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H2020Individual fellowship2016–2018

INTEGRISTEM · Functions of Integrins in Mammary Stem Cell Activity and Tumorigenesis

Horizon 2020 — Marie Skłodowska-Curie Actions

Duration
2016-05-01 → 2018-04-30
EU contribution
€185,076
Participants
1
Scheme
MSCA-IF

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Results in brief

Functions of Integrins in Mammary Stem Cell Activity and Tumorigenesis

Mammary gland is a bilayer of epithelial cells: the milk-producing luminal cell layer and the contractile basal cell layer that allows milk expulsion. Both layers contain stem cells, which are essential for the normal development of the gland during adult life (puberty, pregnancy, lactation). This bilayer is surrounded by a matrix, called extracellular matrix, whose main component, laminin, controls epithelial cell proliferation and survival. Anomalies of stem cells can lead to their uncontrolled proliferation and the development of cancer. Recent studies indicated that basal-like breast tumors, notably those with BRCA1 mutations, might originate from stem cells of the luminal cell layer. These tumors are aggressive and difficult to treat. Our project aimed to elucidate the role of receptors at the surface of luminal cells that interact with laminin, called integrins, as it might help identifying new targets for breast cancer treatment. To this end, laminin-binding integrins were inactivated specifically in luminal stem cells and consequences on normal mammary development and tumorigenesis studied. Our results demonstrated that laminin-binding integrins are essential for mammary gland development during gestation/lactation. Their impact on luminal stem cell amplification during tumor initiation is still under investigation.

Data: CORDIS, © European Union

Project objective

Understanding the functional interactions between mammary epithelium and its microenvironment, with a particular focus on the stem cell niche, represents a challenge for developmental and cancer biologists. Mammary epithelium is a bilayer, with a layer of luminal cells, producing milk, and a layer of basal myoepithelial cells. Both layers contain clonogenic stem/progenitor cells, which ensure the drastic epithelial expansion in puberty and pregnancy. Whilst basal stem cells are thought to be bipotent, luminal progenitors appear to be lineage-restricted in normal gland. Recent studies indicated that basal-like breast tumors, notably those with BRCA1 mutations, might originate from luminal progenitors. Our project aims to elucidate the role of integrin receptors for Laminin, major component of the mammary basement membrane, in the regulation of the luminal progenitor function during normal mammary development and tumorigenesis. To this end, α3 and α6 integrin chains were deleted from mammary luminal cells in vivo using CreLoxP system. Cre expression was driven to luminal progenitors by the Blg promoter, activated in this cell population in adult virgin mice and further on, during lobulo-alveolar development in pregnancy. The stem cell activity and the maintenance of the stem cell populations in mutant mammary glands will be analyzed at different developmental stages. Morphogenesis, proliferation, survival, differentiation as well as the regenerative and clonogenic potential of the mutant epithelium will be examined. We will study the cytoskeleton organization and the capacity of mutant cells for baso-apical polarization. To analyze the responses of integrin-depleted cells to hormones and growth factors at the molecular level, organotypic ex vivo cultures will be employed. The impact of Laminin-binding integrins on abnormal luminal progenitor amplification during tumor initiation will be tested in a mouse model of basal-like breast cancer induced by p53 and BRCA1 loss.

Original text from CORDIS.

Participants

  • INSTITUT CURIE · ParisCoordinatorFrance

Links

Data: CORDIS, © European Union