Upregulation of an estrogen receptor-regulated gene by first generation progestins requires both the progesterone receptor and estrogen receptor alpha

Abstract

Progestins, synthetic compounds designed to mimic the activity of natural progesterone (P 4 ), are used globally in menopausal hormone therapy. Although the older progestins medroxyprogesterone acetate (MPA) and norethisterone (NET) have been implicated in increased breast cancer risk, little is known regarding newer progestins, and no significant risk has been associated with P 4 . Considering that breast cancer is the leading cause of mortality in women, establishing which progestins increase breast cancer incidence and elucidating the underlying mechanisms is a global priority. We showed for the first time that the newer-generation progestin drospirenone (DRSP) is the least potent progestin in terms of proliferation of the estrogen-responsive MCF-7 BUS breast cancer cell line, while NET and P 4 have similar potencies to estradiol (E 2 ), the known driver of breast cancer cell proliferation. Notably, MPA, the progestin most frequently associated with increased breast cancer risk, was significantly more potent than E 2 . While all the progestogens enhanced the anchorage-independent growth of the MCF-7 BUS cell line, MPA promoted a greater number of colonies than P 4 , NET or DRSP. None of the progestogens inhibited E 2 -induced proliferation and anchorage-independent growth. We also showed that under non-estrogenic conditions, MPA and NET, unlike P 4 and DRSP, increased the expression of the estrogen receptor (ER) target gene, cathepsin D, via a mechanism requiring the co-recruitment of ERa and the progesterone receptor (PR) to the promoter region. In contrast, all progestogens promoted the association of the PR and ERa on the promoter of the PR target gene, MYC, thereby increasing its expression under nonestrogenic and estrogenic conditions. These results suggest that progestins differentially regulate the way the PR and ER converge to modulate the expression of PR and ER-regulated genes. Our novel findings indicating similarities and differences between P 4 and the progestins, emphasize the importance of comparatively investigating effects of individual progestins rather than grouping them as a class. Further studies are required to underpin the clinical relevance of PR/ERa crosstalk in response to different progestins in both normal and malignant breast tissue, to either confirm or refute their suitability in combination therapy for ER-positive breast cancer.

Expression of Cathepsin D in early-stage breast cancer and its prognostic and predictive value

“…This finding remained significant even after accounting for other key prognostic factors such as lymph node status, tumour size, tumour grade and oestrogen receptor status. These results align with previous research [ 31 – 35 ].…”

“…Cathepsin D-negative patients have significantly better BCSS and less risk of either recurrence or metastasis than Cathepsin D-positive patients within this ER+ patient group. Other studies have reported similar findings [ 11 , 31 ]. While some studies found no association between Cathepsin D expression and ER status, their conclusions may be limited by their small sample sizes and reliance on ELISA for cytosolic Cathepsin D measurement [ 25 , 32 ].…”

“…The level of expression of Cathepsin D was correlated with oestrogen receptor status in breast cancer [ 31 ]. Studies of RNA levels of Cathepsin D showed that tamoxifen increased Cathepsin D RNA level regardless of the ER status of the tumours and that this increase is directly proportional to protein level in the cytosol in ER+ tumours but not in ER− tumours [ 33 ].…”

The 100 top-cited articles in menopausal syndrome: a bibliometric analysis

“…With fewer AEs and more benefits in better sexual life, skin condition and physical activity, alternative therapies receives more and more attention [29]. Compared with, medroxyprogesterone acetate (MPA) and norethisterone (NET) which increased breast cancer risk, evidence suggests a differential effect of MHT containing E2 or natural progesterone (P4) and those containing CEE or progestins, with some evidence trending to a potentially better safety profile with E2 and/or P4 [30][31][32]…”