Analytical validation of CanAssist-Breast: an immunohistochemistry based prognostic test for hormone receptor positive breast cancer patients.

Background: CanAssist-Breast is an immunohistochemistry based test that predicts risk of distant recurrence in early-stage hormone receptor positive breast cancer patients within first five years of diagnosis. Immunohistochemistry gradings for 5 biomarkers (CD44, ABCC4, ABCC11, N-Cadherin and pan-Cadherins) and 3 clinical parameters (tumor size, tumor grade and node status) of 298 patient cohort were used to develop a machine learning based statistical algorithm. The algorithm generates a risk score based on which patients are stratified into two groups, low- or high-risk for recurrence.

Clinical validation of an immunohistochemistry-based CanAssist-Breast test for distant recurrence prediction in hormone receptor-positive breast cancer patients.

CanAssist-Breast (CAB) is an immunohistochemistry (IHC)-based prognostic test for early-stage Hormone Receptor (HR+)-positive breast cancer patients. CAB uses a Support Vector Machine (SVM) trained algorithm which utilizes expression levels of five biomarkers (CD44, ABCC4, ABCC11, N-Cadherin, and Pan-Cadherin) and three clinical parameters such as tumor size, grade, and node status as inputs to generate a risk score and categorizes patients as low- or high-risk for distant recurrence within 5 years of diagnosis. In this study, we present clinical validation of CAB.

Development of a Novel Proteomic Risk-Classifier for Prognostication of Patients With Early-Stage Hormone Receptor-Positive Breast Cancer.

Use of proteomic strategies to identify a risk classifier that estimates probability of distant recurrence in early-stage hormone receptor (HR)-positive breast cancer is relevant to physiological cellular function and therefore to intrinsic tumor biology. We used a 298-sample retrospective training set to develop an immunohistochemistry-based novel risk classifier called CanAssist-Breast (CAB) which combines 5 prognostically relevant biomarkers and 3 clinico-pathological parameters to arrive at probability of distant recurrence within 5 years from diagnosis. Five selected biomarkers, namely, CD44, ABCC4, ABCC11, N-cadherin, and pan-cadherin, were chosen based on their role in tumor metastasis.

A Circulating microRNA Signature Predicts Age-Based Development of Lymphoma.

Extensive epidemiological data have demonstrated an exponential rise in the incidence of non-Hodgkin lymphoma (NHL) that is associated with increasing age. The molecular etiology of this remains largely unknown, which impacts the effectiveness of treatment for patients. We proposed that age-dependent circulating microRNA (miRNA) signatures in the host influence diffuse large B cell lymphoma (DLBCL) development.

Smurf2 regulates hematopoietic stem cell self-renewal and aging.

The age-dependent decline in the self-renewal capacity of stem cells plays a critical role in aging, but the precise mechanisms underlying this decline are not well understood. By limiting proliferative capacity, senescence is thought to play an important role in age-dependent decline of stem cell self-renewal, although direct evidence supporting this hypothesis is largely lacking. We have previously identified the E3 ubiquitin ligase Smurf2 as a critical regulator of senescence.

Smurf2 suppresses B-cell proliferation and lymphomagenesis by mediating ubiquitination and degradation of YY1.

About half of patients with diffuse large B-cell lymphoma (DLBCL) do not respond to or relapse soon after the standard chemotherapy, indicating a critical need to better understand the specific pathways perturbed in DLBCL for developing effective therapeutic approaches. Mice deficient in the E3 ubiquitin ligase Smurf2 spontaneously develop B-cell lymphomas that resemble human DLBCL with molecular features of germinal centre or post-germinal centre B cells. Here we show that Smurf2 mediates ubiquitination and degradation of YY1, a key germinal centre transcription factor.

Serial transplantation of bone marrow to test self-renewal capacity of hematopoietic stem cells in vivo.

Hematopoietic stem cells (HSCs) have the ability to self-renew and replenish the blood and immune system for the life span of an individual. An age-associated decline in HSC function is responsible for the decreased immune function and increased incidence of myeloid diseases and anemia in the elderly. The changes in HSC function are thought to occur as the result of an intrinsic defect in the self-renewal potential of HSCs as they age.

Smurf2 regulates the senescence response and suppresses tumorigenesis in mice.

The E3 ubiquitin ligase Smurf2 mediates ubiquitination and degradation of several protein targets involved in tumorigenesis and induces senescence in human cells. However, the functional role of Smurf2 in tumorigenesis has not been fully evaluated. In this study, we generated a mouse model of Smurf2 deficiency to characterize the function of this E3 ligase in tumorigenesis.

Regulation of senescence in cancer and aging.

Senescence is regarded as a physiological response of cells to stress, including telomere dysfunction, aberrant oncogenic activation, DNA damage, and oxidative stress. This stress response has an antagonistically pleiotropic effect to organisms: beneficial as a tumor suppressor, but detrimental by contributing to aging. The emergence of senescence as an effective tumor suppression mechanism is highlighted by recent demonstration that senescence prevents proliferation of cells at risk of neoplastic transformation.