Cytokine sensitivity screening highlights BMP4 pathway signaling as a therapeutic opportunity in ER+ breast cancer

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
Kevin SheeTodd W Miller

Abstract

Despite the success of approved systemic therapies for estrogen receptor α (ER)-positive breast cancer, drug resistance remains common. We hypothesized that secreted factors from the human tumor microenvironment could modulate drug resistance. We previously screened a library of 297 recombinant-secreted microenvironmental proteins for the ability to confer resistance to the anti-estrogen fulvestrant in 2 ER+ breast cancer cell lines. Herein, we considered whether factors that enhanced drug sensitivity could be repurposed as therapeutics and provide leads for drug development. Screening data revealed bone morphogenic protein (BMP)4 as a factor that inhibited cell growth and synergized with approved anti-estrogens and cyclin-dependent kinase 4/6 inhibitors (CDK4/6i). BMP4-mediated growth inhibition was dependent on type I receptor activin receptor-like kinase (ALK)3-dependent phosphorylation (P) of mothers against decapentaplegic homolog (SMAD/P-SMAD)1 and 5, which could be reversed by BMP receptor inhibitors and ALK3 knockdown. The primary effect of BMP4 on cell fate was cell-cycle arrest, in which RNA sequencing, immunoblot analysis, and RNA interference revealed to be dependent on p21WAF1/Cip1 upregulation. BMP4 also enhanced ...Continue Reading

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Citations

Jul 6, 2019·Growth Factors·Lap Hing ChiRobin L Anderson
Jan 17, 2020·Cancer Research·Bedrich L EckhardtRobin L Anderson
Oct 10, 2020·Molecular Cancer Research : MCR·Josh W DiGiacomoDaniele M Gilkes
May 10, 2021·Reproductive Sciences·Dongyong YangYanxiang Cheng
Oct 6, 2021·Journal of Cell Communication and Signaling·Renu SharmaBithiah Grace Jaganathan

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