Lnc RNA H19 is associated with poor prognosis in breast cancer patients and promotes cancer stemness.

PURPOSE: Aldehyde dehydrogenase1 (ALDH1) is widely accepted as a stem cell marker for normal breast as well as in breast cancer. Although the clinical impact of ALDH1 was observed in our previous study, we do not know how ALDH1 affects stem cell features resulting in worsening of prognosis in breast cancer. The purpose of this study is to explore ALDH1-related gene and its function on cancer stem cell (CSC). METHODS: In five cases of ALDH1-positive triple-negative breast cancer, mRNA expression profile was compared between ALDH1-positive and ALDH1-negative cells by Affymetrix microarray analysis after microdissection. Among the genes modulated in ALDH1-positive cells, we focused on H19, which encodes a long non-coding RNA, in this study. An in-vitro study was conducted with H19 siRNA in HCC1934 and iCSCL10A cell lines. The association of H19 with prognosis was examined in 180 breast cancer cases. RESULTS: Network analysis revealed the existence of five genes related with H19, including miR-103, miR-107, let-7, miR-29b-1, and Trx. In-vitro analysis showed that suppression of H19 using siRNA reduces sphere formation capacity in both HCC1934 and iCSCL10A cell lines. In clinical studies, H19 expression was associated with hormone negativity, tumor size, and nodal status. Patients with H19 expression had significantly poor disease-free survival (DFS) (26.3 vs. 64.8% at 5 years, p = 0.001) and overall survival (OS) (28.9 vs. 68.3% at 5 years, p = 0.004). The effect of H19 expression on prognosis was the most significant in triple-negative breast cancer compared to that in other subtypes (20.0 vs. 65.4% at 5 years DFS, p = 0.012, 20.0 vs. 69.2% at 5 years OS, p = 0.016). CONCLUSION: This study indicated that H19 was associated with stem cell phenotype in ALDH1-positive breast cancer. H19 regulates CSC and is associated with poor prognosis in breast cancer patients, particularly in triple-negative subtype.

Incidence and risk factors for rectovaginal fistula after low anterior resection for rectal cancer.

BACKGROUND: The rectovaginal fistula (RVF) is a rare complication after low anterior resection (LAR) for rectal cancer. The aim of this study was to evaluate the risk factors for RVF after LAR for rectal cancer. METHODS: This was a retrospective multi-institution study of 371 female rectal cancer patients who underwent LAR with anastomosis between January 2007 and December 2011. Patient-, tumor-, and surgery-related variables were examined by univariate and multivariate analyses. RESULTS: The overall RVF rate was 3.0 % (11/371). The RVF was diagnosed on median postoperative day 83 (15-766). In 81.8 % (9/11) of the patients, the diagnosis of RVF was made after hospital discharge. Multivariate analysis identified prognostic nutritional index (PNI; odds ratio (OR) 6.97; 95 % confidence interval (CI) 1.47-33.08; P = 0.015), preoperative chemotherapy (OR 27.31; CI 3.49-213.62; P = 0.002), tumor size (OR 5.90; CI 1.04-33.47; P = 0.045), intraoperative bleeding (OR 13.91; CI 1.34-144.42; P = 0.027), and lateral lymph node dissection (OR 4.92; CI 1.02-23.63; P = 0.045) as independent risk factors for RVF after LAR. CONCLUSIONS: Risk factors of RVF were PNI (<45), preoperative chemotherapy, tumor size (≧ 50 mm), intraoperative bleeding (≧ 200 ml), and lateral lymph node dissection. Before an operation, obtaining the information about these risk factors is of great importance in LAR for rectal cancer.

Bromodomain-containing Protein 4 Is a Favourable Prognostic Factor in Breast Cancer Patients.

AIM: To evaluate the association between bromodomain-containing protein 4 (BRD4) expression and clinicopathological factors and prognosis in human breast cancer specimens. PATIENTS AND METHODS: We used tissue microarrays constructed from samples of patients (n=183) who underwent surgery. We validated the association between BRD4 expression and prognosis in solid tumours, including breast cancer, using The Cancer Genome Atlas (TCGA) database. RESULTS: Immunohistochemical staining showed that BRD4 was widely distributed in breast cancer tissues. BRD4 was strongly expressed in 19.7% of patients but BRD4 staining intensity was not correlated with other clinicopathological factors. Most importantly, patients with a strong BRD4 expression had a significantly longer disease-specific survival than those with a weak BRD4 expression (100.0% vs. 91.3% at 5 years, p=0.027). mRNA expression analysis showed similar results (91.2% vs. 80.2% at 6 years, p=0.047). CONCLUSION: Strong BRD4 expression was associated with a significantly better prognosis in breast cancer tumours.

Development of an invasive ductal carcinoma in a contralateral composite nipple graft after an autologous breast reconstruction: a case report.

BACKGROUND: Nipple-areola complex (NAC) reconstruction is a technique used in breast reconstructive surgery, which is performed during the final stage of breast reconstruction after total mastectomy of primary breast cancer. Composite nipple grafts utilizing the contralateral NAC are common; however, to our knowledge, there are no reports of new primary invasive ductal carcinoma development within the graft. Here, we describe one such case for the first time. CASE PRESENTATION: A 54-year-old woman was referred to us by the Department of Plastic and Reconstructive Surgery in our medical center for further evaluation of right nipple erosion. She had undergone total mastectomy of the right breast following a breast cancer diagnosis 15 years ago, at which time tumor biological profiling revealed the following: estrogen receptor (ER), positive; progesterone receptor (PgR), negative; and human epidermal growth factor receptor 2 (HER2), undetermined. She received adjuvant chemotherapy and endocrine therapy. She defaulted endocrine therapy for a few years, and 7 years after surgery, she underwent autologous breast reconstruction with a deep inferior epigastric perforator (DIEP) flap. In the following year, NAC reconstruction was performed using a composite graft technique. Seven years after the NAC reconstruction, erosion appeared on the nipple grafted from its contralateral counterpart; scrape cytology revealed malignancy. The skin on the right side of her chest around the NAC and subcutaneous fat tissue consisted of transferred tissue from the abdomen, as the DIEP flap and grafted nipple were located on the graft skin. The right nipple carcinoma arose from the tissue taken from the left nipple. Magnetic resonance imaging (MRI) or computed tomography showed no malignant findings in the left breast. As the malignant lesion seemed limited to the area around the grafted right nipple on MRI, surgical resection with sufficient lateral and deep margins was performed around the right nipple. Pathological findings revealed invasive ductal carcinoma with comedo ductal components infiltrating the graft skin and underlying adipose tissue. Immunohistochemistry revealed positive for ER, PgR, and HER2. CONCLUSIONS: To our knowledge, this is the first case involving the development of invasive ductal carcinoma in a nipple graft constructed on the skin of a DIEP flap, with the origin from the contralateral breast's nipple.

Aldehyde Dehydrogenase 1-related Genes in Triple-negative Breast Cancer Investigated Using Network Analysis.

BACKGROUND/AIM: Aldehyde dehydrogenase 1 (ALDH1) is known as a breast cancer stem cell (CSC) marker. This study aimed to identify genes associated with ALDH1. MATERIALS AND METHODS: ALDH1-positive and -negative breast cancer cells were isolated using laser capture microdissection from five tissue samples of ALDH1-positive breast cancer patients. Messenger RNA expression levels were compared between ALDH1-positive and -negative cells. RESULTS: We found 104 differentially expressed genes between ALDH1-positive and -negative cells. Gene ontology and pathway analysis revealed that these genes were correlated with CSC functions and pathways. Network analyses identified 10 genes that were closely associated with ALDH1. We validated these 10 genes utilizing The Cancer Genome Atlas and the Molecular Taxonomy of Breast Cancer International Consortium cohort, and found that they were associated with ALDH1 expression and correlated with Wnt pathway signaling. CONCLUSION: The 10 genes we identified could be potential targets for CSC therapy of breast cancer.

Are breast cancer stem cells the key to resolving clinical issues in breast cancer therapy?

Despite the dramatic advances in breast cancer treatment over the past two decades, it is still the most common malignancies in women. One of the reasons patients succumb to breast cancer is treatment resistance leading to metastasis and recurrence. Recently, cancer stem cells (CSCs) have been suggested as a cause of metastasis and recurrence in several cancers because of their unique characteristics, including self-renewal, pluripotency, and high proliferative ability. Increasing evidence has implicated breast cancer stem cells (BCSCs) as essential for tumor development, progression, recurrence, and treatment resistance. BCSCs exhibit resistance to treatment owing to several inter-related factors, including overexpression of ATP-binding cassette (ABC) transporters and increased aldehyde dehydrogenase (ALDH) activity, DNA repair, and reactive oxygen species (ROS) scavenging. In addition, the Notch, Hedgehog, and Wnt signaling pathways have been suggested as the major pathways involved in the self-renewal and differentiation of BCSCs. Despite growing evidence suggesting the importance of BCSCs in progression and metastasis, clear criteria for the identification of BCSCs in clinical practice have yet to be established. Several potential markers have been suggested, including CD44+/CD24-/low, ALDH1, EpCAM/ESA, and nestin; however, there is no standard method to detect BCSCs. Triple-negative breast cancer, which shows initial chemosensitivity, demonstrates worsened prognosis due to therapy resistance, which might be related to the presence of BCSCs. Several clinical trials aimed at the identification of BCSCs or the development of BCSC-targeted therapy are in progress. Determining the clinical relevance of BCSCs may provide clues for overcoming therapy resistance in breast cancer.