Semaphorin signaling via MICAL3 induces symmetric cell division to expand breast cancer stem-like cells.

Cancer stem-like cells (CSCs) are expanded in the CSC niche by increased frequency of symmetric cell divisions at the expense of asymmetric cell divisions. The symmetric division of CSCs is important for the malignant properties of cancer; however, underlying molecular mechanisms remain largely elusive. Here, we show a cytokine, semaphorin 3 (Sema3), produced from the CSC niche, induces symmetric divisions of CSCs to expand the CSC population. Our findings indicate that stimulation with Sema3 induced sphere formation in breast cancer cells through neuropilin 1 (NP1) receptor that was specifically expressed in breast CSCs (BCSCs). Knockdown of MICAL3, a cytoplasmic Sema3 signal transducer, greatly decreased tumor sphere formation and tumor-initiating activity. Mechanistically, Sema3 induced interaction among MICAL3, collapsin response mediator protein 2 (CRMP2), and Numb. It appears that activity of MICAL3 monooxygenase (MO) stimulated by Sema3 is required for tumor sphere formation, interaction between CRMP2 and Numb, and accumulation of Numb protein. We found that knockdown of CRMP2 or Numb significantly decreased tumor sphere formation. Moreover, MICAL3 knockdown significantly decreased Sema3-induced symmetric divisions in NP1/Numb-positive BCSCs and increased asymmetric division that produces NP1/Numb negative cells without stem-like properties. In addition, breast cancer patients with NP1-positive cancer tissues show poor prognosis. Therefore, the niche factor Sema3-stimulated NP1/MICAL3/CRMP2/Numb axis appears to expand CSCs at least partly through increased frequency of MICAL3-mediated symmetric division of CSCs.

ErbB receptor tyrosine kinase/NF-κB signaling controls mammosphere formation in human breast cancer.

Breast cancer is one of the most common cancers in humans. However, our understanding of the cellular and molecular mechanisms underlying tumorigenesis in breast tissues is limited. Here, we identified a molecular mechanism that controls the ability of breast cancer cells to form multicellular spheroids (mammospheres). We found that heregulin (HRG), a ligand for ErbB3, induced mammosphere formation of a breast cancer stem cell (BCSC)-enriched population as well as in breast cancer cell lines. HRG-induced mammosphere formation was reduced by treatment with inhibitors for phosphatidyl inositol 3-kinase (PI3K) or NF-κB and by expression of IκBα-Super Repressor (IκBαSR), a dominant-negative inhibitor for NF-κB. Moreover, the overexpression of IκBαSR in breast cancer cells inhibited tumorigenesis in NOD/SCID mice. Furthermore, we found that the expression of IL8, a regulator of self-renewal in BCSC-enriched populations, was induced by HRG through the activation of the PI3K/NF-κB pathway. These findings illustrate that HRG/ErbB3 signaling appears to maintain mammosphere formation through a PI3K/NF-κB pathway in human breast cancer.

Primary non-Hodgkin's lymphoma of the breast treated nonsurgically: report of three cases.

Extranodal non-Hodgkin's lymphoma (NHL) is a rare breast disease. Here we report three cases of primary NHL of the breast. The first patient was a 29-year-old woman with a firm mass in her right breast with ipsilateral axillary lymphadenopathy. An excisional biopsy revealed NHLs. Clinical stage was IIAE. The tumor and enlarged lymph nodes had successfully been treated following the combination therapy. The second patient was a 70-year-old women with an elastic hard mass in her left breast. An excisional biopsy revealed NHLs and clinical stage was 1AE. The tumor disappeared following the combination therapy. The third patient was a 67-year-old women with a hard mass in her left breast. Core needle biopsy revealed NHLs and clinical stage was 1AE. The tumor disappeared following chemotherapy. All patients are alive with no evidence of recurrence 4-8 years after the initial treatment. Although a standard treatment has yet to be established, an initial treatment with combination therapy without surgical intervention including axillary dissection appears to be appropriate for this rare disease.

Luminal and cancer cells in the breast show more rapid telomere shortening than myoepithelial cells and fibroblasts.

Critically shortened, dysfunctional telomeres may play a role in the genetic instabilities commonly found in cancer. We analyzed 30 surgical specimens of invasive breast carcinoma from women aged 34 to 91 years and estimated telomere lengths as telomere-to-centromere ratio values in the 5 different cell types comprising breast tissue in order to clarify telomere length variations within and between individuals using our tissue quantitative fluorescence in situ hybridization method. We obtained 3 novel findings. (1) In corresponding normal tissues, telomere length decreased in the order myoepithelial cells > normal-appearing fibroblasts > luminal epithelial cells, and telomere lengths were characteristic in these 3 cell types within each individual. (2) As expected, cancer cells had significantly shorter telomeres than myoepithelial cells (P < .0001) and normal-appearing fibroblasts (P = .0161), but there was no significant difference in telomere length between luminal cells and cancer cells (P = .6270). (3) Fibroblasts adjacent to cancer had longer telomeres than normal-appearing fibroblasts distant from cancer (P < .0001). This study, which represents the first reported assessment of telomere length variations in the 5 cell types comprising breast tissue within and between individuals, revealed that normal luminal epithelial cells and cancer cells had the shortest telomeres. Our new findings indicate that telomeres of background luminal cells are as short as those of cancer cells. Tissue quantitative fluorescence in situ hybridization, applicable to analysis of individual cells in tissue sections, is considered to be a powerful technique with considerable promise for studies in oncology.

Excision of postesophageal parathyroid adenoma in posterior mediastinum with intraoperative 99mTechnetium sestamibi scanning.

Although approximately 25% of parathyroid tumors in patients with primary hyperparathyroidism are located in the mediastinum, nearly all these tumors can be removed through cervical exploration. However, 1% to 2% of the mediastinal tumors require a transthoracic approach for removal. The mediastinal tumors are usually located in the inferior parathyroid gland, and the ectopic mediastinal tumors derived from the superior glands are extremely rare. We present a case of retroesophageal mediastinal parathyroid adenoma that developed in the left superior parathyroid gland. A thoracotomy was required to remove this tumor. Radioisotope-guided surgery was effective at identifying the tumor.

Preoperative evaluation of thyroid pathology in patients with primary hyperparathyroidism.

In parathyroidectomy, it has been recognized that a shift to a minimally invasive procedure may be accompanied by a possibility of missing thyroid pathology. However, only a few findings concerning preoperative thyroid evaluation have been reported. We investigated the prevalence of concomitant thyroid pathology by preoperative neck ultrasonography (US) in patients with primary hyperparathyroidism. There were 85 patients (66 women, 19 men; mean age 57 years) in the study group. The mean preoperative calcium level was 11.2mg/dL, and the mean intact parathyroid hormone level was 206 pg/mL. All patients underwent neck US following fine-needle aspiration biopsy (FNAB). Of the 85 patients, 21 (24.7%) had thyroid nodules. Among 21 patients with thyroid nodules, 9 (10.6%) had malignant thyroid tumors, while 12 (14.1%) patients had benign thyroid nodules including multinodular goiter. Of the 9 patients with malignant thyroid nodules, 4 had papillary carcinomas with lymph node metastases. The prevalence of thyroid disease associated with hyperparathyroidism is high, and evaluation of the thyroid pathology by US enables the shift from bilateral neck exploration to the minimally invasive parathyroid surgery.

The pathological findings of vasculitis simultaneously occurring with carcinoma, invasive breast carcinoma in a patient with Behçet's disease.

We present a rare case of invasive right breast carcinoma in a 72-year-old woman with Behçet's disease (BD). A radical modified right mastectomy and axillary lymphadenectomy were performed and postoperative hormonal therapy with the aromatase inhibitor anastrozole was administered for adjuvant therapy. At 10 months follow-up the patient remains disease free. Malignancies associated with BD are very uncommon. The pathological findings showed small vessel vasculitis and lobulitis of the breast in association with invasive carcinoma.