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June 20, 2018

Breast Cancer Epigenetics Study Reveals Potential Drug Targets

In a study of mammary cell lineage, discovery proteomics has exposed stem and progenitor cell vulnerabilities to epigenetic drugs. Such drugs may inhibit the proliferative response to progesterone, which has been implicated in breast cancer. In these images, the epigenetic regulatory protein DNA methyltransferase 1 (green) is highly expressed in the luminal cells of mammary gland ducts (compared with basal cells, red). Treatment with the inhibitor decitabine (right) prevents luminal cell progenitors from expanding this population of cells in response to progesterone. [Casey et al., J. Cell Biol. 2018.]

  • Cell lineages that culminate in mammary gland development may also lead to breast cancer. Although these lineages, as well as the stem cells and progenitor cells they comprise, have been subjected to extensive study, the perturbations of these lineages that increase the risk of breast cancer have remained obscure, frustrating the search for chemoprevention drugs. Consequently, scientists based at the Princess Margaret Cancer Center in Toronto took a closer look at mammary cell lineages. These scientists now report that the proliferation of mammary gland stem cells in response to progesterone is promoted by epigenetic proteins.

    This discovery was detailed in a paper (“Mammary Molecular Portraits Reveal Lineage-Specific Features and Progenitor Cell Vulnerabilities”) that appeared June 19 in the Journal of Cell Biology. This paper, which describes the comprehensive profiling of the epigenomes, transcriptomes, and proteomes of cells isolated from mice and women and high risk of developing breast cancer, suggests that inhibiting epigenetic proteins with drugs could prevent the development of breast cancer in women at high risk of the disease.

    "Currently, there are no standard-of-care preventative interventions for women at high risk of breast cancer," said Rama Khokha, Ph.D., a senior scientist at Princess Margaret Cancer Center and a professor of medical biophysics at the University of Toronto. "Although it is becoming increasingly clear that stem and progenitor cells underlie cancer development, we lack strategies to target these cells for chemoprevention."

    To learn more about these progenitor cells and identify any vulnerabilities that could potentially be exploited to prevent the development of breast cancer, Dr. Khokha and colleagues isolated cells from the mammary glands of mice and examined how they changed in response to progesterone. The researchers had previously measured all of the RNA molecules produced by mammary gland cells. Now they quantified all of the cells' proteins and assessed the cells' epigenomes—the various chemical modifications to a cell's chromosomes that help determine which genes are turned on and off.

    “We define systems-level relationships between chromatin–DNA–RNA–protein states, identify lineage-specific DNA methylation of transcription factor binding sites, and pinpoint proteins underlying progesterone responsiveness,” wrote the authors of the JCB article. “Comparative proteomics of estrogen and progesterone receptor–positive and –negative cell populations, extensive target validation, and drug testing lead to discovery of stem and progenitor cell vulnerabilities.”

    This global overview of mammary gland cells revealed that in response to progesterone, progenitor cells—particularly luminal progenitor cells—upregulate many of the epigenetic regulatory proteins responsible for modifying the cells' chromosomes.

    Mammary glands contain two types of cells, basal and luminal, that arise from specialized stem or progenitor cells. During pregnancy or the menstrual cycle, progesterone induces basal and luminal progenitor cell numbers to expand and drive mammary gland formation. But mammary gland progenitors may also give rise to cancer. Progesterone exposure and stem cell proliferation have been linked to the development of breast cancer, and the number of progenitor cells is often elevated in women carrying mutations in BRCA1 or other genes that put them at a high risk of developing the disease.

    Following up on their discovery of “stem and progenitor cell vulnerabilities,” Dr. Khokha and colleagues tested multiple epigenetic inhibitors. "We thought,” Dr. Khoka explained, “that drugs that inhibit epigenetic regulatory proteins might suppress the proliferation of stem and progenitor cells in response to progesterone."

    “Top epigenetic drugs exert cytostatic effects; prevent adult mammary cell expansion, clonogenicity, and mammopoiesis; and deplete stem cell frequency,” the JBC paper added. “Select drugs also abrogate human breast progenitor cell activity in normal and high-risk patient samples.”

    The researchers tested multiple epigenetic inhibitors, many of which are already approved for use in humans by the FDA. Several of these drugs inhibited the proliferation of mammary gland progenitor cells and decreased their total number in mice. One, a drug called decitabine that inhibits DNA methyltransferase enzymes and is approved to treat myelodysplastic syndrome, delayed the formation of tumors in breast cancer–prone rodents.

    Khokha and colleagues then tested the effects of epigenetic inhibitors on mammary gland progenitor cells isolated from women at high risk of developing breast cancer. Progenitor cells from patients with BRCA1 mutations were particularly vulnerable to epigenetic inhibitors, including decitabine. Decitabine also suppressed the activity of progenitor cells from patients with mutations in the BRCA2 gene.

    "This demonstrates that the dependency of progenitor cells on specific epigenetic proteins is conserved between mice and humans and highlights the potential of epigenetic therapies to target these important cell types in the human breast as a form of chemoprevention," concluded Dr. Khokha.

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