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Neoadjuvant chemotherapy modifies serum pyrrolidone carboxypeptidase specific activity in women with breast cancer and influences circulating levels of GnRH and gonadotropins

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Abstract

Purpose

Functional studies have demonstrated that gonadotropin-releasing hormone (GnRH) regulates cell proliferation, apoptosis, and tissue remodeling. GnRH is metabolized by the proteolytic regulatory enzyme pyrrolidone carboxypeptidase (Pcp) (E.C. 3.4.19.3), which is an omega peptidase widely distributed in fluids and tissues. We previously reported a decrease in both rat and human Pcp activity in breast cancer, suggesting that GnRH may be an important local hormonal factor in the pathogenesis of breast cancer. Recently, we have described that postmenopausal women with breast cancer show lower levels of serum Pcp activity than control postmenopausal women. To determine the effect of neoadjuvant chemotherapy (NACT) on serum Pcp specific activity and circulating levels of GnRH, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and steroid hormones 17-ß-estradiol and progesterone in pre- and postmenopausal women diagnosed with infiltrating ductal carcinoma.

Methods

Serum Pcp activity was measured fluorometrically using pyroglutamyl-ß-naphthylamide. Circulating GnRH levels were dosed using a commercial RIA kit. Circulating LH and FSH levels were measured by enzyme immunoassays. Levels of steroid hormones were measured in serum samples by dissociation-enhanced lanthanide fluorescence immunoassay.

Results and conclusion

Our results show the effect of NACT on the hypothalamic-pituitary axis, with the consequent alteration of circulating gonadotropins in premenopausal women with breast cancer. However, the results obtained in postmenopausal women with breast cancer treated with NACT, that is, the significant decrease in the concentration of GnRH and FSH compared to control postmenopausal women, differ from those obtained for premenopausal women. The only difference between pre- and postmenopausal women is their hormonal profile at the beginning of the study, that is, the presence of menopause and the consequent alteration of the hypothalamic-pituitary–gonadal axis.

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Fig. 1
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Fig. 3

Abbreviations

ATC:

Anthracycline

AUC:

Area under the curve

BMI:

Body mass index

BSA:

Bovine serum albumin

DELFIA:

Dissociation enhanced lanthanide fluorescence immunoassay

DTT:

Dithiothreitol

EDTA:

Ethylenediaminetetraacetic acid

FSH:

Follicle-stimulating hormone

GnRH:

Gonadotropin-releasing hormone

LH:

Luteinizing hormone

NACT:

Neoadjuvant chemotherapy

PCL:

Paclitaxel

PGluNNap:

Pyroglutamyl-ß-naphthylamide

Pcp:

Pyrrolidone carboxypeptidase

TNBC:

Triple-negative breast cancers

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Acknowledgements

Supported by Consejería de Salud de la Junta de Andalucía (Grant SAS-PI0253) and Plan Propio de la Universidad de Jaén (Grants UJA2016/08/04 and PAIUJA 2017/00319/001). The authors would like to thank Nutraceutical Translations for English language editing of this manuscript.

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Authors and Affiliations

  1. Experimental and Clinical Physiopathology Research Group, Department of Health Sciences, Faculty of Experimental and Health Sciences, University of Jaén, 23071, Jaén, Spain

    María Jesús Ramírez-Expósito, José Manuel Martínez-Martos & María Pilar Carrera-González

  2. Unit of Breast Pathology, Complejo Hospitalario de Jaén, Jaén, Spain

    Basilio Dueñas-Rodríguez & Joaquín Navarro-Cecilia

  3. Department of Nursing, Pharmacology and Physiotherapy, Faculty of Medicine and Nursing, University of Córdoba. IMIBIC, Av. Menéndez Pidal, 7, 14004, Córdoba, Spain

    María Pilar Carrera-González

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  1. María Jesús Ramírez-Expósito
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Correspondence to María Pilar Carrera-González.

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Ramírez-Expósito, M.J., Martínez-Martos, J.M., Dueñas-Rodríguez, B. et al. Neoadjuvant chemotherapy modifies serum pyrrolidone carboxypeptidase specific activity in women with breast cancer and influences circulating levels of GnRH and gonadotropins. Breast Cancer Res Treat 182, 751–760 (2020). https://doi.org/10.1007/s10549-020-05723-1

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