[show abstract][hide abstract] ABSTRACT: DNAJB6 is a constitutively expressed member of the HSP40 family. It has been described as a negative regulator of breast tumor progression and a regulator of epithelial phenotype. Expression of DNAJB6 is reported to be compromised with tumor progression. However, factors responsible for its downregulation are still undefined. We used a knowledge-based screen for identifying miRNAs capable of targeting DNAJB6. In this work, we present our findings that hsa-miR-632 (miR-632) targets the coding region of DNAJB6. Invasive and metastatic breast cancer cells express high levels of miR-632 compared with mammary epithelial cells. Analysis of RNA from breast tumor specimens reveals inverse expression patterns of DNAJB6 transcript and miR-632. In response to exogenous miR-632 expression, DNAJB6 protein levels are downregulated and the resultant cell population shows significantly increased invasive ability. Silencing endogenous miR-632 abrogates invasive ability of breast cancer cells and promotes epithelial like characteristics noted by E-cadherin expression with concomitant decrease in mesenchymal markers such as Zeb2 and Slug. Thus, miR-632 is a potentially important epigenetic regulator of DNAJB6, which contributes to the downregulation of DNAJB6 and plays a supportive role in malignant progression.
[show abstract][hide abstract] ABSTRACT: Non-steroidal anti-inflammatory drugs (NSAIDs) have been widely reported to display strong efficacy for cancer chemoprevention, although their mechanism of action is poorly understood. The most well-documented effects of NSAIDs include inhibition of tumor cell proliferation and induction of apoptosis, but their effect on tumor cell invasion has not been well studied. Here, we show that the NSAID, sulindac sulfide (SS) can potently inhibit the invasion of human MDA-MB-231 breast and HCT116 colon tumor cells in vitro at concentrations less than those required to inhibit tumor cell growth. To study the molecular basis for this activity, we investigated the involvement of microRNA (miRNA). A total of 132 miRNAs were found to be altered in response to SS treatment, including miR-10b, miR-17, miR-21 and miR-9, which have been previously implicated in tumor invasion and metastasis. We confirmed that these miRNA can stimulate tumor cell invasion and show that SS can attenuate their invasive effects by downregulating their expression. Employing luciferase and chromatin immunoprecipitation assays, NF-κB was found to bind the promoters of all four miRNAs to suppress their expression at the transcriptional level. We show that SS can inhibit the translocation of NF-κB to the nucleus by decreasing the phosphorylation of IKKβ and IκB. Analysis of the promoter sequences of the miRNAs suppressed by SS revealed that 81 of 115 sequences contained NF-κB-binding sites. These results show that SS can inhibit tumor cell invasion by suppressing NF-κB-mediated transcription of miRNAs.Oncogene advance online publication, 30 January 2012; doi:10.1038/onc.2011.655.
[show abstract][hide abstract] ABSTRACT: Surgical resection was the first effective treatment for breast cancer and remains the most important treatment modality for curative intent. Refinements in operative techniques along with the use of adjuvant radiotherapy and advanced chemotherapeutic agents have facilitated increasingly focused breast cancer operations. Surgical management of breast cancer has shifted from extensive and highly morbid procedures, to the modern concept obtaining the best possible cosmetic result in tandem with the appropriate oncological resection. An ever-growing comprehension of breast cancer biology has led to substantial advances in molecular diagnosis and targeted therapies. An emerging frontier involves the breast cancer microenvironment, as a thorough understanding, while currently lacking, represents a critical opportunity for diagnosis and treatment. Collectively, these improvements will continue to push all therapeutic interventions, including operative, toward the goal of becoming more focused, targeted, and less morbid.
International journal of breast cancer. 01/2012; 2012:516417.
[show abstract][hide abstract] ABSTRACT: Matrix-producing carcinoma (MPC) of the breast is a rare variant of the uncommon group of malignancies categorized as metaplastic breast carcinomas with heterologous elements. The major criterion for a diagnosis of MPC is the presence of invasive breast carcinoma with the direct transition to a cartilaginous or osseous stromal matrix without an intervening spindle cell component. The cellular origin of MPC remains unclear. It has been suggested that tumor cells in MPC have combined epithelial and mesenchymal features. Several reports have suggested that the tumor cells originate from myoepithelial cells. The prognosis of patients with MPC was originally described as similar to invasive mammary carcinomas of no special type (NST) of the same stage, but a more recent study has shown a worse prognosis than same-stage NSTs.
The Breast Journal 01/2010; 16(4):420-3. · 1.83 Impact Factor
[show abstract][hide abstract] ABSTRACT: Breast Cancer Metastasis Suppressor 1 (BRMS1) suppresses metastasis of human breast cancer, ovarian cancer and melanoma in athymic mice. Studies have also shown that BRMS1 is significantly downregulated in some breast tumors, especially in metastatic disease. However, the mechanisms which regulate BRMS1 expression are currently unknown. Upon examination of the BRMS1 promoter region by methylation specific PCR (MSP) analysis, we discovered a CpG island (-3477 to -2214), which was found to be hypermethylated across breast cancer cell lines. A panel of 20 patient samples analyzed showed that 45% of the primary tumors and 60% of the matched lymph node metastases, displayed hypermethylation of BRMS1 promoter. Furthermore, we found a direct correlation between the methylation status of the BRMS1 promoter in the DNA isolated from tissues, with the loss of BRMS1 expression assessed by immunohistochemistry. There are several studies investigating the mechanism by which BRMS1 suppresses metastasis; however thus far there is no study that reports the cause(s) of loss of BRMS1 expression in aggressive breast cancer. Here we report for the first time that BRMS1 is a novel target of epigenetic silencing; and aberrant methylation in the BRMS1 promoter may serve as a cause of loss of its expression.
Clinical and Experimental Metastasis 07/2008; 25(7):753-63. · 3.46 Impact Factor
[show abstract][hide abstract] ABSTRACT: Metaplastic breast carcinoma is a rare entity with the distinguishing feature of having epithelial and mesenchymal tissue types incorporated within one tumor. This is a case report of a patient found to have a rare metaplastic breast carcinoma with prominent osseous differentiation. Radiologic and pathologic correlation is provided.
Southern Medical Journal 03/2006; 99(2):168-70. · 0.92 Impact Factor
[show abstract][hide abstract] ABSTRACT: Fibromatosis of the breast is a rare benign tumor that should be included in the differential diagnosis for breast cancer. It is usually indistinguishable from malignancy on ultrasound, mammography, physical examination, and on gross evaluation. Distinction is easily made by histologic findings. This benign tumor does not metastasize, but is locally aggressive and tends to recur postoperatively, which accounts for considerable morbidity. We present two cases and a discussion from the perspective of the radiologist, the surgeon, and the pathologist.
Southern Medical Journal 12/2004; 97(11):1100-3. · 0.92 Impact Factor
[show abstract][hide abstract] ABSTRACT: Infiltrating syringomatous adenomas are rare lesions of the nipple that were first described in 1983. The exact origin of these lesions is uncertain, although derivation from eccrine structures of the nipple has been postulated because the lesions are microscopically reminiscent of other tumors of eccrine origin, such as syringomatous carcinoma. The lesions are usually infiltrative, showing an expansile pattern of proliferation into adjacent tissues of the nipple and underlying breast. Involvement of the epidermis, however, has not been described. The lesions behave in a benign fashion, with no evidence of regional or distant metastasis in any of the reported cases. Complete local excision appears to be sufficient therapy, with only incompletely excised cases showing recurrence. We report an additional case of infiltrating syringomatous adenoma of the nipple and review the medical literature related to this lesion published in the 20 years since its initial description.
The Breast Journal 01/2004; 10(5):443-7. · 1.83 Impact Factor