type of breast cancer. Here, we provide a whole transcriptome shotgun sequencing (called RNA-seq) dataset conducted with ten samples of invasive ductal carcinoma tissue and three samples of adjacent normal tissue from a single Korean breast cancer patient (luminal B subtype). Differentially expressed genes (DEGs) were identified with a false discovery rate (FDR)-adjusted p-value of 0.05. Gene ontology analysis identified several key pathways, including lymphocyte activation. A list of differentially expressed genes is provided. The raw data was uploaded to the sequence read archive (SRA) database and the BioProject ID is PRJNA432903.

Luminal B breast cancer: patterns of recurrence and clinical outcome.

In recent years, most studies on breast cancer relapse and metastasis have focused on non-luminal breast cancers (including the basal-like and HER-2 subtypes) because of their poor prognosis. However, the luminal B subtype is more common, but this type has not been investigated as thoroughly. In the current study, we collected data on 258 patients with luminal-B breast cancer patients with recurrence and metastasis served as the observation group, and 189 patients with non-luminal breast cancer during the same period served as the control group. This study aimed to investigate the pattern of recurrence and clinical outcome after follow-up treatment for luminal B breast cancer. We found a higher proportion of local recurrence and single bone metastasis in patients with luminal B breast cancer than in patients in the non-luminal groups. The risk of recurrence and metastasis in patients with luminal B breast cancer during a 2- to 5-year period and after 5 years was still present, but the risk in patients with non-luminal breast cancers had obviously decreased during the same period. Patients with luminal B breast cancer with recurrence or/and metastasis had a better prognosis after reasonable treatment. The recurrence patterns and clinical outcomes of patients with luminal B breast cancer according to HER2 status were also different, to some degree. These results are of potential clinical relevance especially for the monitoring of clinical prognosis and targeted therapy intervention for luminal B breast cancer.