Study of breast cancer incidence in patients of lymphangioleiomyomatosis

The online version of this article (doi:10.1007/s10549-016-3737-8) contains supplementary material, which is available to authorized user

Study of breast cancer incidence in patients of lymphangioleiomyomatosis

Molecular evidence has linked the pathophysiology of lymphangioleiomyomatosis (LAM) to that of metastatic breast cancer. Following on this observation, we assessed the association between LAM and subsequent breast cancer. An epidemiological study was carried out using three LAM country cohorts, from Japan, Spain, and the United Kingdom. The number of incident breast cancer cases observed in these cohorts was compared with the number expected on the basis of the country-specific incidence rates for the period 2000–2014. Immunohistochemical studies and exome sequence analysis were performed in two and one tumors, respectively. All cohorts revealed breast cancer standardized incidence ratios (SIRs) ≥ 2.25. The combined analysis of all cases or restricted to pre-menopausal age groups revealed significantly higher incidence of breast cancer: SIR = 2.81, 95 % confidence interval (CI) = 1.32–5.57, P = 0.009; and SIR = 4.88, 95 % CI = 2.29–9.99, P = 0.0007, respectively. Immunohistochemical analyses showed positivity for known markers of lung metastatic potential. This study suggests the existence of increased breast cancer risk among LAM patients. Prospective studies may be warranted to corroborate this result, which may be particularly relevant for pre-menopausal women with LAM. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10549-016-3737-8) contains supplementary material, which is available to authorized users

Situación de la Enseñanza General Básica en los centros públicos de la Comunidad de Madrid : estudio sobre el nivel de pensamiento y maduración psicosocial en los alumnos de octavo de EGB

Investigación realizada por los servicios psicopedagógicos de la Comunidad de Madrid sobre la situación de la Enseñanza General Básica en los centros públicos de la Comunidad de Madrid. Se trata de analizar como la escolaridad contribuye a la madurez intelectual y psicosocial de los niños, por lo que se escoge como muestra para dicha investigación al alumnado de octavo de EGB, último nivel de escolaridad. La investigación consiste, por una parte, en conocer la valoración que estos alumnos hacen del proceso seguido, el presente y su futuro inmediato. Y por otra parte, en realizar un análisis comparativo de las pruebas de rendimiento, pensamiento y madurez psicosocial por zonas geográficas de la Comunidad (capital, cinturón industrial o periférico y zona rural).MadridES

Correction: Lymphangioleiomyomatosis Biomarkers Linked to Lung Metastatic Potential and Cell Stemness.

[This corrects the article DOI: 10.1371/journal.pone.0132546.]

Study of breast cancer incidence in patients of lymphangioleiomyomatosis

The online version of this article (doi:10.1007/s10549-016-3737-8) contains supplementary material, which is available to authorized user

Lymphangioleiomyomatosis biomarkers linked to lung metastatic potential and cell stemness

Lymphangioleiomyomatosis (LAM) is a rare lung-metastasizing neoplasm caused by the proliferation of smooth muscle-like cells that commonly carry loss-of-function mutations in either the tuberous sclerosis complex 1 or 2 (TSC1 or TSC2) genes. While allosteric inhibition of the mechanistic target of rapamycin (mTOR) has shown substantial clinical benefit, complementary therapies are required to improve response and/or to treat specific patients. However, there is a lack of LAM biomarkers that could potentially be used to monitor the disease and to develop other targeted therapies. We hypothesized that the mediators of cancer metastasis to lung, particularly in breast cancer, also play a relevant role in LAM. Analyses across independent breast cancer datasets revealed associations between low TSC1/2 expression, altered mTOR complex 1 (mTORC1) pathway signaling, and metastasis to lung. Subsequently, immunohistochemical analyses of 23 LAM lesions revealed positivity in all cases for the lung metastasis mediators fascin 1 (FSCN1) and inhibitor of DNA binding 1 (ID1). Moreover, assessment of breast cancer stem or luminal progenitor cell biomarkers showed positivity in most LAM tissue for the aldehyde dehydrogenase 1 (ALDH1), integrin-ß3 (ITGB3/CD61), and/or the sex-determining region Y-box 9 (SOX9) proteins. The immunohistochemical analyses also provided evidence of heterogeneity between and within LAM cases. The analysis of Tsc2-deficient cells revealed relative over-expression of FSCN1 and ID1; however, Tsc2-deficient cells did not show higher sensitivity to ID1-based cancer inhibitors. Collectively, the results of this study reveal novel LAM biomarkers linked to breast cancer metastasis to lung and to cell stemness, which in turn might guide the assessment of additional or complementary therapeutic opportunities for LAM

Lymphangioleiomyomatosis biomarkers linked to lung metastatic potential and cell stemness

Lymphangioleiomyomatosis (LAM) is a rare lung-metastasizing neoplasm caused by the proliferation of smooth muscle-like cells that commonly carry loss-of-function mutations in either the tuberous sclerosis complex 1 or 2 (TSC1 or TSC2) genes. While allosteric inhibition of the mechanistic target of rapamycin (mTOR) has shown substantial clinical benefit, complementary therapies are required to improve response and/or to treat specific patients. However, there is a lack of LAM biomarkers that could potentially be used to monitor the disease and to develop other targeted therapies. We hypothesized that the mediators of cancer metastasis to lung, particularly in breast cancer, also play a relevant role in LAM. Analyses across independent breast cancer datasets revealed associations between low TSC1/2 expression, altered mTOR complex 1 (mTORC1) pathway signaling, and metastasis to lung. Subsequently, immunohistochemical analyses of 23 LAM lesions revealed positivity in all cases for the lung metastasis mediators fascin 1 (FSCN1) and inhibitor of DNA binding 1 (ID1). Moreover, assessment of breast cancer stem or luminal progenitor cell biomarkers showed positivity in most LAM tissue for the aldehyde dehydrogenase 1 (ALDH1), integrin-ß3 (ITGB3/CD61), and/or the sex-determining region Y-box 9 (SOX9) proteins. The immunohistochemical analyses also provided evidence of heterogeneity between and within LAM cases. The analysis of Tsc2-deficient cells revealed relative over-expression of FSCN1 and ID1; however, Tsc2-deficient cells did not show higher sensitivity to ID1-based cancer inhibitors. Collectively, the results of this study reveal novel LAM biomarkers linked to breast cancer metastasis to lung and to cell stemness, which in turn might guide the assessment of additional or complementary therapeutic opportunities for LAM

Lymphangioleiomyomatosis Biomarkers Linked to Lung Metastatic Potential and Cell Stemness

<div><p>Lymphangioleiomyomatosis (LAM) is a rare lung-metastasizing neoplasm caused by the proliferation of smooth muscle-like cells that commonly carry loss-of-function mutations in either the tuberous sclerosis complex 1 or 2 (<i>TSC1</i> or <i>TSC2</i>) genes. While allosteric inhibition of the mechanistic target of rapamycin (mTOR) has shown substantial clinical benefit, complementary therapies are required to improve response and/or to treat specific patients. However, there is a lack of LAM biomarkers that could potentially be used to monitor the disease and to develop other targeted therapies. We hypothesized that the mediators of cancer metastasis to lung, particularly in breast cancer, also play a relevant role in LAM. Analyses across independent breast cancer datasets revealed associations between low <i>TSC1/2</i> expression, altered mTOR complex 1 (mTORC1) pathway signaling, and metastasis to lung. Subsequently, immunohistochemical analyses of 23 LAM lesions revealed positivity in all cases for the lung metastasis mediators fascin 1 (FSCN1) and inhibitor of DNA binding 1 (ID1). Moreover, assessment of breast cancer stem or luminal progenitor cell biomarkers showed positivity in most LAM tissue for the aldehyde dehydrogenase 1 (ALDH1), integrin-ß3 (ITGB3/CD61), and/or the sex-determining region Y-box 9 (SOX9) proteins. The immunohistochemical analyses also provided evidence of heterogeneity between and within LAM cases. The analysis of <i>Tsc2</i>-deficient cells revealed relative over-expression of FSCN1 and ID1; however, <i>Tsc2</i>-deficient cells did not show higher sensitivity to ID1-based cancer inhibitors. Collectively, the results of this study reveal novel LAM biomarkers linked to breast cancer metastasis to lung and to cell stemness, which in turn might guide the assessment of additional or complementary therapeutic opportunities for LAM.</p></div

Positivity for breast cancer lung metastasis mediators in LAM tissue.

<p>(A) Representative results for FSCN1 and ID1 in two LAM cases. Arrows mark magnified fields shown in the insets. (B) Representative immunohistochemistry results for CD34 and FSCN1 in LAM tissue. Positivity for FSCN1 is greater and not limited to endothelial cells.</p

Immunohistochemical characterization of biomarkers in normal breast and lung tissue.

<p>(A) Representative hematoxylin-eosin and immunohistochemical staining in normal breast tissue. The observed patterns of positivity were those expected with the exception of ALDH1, which could have showed positivity in the basal and luminal cell layers of the acini; nonetheless, this can only be observed at the growing end and branching of the ducts [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0132546#pone.0132546.ref048" target="_blank">48</a>], which may be represented by the image shown in the right panel. Expression of ALDH1, CD61, FSCN1 and SOX9 was also seen in spindle-like cells surrounding the terminal extra-lobular ducts as well as in similar cells of the loose specialized intra-lobular stroma (arrows in insets). The results of CD61 are detailed for the basal cell layer in differentiated acini (a) and for spindle-like intra-lobular cells (b). The arrows mark magnified fields. (B) Representative hematoxylin-eosin and immunohistochemical staining in normal lung tissue. ALDH1 and FSCN1 mark the alveolar endothelium, and ALDH1 also marks the basal and luminal layers of the bronchioles. CD61, ID1 and SOX9 are not expressed in differentiated alveoli, and CD61 and SOX9 show positivity in the luminal and/or basal layers of the bronchioles.</p