Luminal epithelial cells within the mammary gland can produce basal cells upon oncogenic stress.

In the normal mammary gland, the basal epithelium is known to be bipotent and can generate either basal or luminal cells, whereas the luminal epithelium has not been demonstrated to contribute to the basal compartment in an intact and normally developed mammary gland. It is not clear whether cellular heterogeneity within a breast tumor results from transformation of bipotent basal cells or from transformation and subsequent basal conversion of the more differentiated luminal cells. Here we used a retroviral vector to express an oncogene specifically in a small number of the mammary luminal epithelial cells and tested their potential to produce basal cells during tumorigenesis. This in-vivo lineage-tracing work demonstrates that luminal cells are capable of producing basal cells on activation of either polyoma middle T antigen or ErbB2 signaling. These findings reveal the plasticity of the luminal compartment during tumorigenesis and provide an explanation for cellular heterogeneity within a cancer.

Contribution of an alveolar cell of origin to the high-grade malignant phenotype of pregnancy-associated breast cancer.

Pregnancy-associated breast cancers (PABCs) are tumors diagnosed during pregnancy or up to 5 years following parturition, and are usually high-grade, connective tissue-rich, and estrogen receptor (ER)/progesterone receptor-negative. Little is known about the cellular origin of PABCs or the mechanisms by which PABCs are initiated. Using the RCAS retrovirus to deliver the ErbB2 oncogene into the mammary epithelium of our previously reported MMTV-tva transgenic mice, we detected high-grade, poorly differentiated, stroma-rich and ER-negative tumors during pregnancy and lactation. These high-grade and stroma-rich tumors were less frequent in involuted mice or in age-matched nulliparous mice. More importantly, by generating a WAP-tva transgenic line for expression of ErbB2 selectively in WAP(+) mammary alveolar cells, we found that tumors had similar morphological phenotypes (high grade, poorly differentiated, stroma-rich and ER-negative), irrespective of the time since pregnancy and even in the absence of pregnancy. These data suggest that PABCs arise preferentially from an alveolar cell population that expands during pregnancy and lactation. This somatic mouse model may also be useful for preclinical testing of new prophylactic and therapeutic strategies against PABC.

Maternal obesity in ewes results in reduced fetal pancreatic ß-cell numbers in late gestation and decreased circulating insulin concentration at term.

About 30% of U.S. women of reproductive age are obese, a condition linked to offspring obesity and diabetes. This study utilized an ovine model of maternal obesity in which ewes are overfed to induce obesity at conception and throughout gestation. At mid-gestation, fetuses from these obese ewes are macrosomic, hyperglycemic, and hyperinsulinemic, and they exhibited markedly increased pancreatic weight and ß-cell numbers compared with fetuses of ewes fed to requirements. This study was conducted to establish fetal pancreatic phenotype and function in late gestation and at term in this ovine model. Multiparous ewes were fed a control (C, 100% National Research Council [NRC] recommendations) or obesogenic (OB, 150% NRC) diet from 60 days before conception to necropsy at day 135 of gestation or to lambing. No differences were observed in fetal size or weight on day 135 or in lamb birth weights between C and OB ewes. In contrast to our previously published results at mid-gestation, pancreatic weights (P < 0.01) and ß-cell numbers (P < 0.05) of OB fetuses were markedly lower than those from C fetuses, whereas the ß-cell apoptotic rate was increased (P < 0.05) in day 135 OB versus C fetuses. At birth, blood insulin concentration was lower (P < 0.05) and glucose level was higher (P < 0.05) in newborn lambs from OB versus C ewes. These data demonstrate differential impacts of maternal obesity on fetal pancreatic growth and ß-cell numbers during early and late gestation. During the first half of gestation there was a marked increase in pancreatic growth, ß-cell proliferation, and insulin secretion, followed by a reduction in pancreatic growth and ß-cell numbers in late gestation, resulting in reduced circulating insulin at term. It is speculated that the failure of the pancreas to return to a normal cellular composition and function postnatally could result in glucose/insulin dysregulation, leading to obesity, glucose intolerance, and diabetes in postnatal life.

Arugosin F: a new antifungal metabolite from the coprophilous fungus Ascodesmis sphaerospora.

Chemical studies of the coprophilous fungus Ascodesmis sphaerospora (JS 247) have led to the isolation of arugosin F (1), a new antifungal and antibacterial metabolite. The structure was determined based on NMR and MS data and on comparison with data for known members of the arugosin class. A known xanthone (2) was also isolated.

Bombardolides: new antifungal and antibacterial gamma-lactones from the coprophilous fungus Bombardioidea anartia.

Chemical studies of organic extracts from cultures of the coprophilous fungus Bombardioidea anartia have led to the discovery of bombardolides A--D (1--4), a series of new antifungal and antibacterial metabolites. Three of these metabolites (1--3) were obtained as inseparable pairs of geometric isomers. A new 3-substituted phenol (5) and the known compound asterriquinone B4 were also encountered. The structures of compounds 1--5 were determined by analysis of NMR and MS data.