Lost but Not Least—Novel Insights into Progesterone Receptor Loss in Estrogen Receptor-Positive Breast Cancer

Abstract

Estrogen receptor α (ERα) and progesterone receptor (PgR) are crucial prognostic and predictive biomarkers that are usually co-expressed in breast cancer (BC). However, 12–24% of BCs present ERα(+)/PgR(−) phenotype at immunohistochemical evaluation. In fact, BC may either show primary PgR(−) status (in chemonaïve tumor sample), lose PgR expression during neoadjuvant treatment, or acquire PgR(−) phenotype in local relapse or metastasis. The loss of PgR expression in ERα(+) breast cancer may signify resistance to endocrine therapy and poorer outcomes. On the other hand, ERα(+)/PgR(−) BCs may have a better response to neoadjuvant chemotherapy than double-positive tumors. Loss of PgR expression may be a result of pre-transcriptional alterations (copy number loss, mutation, epigenetic modifications), decreased transcription of the PGR gene (e.g. by microRNAs), and post-translational modifications (e.g. phosphorylation, sumoylation). Various processes involved in the down-regulation of PgR have distinct consequences on the biology of cancer cells. Occasionally, negative PgR status detected by immunohistochemical analysis is paradoxically associated with enhanced transcriptional activity of PgR that might be inhibited by antiprogestin treatment. Identification of the mechanism of PgR loss in each patient seems challenging, yet it may provide important information on the biology of the tumor and predict its responsiveness to the therapy.

Characteristics and survival in bone metastatic breast cancer patients with different hormone receptor status: A population-based cohort study

“…In contrast, PR loss, leading to a single ER-positive subpopulation, is prevalent in 6.9%-15.6% breast cancers, which could be attributed to multiple causes (31). PR loss in breast cancer confers resistance to hormone treatment but better response to chemotherapy (31). A reduced estrogen level in the elderly leads to a lower expression of PGR, which is one ERadependent gene and encodes PR, which could explain the higher prevalence of PR loss in older patients.…”

“…Since PR expression is dependent on ER signaling pathways, ER-positive/PR-positive is the most common HR status in breast cancer and confers the most sensitive response to endocrine therapy (30). In contrast, PR loss, leading to a single ER-positive subpopulation, is prevalent in 6.9%-15.6% breast cancers, which could be attributed to multiple causes (31). PR loss in breast cancer confers resistance to hormone treatment but better response to chemotherapy (31).…”

Molecular Mechanisms of Anti-Estrogen Therapy Resistance and Novel Targeted Therapies

“…On the other hand, PR negativity in ERα+ BC patients is associated with better response rates for neoadjuvant chemotherapy than in ER+/PR+ BC patients [ 81 , 82 ]. Therefore, PR status may be the determining factor in predicting response to neoadjuvant chemotherapy in ERα+ BC patients [ 83 ]. Lack or loss of PR expression in ERα+ BC cases may be due to various potential mechanisms, but the exact molecular, pathological, and clinical heterogeneity of PR remains poorly understood.…”

Exploring new pathways in endocrine-resistant breast cancer

“…Moreover, breast carcinomas that co-express ER and PR tend to have a better response to ET [ 16 , 17 ]. PR signaling is dependent on ERα, therefore tumors with negative PR status may present altered ERα signaling and therefore an ineffective ET response [ 18 ].…”

“…SERDs, considered pure ER antagonists, also competitively bind to ER, but inhibit ER transcription by causing ER complex changes that lead to ER proteasome-dependent degradation Moreover, breast carcinomas that co-express ER and PR tend to have a better response to ET [16,17]. PR signaling is dependent on ERα, therefore tumors with negative PR status may present altered ERα signaling and therefore an ineffective ET response [18]. However, 40-50% of patients treated with ET are at risk of cancer recurrence or progression due to intrinsic or acquired resistance [19].…”