Recombinant human chorionic gonadotropin induces signaling pathways towards cancer prevention in the breast of BRCA1/2 mutation carriers : European Journal of Cancer Prevention

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Research article

Recombinant human chorionic gonadotropin induces signaling pathways towards cancer prevention in the breast of BRCA1/2 mutation carriers

Su, Yanronga,*; Dang, Nhi M.a,*; Depypere, Hermanb,*; Santucci-Pereira, Juliaa; Gutiérrez-Díez, Pedro J.c; Kanefsky, Joicea; Janssens, Jaak Ph.d; Russo, Josea,#

Author Information

aThe Irma H Russo, MD, Breast Cancer Research Laboratory at the Fox Chase Cancer Center-Temple Health, Philadelphia, Pennsylvania, USA

bDepartment of Gynecology, Breast and Menopause Clinic, University Hospital of Ghent, Ghent, Belgium

cIMUVA Mathematical Institute, University of Valladolid, Valladolid, Spain

dEuropean Cancer Prevention Organization, University of Hasselt, Hasselt, Belgium

Received 11 May 2022 Accepted 12 May 2022

*Yanrong Su, Nhi M. Dang, and Herman Depypere contributed equally to this work.

#Dr. Russo conceived the study and supervised the work. Dr. Russo passed away on 24 September 2021.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (www.eurjcancerprev.com).

Correspondence to Yanrong Su, PhD, The Irma H Russo, MD, Breast Cancer Research Laboratory at the Fox Chase Cancer Center-Temple Health, 333 Cottman Avenue, Philadelphia, PA 19111, USA, Tel: +1 215 728 3486; e-mail: [email protected].

European Journal of Cancer Prevention 32(2):p 126-138, March 2023. | DOI: 10.1097/CEJ.0000000000000763

Abstract

Background 

Strategies for breast cancer prevention in women with germline BRCA1/2 mutations are limited. We previously showed that recombinant human chorionic gonadotropin (r-hCG) induces mammary gland differentiation and inhibits mammary tumorigenesis in rats. The present study investigated hCG-induced signaling pathways in the breast of young nulliparous women carrying germline BRCA1/2 mutations.

Methods 

We performed RNA-sequencing on breast tissues from 25 BRCA1/2 mutation carriers who received r-hCG treatment for 3 months in a phase II clinical trial, we analyzed the biological processes, reactome pathways, canonical pathways, and upstream regulators associated with genes differentially expressed after r-hCG treatment, and validated genes of interest.

Results 

We observed that r-hCG induces remarkable transcriptomic changes in the breast of BRCA1/2 carriers, especially in genes related to cell development, cell differentiation, cell cycle, apoptosis, DNA repair, chromatin remodeling, and G protein-coupled receptor signaling. We revealed that r-hCG inhibits Wnt/β-catenin signaling, MYC, HMGA1, and HOTAIR, whereas activates TGFB/TGFBR-SMAD2/3/4, BRCA1, TP53, and upregulates BRCA1 protein.

Conclusion 

Our data suggest that the use of r-hCG at young age may reduce the risk of breast cancer in BRCA1/2 carriers by inhibiting pathways associated with stem/progenitor cell maintenance and neoplastic transformation, whereas activating genes crucial for breast epithelial differentiation and lineage commitment, and DNA repair.

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