Biological and clinical impact of imbalanced progesterone receptor isoform ratios in breast cancer

Abstract

There is a consensus that progestins and thus their cognate receptor molecules, the progesterone receptors (PR), are essential in the development of the adult mammary gland and regulators of proliferation and lactation. However, a role for natural progestins in breast carcinogenesis remains poorly understood. A hint to that possible role came from studies in which the synthetic progestin medroxyprogesterone acetate was associated with an increased breast cancer risk in women under hormone replacement therapy. However, progestins have been also used for breast cancer treatment and to inhibit the growth of several experimental breast cancer models. More recently, PR have been shown to be regulators of estrogen receptor signaling. With all this information, the question is how can we target PR, and if so, which patients may benefit from such an approach? PR are not single unique molecules. Two main PR isoforms have been characterized, PRA and PRB, that exert different functions and the relative abundance of one isoform respect to the other determines the response of PR agonists and antagonists. Immunohistochemistry with standard antibodies against PR do not discriminate between isoforms. In this review, we summarize the current knowledge on the expression of both PR isoforms in mammary glands, in experimental models of breast cancer and in breast cancer patients, to better understand how the PRA/PRB ratio can be exploited therapeutically to design personalized therapeutic strategies.

Progesterone and Breast Cancer: an NCI Workshop Report

“…Both ER and PR expression varies widely in luminal breast cancer. LOH of the PGR gene locus occurs with high frequency in breast cancer, as does loss of ER (23). Thus, while approximately 70% of newly diagnosed luminal type breast tumors are ER+/PR+, about 40% and 25% of these tumors exhibit loss of heterozygosity (LOH) at either the PGR or ESR1 gene locus, respectively (5); ER and PR LOH are positively correlated.…”

Virtual Inhibition Analysis of Bioactive Compound Brazilin (Caesalpinia sappan L.) Toward Progesterone Receptor or Lonaprisan in Breast Cancer Proliferation

“…In this region, it has acted as AF2; mediates transcriptional activation [20]. AF-2 is needed for recruitment of hormonedependent, dimerized coactivators and interactions with companion proteins in an inactive state then transcription modulation and proliferation of breast cancer cells are disrupted [21] [22]. Additionally, all bonds that occur are not on the binding site PR-Progesterone ARG766 [23].…”

Involvement of the Estrogen and Progesterone Axis in Cancer Stemness: Elucidating Molecular Mechanisms and Clinical Significance

“…These are transcribed from the same gene by two distinct promoters, resulting in different transcriptional and functional activities (146). The level and ratio of PR-A and PR-B in reproductive tissues vary based on developmental stage and hormonal status (147,148). In normal breast cells, the isoforms are coexpressed at similar levels, but in breast cancer cells, the ratio is disrupted, with PR-A being overexpressed (35,149).…”