The Ability to Generate Senescent Progeny as a Mechanism Underlying Breast Cancer Cell Heterogeneity

Background

Breast cancer is a remarkably heterogeneous disease. Luminal, basal-like, “normal-like”, and ERBB2+ subgroups were identified and were shown to have different prognoses. The mechanisms underlying this heterogeneity are poorly understood. In our study, we explored the role of cellular differentiation and senescence as a potential cause of heterogeneity.

Methodology/Principal Findings

A panel of breast cancer cell lines, isogenic clones, and breast tumors were used. Based on their ability to generate senescent progeny under low-density clonogenic conditions, we classified breast cancer cell lines as senescent cell progenitor (SCP) and immortal cell progenitor (ICP) subtypes. All SCP cell lines expressed estrogen receptor (ER). Loss of ER expression combined with the accumulation of p21^Cip1 correlated with senescence in these cell lines. p21^Cip1 knockdown, estrogen-mediated ER activation or ectopic ER overexpression protected cells against senescence. In contrast, tamoxifen triggered a robust senescence response. As ER expression has been linked to luminal differentiation, we compared the differentiation status of SCP and ICP cell lines using stem/progenitor, luminal, and myoepithelial markers. The SCP cells produced CD24+ or ER+ luminal-like and ASMA+ myoepithelial-like progeny, in addition to CD44+ stem/progenitor-like cells. In contrast, ICP cell lines acted as differentiation-defective stem/progenitor cells. Some ICP cell lines generated only CD44+/CD24-/ER-/ASMA- progenitor/stem-like cells, and others also produced CD24+/ER- luminal-like, but not ASMA+ myoepithelial-like cells. Furthermore, gene expression profiles clustered SCP cell lines with luminal A and “normal-like” tumors, and ICP cell lines with luminal B and basal-like tumors. The ICP cells displayed higher tumorigenicity in immunodeficient mice.

Conclusions/Significance

Luminal A and “normal-like” breast cancer cell lines were able to generate luminal-like and myoepithelial-like progeny undergoing senescence arrest. In contrast, luminal B/basal-like cell lines acted as stem/progenitor cells with defective differentiation capacities. Our findings suggest that the malignancy of breast tumors is directly correlated with stem/progenitor phenotypes and poor differentiation potential.     

Correlation between residual ridge resorption and radiomorphometric indices

doi: 10.1111/j.1741‐2358.2011.00514.x Correlation between residual ridge resorption and radiomorphometric indices Objectives: The study evaluated the relationship between residual ridge resorption (RRR) and radiomorphometric indices, including mandibular cortical index (MCI), mandibular cortical width (MCW) and panoramic mandibular index (PMI), along with demographic factors. Material and methods: Panoramic radiographs of 1863 patients over 20 years of age were assessed. Gender, age and dental status of each patient were recorded. Relationships between RRR and demographic factors and radiomorphometric indices were evaluated using chi‐square and Fisher’s exact tests with level of significance of p = 0.05. Results: Residual ridge resorption was not affected by gender (p > 0.05), but was more frequently seen in patients over the age of 50 compared with those below 49 years of age (p < 0.001). RRR was significantly associated with edentulism (p < 0.001) and with severe erosions of endosteal margin of mandible (p < 0.05). RRR was more frequently seen in patients with PMI below 0.30 (p < 0.001) and with MCW below 3 mm in 50‐ to 69‐year‐old age group (p < 0.001). Conclusions: Patients younger than 50 years of age who demonstrate severe erosions of endosteal margin of mandible and have MCW < 3 mm and PMI < 0.30 appear to be suitable candidates for early implant placement or for maintaining roots or natural teeth to preserve bone, regardless of gender.