Biology of Progesterone Receptor Loss in Breast Cancer and Its Implications for Endocrine Therapy

Abstract

The response to endocrine therapy in breast cancer correlates with estrogen receptor (ER) and progesterone receptor (PR) status. ER-positive/PR-negative breast cancers respond less well to selective ER modulator (SERM) therapy than ER-positive/PR-positive tumors. The predictive value of PR has long been attributed to the dependence of PR expression on ER activity, with the absence of PR reflecting a nonfunctional ER and resistance to hormonal therapy. However, recent clinical and laboratory evidence suggests that ER-positive/PR-negative breast cancers may be specifically resistant to SERMs, whereas they may be less resistant to estrogen withdrawal therapy with aromatase inhibitors, which is a result inconsistent with the nonfunctional ER theory. Novel alternative molecular mechanisms potentially explaining SERM resistance in ER-positive/PR-negative tumors have been suggested by recent experimental indications that growth factors may downregulate PR levels. Thus, the absence of PR may not simply indicate a lack of ER activity, but rather may reflect hyperactive cross talk between ER and growth factor signaling pathways that downregulate PR even as they activate other ER functions. Therefore, ER-positive/PR-negative breast tumors might best be treated by completely blocking ER action via estrogen withdrawal with aromatase inhibitors, by targeted ER degradation, or by combined therapy targeting both ER and growth factor signaling pathways. In this review, we will discuss the biology and etiology of ER-positive/PR-negative breast cancer, highlighting recent data on molecular cross talk between ER and growth factor signaling pathways and demonstrating how PR might be a useful marker of these activities. Finally, we will consider the clinical implications of these observations.

Short-term outcome of primary operated early breast cancer by hormone and HER-2 receptors

“…The proportion of breast cancers defined as ER-positive (87.47%) or PR-positive (75.18%) is higher than literaturereported proportions for ER (75%) and PR (55%) [7,14,48,49]. Improved laboratory sensitivity for detecting ER, different quantification techniques, and dichotomous cutoff values for assessing ER and PR account for important interlaboratory variability [36,50,51].…”

“…The prognostic value of these predictive biomarkers can be summarized as follows. Women with an ER-positive tumor have a better prognosis than those with an ER-negative tumor, although this is not true for very young women and not after approximately eight years of follow-up (FU) when survival curves of ER-positive and ER-negative cases cross [5][6][7]. The combination of ER with PR further refines the short-term prognostic value of ER.…”

Coffee prevents early events in tamoxifen-treated breast cancer patients and modulates hormone receptor status

“…ER+PgR− breast cancers respond less well to tamoxifen than ER+PgR+ tumors [24,25]. However, coffee consumption was associated with a lower frequency of early events in tamoxifen-treated patients with ER+PgR− as well as ER+PgR+ tumors.…”

A mitotically active, cellular tumor stroma and/or inflammatory cells associated with tumor cells may contribute to intermediate or high Oncotype DX Recurrence Scores in low-grade invasive breast carcinomas

“…44,62,63,65,66 Several studies have shown that ER-positive breast cancers with low or absent PR expression have a worse prognosis 67 and benefit less from tamoxifen therapy compared with tumors showing high levels of PR expression. [68][69][70] As the predictive value of the Oncotype DX test is based on the assumption that patients receive adjuvant antihormonal therapy and PR expression levels, with an overall range of 1000-fold in the assay, have a significant role in the calculation of the Recurrence Score, these results are not surprising. In fact, Allison et al 44 found that in addition to histological grade, PR levels can segregate breast carcinomas into different Recurrence Score categories.…”