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Desensitization of human breast progenitors by a transient exposure to pregnancy levels of estrogen

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

Full term pregnancy at an early age is the only factor known to consistently protect against breast cancer. Because hormone receptor positive progenitors in the human breast relay endocrine signaling, we here sought to determine whether an experimental mimicry of the third trimester surge of hormones would change their susceptibility to growth stimulation. Hormone receptor positive, reduction mammoplasty-derived human breast epithelial progenitors were exposed to a short-term, pregnancy-level of estradiol, and their subsequent response to estradiol stimulation was analyzed. Exposure to pregnancy-level of estradiol results in subsequent lower sensitivity to estrogen-induced proliferation. Expression array and immunoblotting reveal upregulation of S100A7 and down-regulation of p27, both associated with parity and epithelial differentiation. Notably, we find that the epithelial differentiation is accompanied by upregulation of E-cadherin and down-regulation of vimentin as well as by diminished migration and more mature luminal epithelial differentiation in a mouse transplantation model. Our findings are in support of a de-sensitization mechanism for pregnancy-induced prevention against breast cancer.

OriginalsprogEngelsk
Artikelnummer17232
TidsskriftScientific Reports
Vol/bind11
Antal sider7
ISSN2045-2322
DOI
StatusUdgivet - 2021

Bibliografisk note

Funding Information:
We thank Lena Kristensen, Tove Marianne Lund, and Anita Sharma Friismose for expert technical assistance and Line S. Dyreborg for help with immunostainings. Capio CFR Hospitaler (Benedikte Thuesen and Trine Foged Henriksen) and the donors are acknowledged for providing breast biopsy material. The Core Facility for Integrated Microscopy (University of Copenhagen) is acknowledged for confocal microscope accessibility, and Gelo Dela Cruz and the DanStem Flow Cytometry Platform for support and use of FCS express software. We thank Drs. Marie Shamseddin and Cathrin Brisken, École Polytechnique Fédérale Lausanne, Switzerland for introducing Marie C. Klitgaard to the intraductal HIM transplantation technique. This work was supported by Novo Nordisk Fonden (NNF17CC0027852) and Danish Research Council grant 10-092798 (to DanStem), Toyota-Fonden Denmark and Anita og Tage Therkelsens Fond (to R.V.), Familien Erichsens Mindefond and Vera og Carl Johan Michaelsens Legat (to J.K.), Harboefonden, Else og Mogens Wedell-Wedellborgs Fond, Danish Cancer Society Grant R146-A9257, Gangstedfonden A31807, and Dagmar Marshalls Fond (to L.R.-J.), Novo Nordisk Fonden (NNF18CC0033666 (to N.G.), the Kirsten and Freddy Johansens Fond (to O.W.P).

Publisher Copyright:
© 2021, The Author(s).

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