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      The Cellular Origin and Evolution of Breast Cancer

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          Abstract

          In this review, we will discuss how the cell of origin may modulate breast cancer intratumoral heterogeneity (ITH) as well as the role of ITH in the evolution of cancer. The clonal evolution and the cancer stem cell (CSC) models, as well as a model that integrates clonal evolution with a CSC hierarchy, have all been proposed to explain the development of ITH. The extent of ITH correlates with clinical outcome and reflects the cellular complexity and dynamics within a tumor. A unique subtype of breast cancer, the claudin-low subtype that is highly resistant to chemotherapy and most closely resembles mammary epithelial stem cells, will be discussed. Furthermore, we will review how the interactions among various tumor cells, some with distinct mutations, may impact breast cancer treatment. Finally, novel technologies that may help advance our understanding of ITH and lead to improvements in the design of new treatments also will be discussed.

          Abstract

          Intratumoral heterogeneity (ITH) reflects tumor complexity and has implications for clinical outcome and treatment. The cell of origin may modulate breast cancer ITH and evolution—as observed in the claudin-low subtype.

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          Evolution of the cancer stem cell model.

          Antonija Kreso, John E. Dick (2014)
          Genetic analyses have shaped much of our understanding of cancer. However, it is becoming increasingly clear that cancer cells display features of normal tissue organization, where cancer stem cells (CSCs) can drive tumor growth. Although often considered as mutually exclusive models to describe tumor heterogeneity, we propose that the genetic and CSC models of cancer can be harmonized by considering the role of genetic diversity and nongenetic influences in contributing to tumor heterogeneity. We offer an approach to integrating CSCs and cancer genetic data that will guide the field in interpreting past observations and designing future studies. Copyright © 2014 Elsevier Inc. All rights reserved.
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            Identification of selective inhibitors of cancer stem cells by high-throughput screening.

            Piyush B Gupta, Tamer Onder, Guozhi Jiang … (2009)
            Screens for agents that specifically kill epithelial cancer stem cells (CSCs) have not been possible due to the rarity of these cells within tumor cell populations and their relative instability in culture. We describe here an approach to screening for agents with epithelial CSC-specific toxicity. We implemented this method in a chemical screen and discovered compounds showing selective toxicity for breast CSCs. One compound, salinomycin, reduces the proportion of CSCs by >100-fold relative to paclitaxel, a commonly used breast cancer chemotherapeutic drug. Treatment of mice with salinomycin inhibits mammary tumor growth in vivo and induces increased epithelial differentiation of tumor cells. In addition, global gene expression analyses show that salinomycin treatment results in the loss of expression of breast CSC genes previously identified by analyses of breast tissues isolated directly from patients. This study demonstrates the ability to identify agents with specific toxicity for epithelial CSCs.
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              Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy.

              Xiaoxian Li, Michael Lewis, Jian Huang … (2008)
              Tumorigenic breast cancer cells that express high levels of CD44 and low or undetectable levels of CD24 (CD44(>)/CD24(>/low)) may be resistant to chemotherapy and therefore responsible for cancer relapse. These tumorigenic cancer cells can be isolated from breast cancer biopsies and propagated as mammospheres in vitro. In this study, we aimed to test directly in human breast cancers the effect of conventional chemotherapy or lapatinib (an epidermal growth factor receptor [EGFR]/HER2 pathway inhibitor) on this tumorigenic CD44(>) and CD24(>/low) cell population. Paired breast cancer core biopsies were obtained from patients with primary breast cancer before and after 12 weeks of treatment with neoadjuvant chemotherapy (n = 31) or, for patients with HER2-positive tumors, before and after 6 weeks of treatment with the EGFR/HER2 inhibitor lapatinib (n = 21). Single-cell suspensions established from these biopsies were stained with antibodies against CD24, CD44, and lineage markers and analyzed by flow cytometry. The potential of cells from biopsy samples taken before and after treatment to form mammospheres in culture was compared. All statistical tests were two-sided. Chemotherapy treatment increased the percentage of CD44(>)/CD24(>/low) cells (mean at baseline vs 12 weeks, 4.7%, 95% confidence interval [CI] = 3.5% to 5.9%, vs 13.6%, 95% CI = 10.9% to 16.3%; P )/CD24(>/low) cells (mean at baseline vs 6 weeks, 10.0%, 95% CI = 7.2% to 12.8%, vs 7.5%, 95% CI = 4.1% to 10.9%) and a statistically non-significant decrease in MSFE (mean at baseline vs 6 weeks, 16.1%, 95% CI = 8.7% to 23.5%, vs 10.8%, 95% CI = 4.0% to 17.6%). These studies provide clinical evidence for a subpopulation of chemotherapy-resistant breast cancer-initiating cells. Lapatinib did not lead to an increase in these tumorigenic cells, and, in combination with conventional therapy, specific pathway inhibitors may provide a therapeutic strategy for eliminating these cells to decrease recurrence and improve long-term survival.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cold Spring Harb Perspect Med
                Journal ID (iso-abbrev): Cold Spring Harb Perspect Med
                Journal ID (publisher-id): cshperspectmed
                Journal ID (hwp): cshperspectmed
                Title: Cold Spring Harbor Perspectives in Medicine
                Publisher: Cold Spring Harbor Laboratory Press (Cold Spring Harbor, New York )
                ISSN (Electronic): 2157-1422
                Publication date (Print): March 2017
                Volume: 7
                Issue: 3
                Electronic Location Identifier: a027128
                Affiliations
                [1 ]Department of Developmental Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213
                [2 ]Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213
                [3 ]Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030
                Author notes
                Article
                Accession ID: PMC5334246 Pmcid ID: PMC5334246 Pmc-uid ID: 5334246 Publisher ID: a027128
                DOI: 10.1101/cshperspect.a027128
                PMC ID: 5334246
                PubMed ID: 28062556
                SO-VID: e5c4203e-a605-4c73-8cb2-83ca137ca1c0
                Copyright © Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved
                History
                Page count
                Pages: 14
                Categories
                Subject: 118
                Subject: Perspectives

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