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.

Risk factors for breast cancer subtypes by race and ethnicity: A scoping review of the literature

“…Hormonal mechanisms (e.g., absence of ovulatory menstrual cycles and shorter lifetime exposure to endogenous sex hormones) may, in part, explain the reduced risk of ER-positive disease among women who have breastfed. 35 Possible mechanisms for the inverse association of breastfeeding on risk of ER-negative disease include permanent changes to the breast histology, demonstrated by involution of terminal duct lobular units (TDLU); although, TDLU involution has also been associated with a lower risk of ER-positive disease 36,37…”

Breastfeeding’s protective role in alleviating ovarian cancer burden: a comprehensive review

“…The mechanisms underlying breastfeeding’s impact on ovarian cancer risk reduction are not entirely elucidated, but several factors are believed to contribute to this association. Hormonal influences play a significant role, as breastfeeding suppresses ovulation and decreases cumulative exposure to ovarian hormones such as oestrogen and progesterone, which may contribute to the development of ovarian cancer 23 , 24 . Moreover, the cellular changes induced by breastfeeding, including alterations in the ovarian microenvironment, potentially create conditions less conducive to the initiation and growth of malignant ovarian cells.…”

Rat Models of Hormone Receptor-Positive Breast Cancer

“…Moreover, similarly to other mammary tumor-inducing carcinogens, most DMBA-induced carcinomas are responsive to hormonal changes, as seen by a reduction in tumor growth once animals were ovariectomized, hypophysectomized or an increase in tumor growth once animals received hormone supplementations such as progesterone, estradiol, or a combination thereof [144]. Interestingly, administration of progesterone alone was shown to enhance DMBA-induced tumor growth and incidence, alluding to the hormone's stimulating effect on tumor development, an event also seen in the clinical setting [144][145][146].…”