Progesterone from ovulatory menstrual cycles is an important cause of breast cancer

Abstract

Many factors, including reproductive hormones, have been linked to a woman's risk of developing breast cancer (BC). We reviewed the literature regarding the relationship between ovulatory menstrual cycles (MCs) and BC risk. Physiological variations in the frequency of MCs and interference with MCs through genetic variations, pathological conditions and or pharmaceutical interventions revealed a strong link between BC risk and the lifetime number of MCs. A substantial reduction in BC risk is observed in situations without MCs. In genetic or transgender situations with normal female breasts and estrogens, but no progesterone (P4), the incidence of BC is very low, suggesting an essential role of P4. During the MC, P4 has a strong proliferative effect on normal breast epithelium, whereas estradiol (E2) has only a minimal effect. The origin of BC has been strongly linked to proliferation associated DNA replication errors, and the repeated stimulation of the breast epithelium by P4 with each MC is likely to impact the epithelial mutational burden. Long-lived cells, such as stem cells, present in the breast epithelium, can carry mutations forward for an extended period of time, and studies show that breast tumors tend to take decades to develop before detection. We therefore postulate that P4 is an important factor in a woman's lifetime risk of developing BC, and that breast tumors arising during hormonal contraception or after menopause, with or without menopausal hormone therapy, are the consequence of the outgrowth of pre-existing neoplastic lesions, eventually stimulated by estrogens and some progestins.

Keywords: Breast cancer; DNA replication; Estrogens; Menstrual cycles; Progesterone; Tumor doubling time; WNT4.

Fig. 1

Mean plasma levels of estradiol (E2 pg/mL), progesterone (P4 ng/mL), and testosterone (T pg/mL) during a normal menstrual cycle of 28 days [14, 22]

Fig. 2

Estrogen levels (ng/mL) during human pregnancy. E1: estrone; E2: estradiol; E3 estriol; E4: estetrol. Adaptation of a figure published by Levitz [119], based on Tulchinsky [120, 121]

Fig. 3

Relative risk of breast cancer in parous women in relation to lifetime duration of breastfeeding [19]. RightsLink Elsevier permission

Fig. 4

Breast cancer incidence and mortality among women of African nations compared with the USA and other international populations [26]. Rates shown are per 100,000 persons. Open Access reference

Fig. 5

The progesterone signaling hub in the adult mammary epithelium progesterone, upon binding to its receptor in the ER⁺/PR⁺ sensor cells (blue) activates different signaling pathways. It can stimulate cell-intrinsic proliferation by a cyclin D1-dependent mechanism (blue) and induce secreted factors like Amphiregulin, CXCL12, or Calcitonin (blue). Distinct PR⁺ cells induce WNT4, which acts on the myoepithelium where it activated canonical WNT signaling, which results in the expression of the secreted protease Adamts18 that cleaves fibronectin. As a result the ECM, part of the stem cells niche is biochemically altered with resulting activation of the hippo signaling pathway and increased transcription of FGFR signaling components (red). In other PR⁺ cells, RANKL is induced that induces the proliferation of neighboring ER⁻/PR⁻ responder cells (green) [84]. Open Access reference and author permission