Project description:Most breast cancers are luminal, depending on estrogens for growth. The remainder lack estrogen receptors, are hormone-resistant and basal-like. It is thought that breast cancers arise from self-renewing normal stem cells that have undergone malignant transformation. However currently reported cancer stem cells are hormone insensitive and generate basal, rather than luminal tumors. We now describe true luminal hormone-responsive breast cancer stem cells that express estrogen and progesterone receptors. Their self-renewal capacity is protected by progesterone. Stem cell levels are depleted by estrogens as tumors transition into differentiated and homogeneous luminal states. But, if added to estrogens, progesterone promotes heterogeneity and “rescues” the stem cells. By keeping luminal cancer stem cells “safe”, progesterone, widely used for contraception and hormone replacement, could be harmful to breast cancer survivors or women with occult disease.
Project description:To evaluate the methylation profiles of breast cell lines, we performed methylation profiling of 55 well-characterized breast cancer cell lines on the Illumina HumanMethylation27 (HM27) platform and made use of publicly available methylation profiles of primary breast tumors for comparison. The available annotation for each cell line includes estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status, as well as the tumor type, and the age of each patient. Additionally, recent publications have described genome-wide mRNA expression profiles for most of these lines, and samples were classified on the basis of the expression profile into Basal A (BaA), Basal B/Claudin Low (BaB/CLDNlow) and Luminal (Lu) subtypes. Finally, GI50 has been calculated for these cell lines for 77 approved therapeutic agents. We find that the DNA methylation profiles of breast cancer cell lines largely retain the features that characterize primary tumors, although there are crucial differences as well. We assayed DNA methylation in 55 breast cancer cell lines. DNA extracted from breast cell lines was bisulfite treated and hybridized to Illumina HM27 arrays.
Project description:Breast cancer is a common disease with distinct tumor subtypes which can be phenotypically characterized by estrogen receptor, progesterone receptor and HER2/neu receptor status. MiRNAs play regulatory roles in tumor initiation and progression. Altered miRNA expression has been demonstrated in a variety of cancer states to date presenting the potential for exploitation as cancer specific biomarkers. Blood presents an attractive medium biomarker discovery. This study investigated systemic miRNAs differentially expressed in Luminal A (ER+PR+HER2/neu-) breast cancer and their effectiveness as oncologic biomarkers in the clinical setting. Blood samples were prospectively collected from consenting patients with Luminal A breast cancer (n=10) and controls (n=10). RNA was extracted, reverse transcribed and subjected to microarray analysis (n=10 Luminal A; n=10 Control). Differentially expressed miRNAs were identified by artificial neural network (ANN) data-mining algorithms.
Project description:Many Luminal breast cancers are heterogeneous, containing substantial numbers of estrogen (ER-) and progesterone (PR-) receptor-negative cells among the ER+PR+ ones. Currently, the Basal-like ER-PR- Luminobasal subpopulation in Luminal disease is not targeted for treatment. To address the relationships between ER+PR+ and ER-PR- cells in Luminal cancers and tightly control their ratios, we have generated isogenic pure Luminal (pLUM) and pure Luminobasal (pLB) cells from the same parental Luminal human breast cancer cell line. We show that pLUM suppress proliferation of pLB cells in mixed-cell 3D colonies in vitro and in pLUM:pLB mixed-cell xenografts in mice. High-throughput screening of FDA-approved oncology drugs reveal pLB cells are sensitive to the EGFR inhibitors Gefitinib and Erlotinib. In mixed-cell 3D colonies and mixed-cell solid mouse tumors, combination therapy with the antiestrogen Fulvestrant and the EGFRi Gefitinib constitutes a robust treatment strategy. We propose that response to combination endocrine/EGFRi therapies in heterogeneous Luminal cancers will improve long-term survival in patients whose primary tumors have been preselected for the appropriate biomarkers.