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Human recombinant fsh induces chemoresistance in human breast cancer cells via hif-1α activation

L Bergandi, S Canosa, G Pittatore, F Silvagno, S Doublier, G Gennarelli, C Benedetto, A Revelli
Biology of Reproduction 2019 April 2
Breast cancer patients under 40 years of age who are candidate to chemotherapy with alkylating drugs may undergo controlled ovarian stimulation (COS) with human recombinant follicle-stimulating hormone (rhFSH) in order to get fertility preservation by mature oocyte cryostorage. The direct effect(s) of exogenous rhFSH on the chemosensitivity of breast cancer is currently unknown. To clarify this issue, we incubated four different breast cancer cell lines with rhFSH (10 IU/L, 24h) and then we exposed them to doxorubicin (DOX) or cyclophosphamide (CPA). The effect(s) of rhFSH on human breast cancer cells treated with DOX or CPA was measured in terms of 1) cell viability, 2) cytotoxicity, 3) multidrug resistance (MDR) genes and proteins expression and activities, and 4) hypoxia-inducible factor 1-alpha (HIF-1α) activation. Pre-treatment with rhFSH significantly increased the viability of breast cancer cells after treatment with DOX or CPA, and reduced the lactate dehydrogenase leakage and reactive oxygen species (ROS) production. Moreover, after pre-incubation with rhFSH, the MDR proteins (Pgp, MPR1 and BCRP) expression and activity resulted up-regulated and the HIF-1α pathway activated. In addition, the use of a widely used HIF-1α inhibitor, the 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1), prevented the rhFSH effect on the onset of multidrug resistance. Taken together, these observations suggest that a short exposure to rhFSH induces chemoresistance to DOX and CPA in human breast cancer cells via HIF-1α activation.


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