Prolactin inhibits a major tumor-suppressive function of wild type BRCA1

Abstract

Even though mutations in the tumor suppressor, BRCA1, markedly increase the risk of breast and ovarian cancer, most breast and ovarian cancers express wild type BRCA1. An important question is therefore how the tumor-suppressive function of normal BRCA1 is overcome during development of most cancers. Because prolactin promotes these and other cancers, we investigated the hypothesis that prolactin interferes with the ability of BRCA1 to inhibit the cell cycle. Examining six different cancer cell lines with wild type BRCA1, and making use of both prolactin and the growth-inhibiting selective prolactin receptor modulator, S179D PRL, we demonstrate that prolactin activation of Stat5 results in the formation of a complex between phospho-Stat5 and BRCA1. Formation of this complex does not interfere with nuclear translocation or binding of BRCA1 to the p21 promoter, but does interfere with the ability of BRCA1 to transactivate the p21 promoter. Overexpression of a dominant-negative Stat5 in prolactin-stimulated cells resulted in increased p21 expression. We conclude that prolactin inhibits a major tumor-suppressive function of BRCA1 by interfering with BRCA1's upregulation of expression of the cell cycle inhibitor, p21.

Z-ligustilide restores tamoxifen sensitivity of ERα negative breast cancer cells by reversing MTA1/IFI16/HDACs complex mediated epigenetic repression of ERα

“…These results are well consistent with their influence on cell cycle arrest. Furthermore, p21 is one of the transcriptional targets of acetylation of p53 (acetyl-p53) and BRCA1 [31–33]. Our results showed that acetyl-p53 and BRCA1 protein level were significantly induced in MDA-MB-231 cells treated by combinatorial Z-LIG and TAM.…”

Prolactin receptor in breast cancer: marker for metastatic risk

“…PRL and the selective PRLR modulator, S179DPRL, (from both the long and short (SF1b) PRLR isoforms), were able to induce BRCA1 levels, although only PRL was able to interfere with BRCA1-mediated transcriptional activation of the cyclin-dependent kinase inhibitor, p21, via its interaction with STAT5 (Chen & Walker 2016). Therefore, PRL-STAT5 signaling interferes with BRCA1 tumor-suppressive function of cell cycle inhibition, while allowing proliferation in the presence of PRL.…”

Involvement of miR-106b in tumorigenic actions of both prolactin and estradiol

“…However, prolactin also functions in immune regulation [3–5], adipocyte differentiation [6, 7], islet proliferation [8, 9] and regulation of bone density [10, 11]. In addition, more and more evidence has accumulated indicating that prolactin promotes tumorigenesis in various types of cancers, including breast [12–14], prostate [14, 15], ovary [14, 16], liver [17], and brain [18], as well as stimulating the growth of pituitary tumors [19, 20]. One of the tumor-promoting mechanisms is decreased expression of the cell cycle inhibitor CDKN1A, also known as p21 [14].…”

“…In addition, more and more evidence has accumulated indicating that prolactin promotes tumorigenesis in various types of cancers, including breast [12–14], prostate [14, 15], ovary [14, 16], liver [17], and brain [18], as well as stimulating the growth of pituitary tumors [19, 20]. One of the tumor-promoting mechanisms is decreased expression of the cell cycle inhibitor CDKN1A, also known as p21 [14]. A reduction in p21 expression may have a direct effect on cell proliferation, but may also contribute to anti-estrogen and other drug resistance in some cancers [21–26].…”

“…A reduction in p21 expression may have a direct effect on cell proliferation, but may also contribute to anti-estrogen and other drug resistance in some cancers [21–26]. As might be expected, the expression of p21 is tightly regulated by several molecules, including p53 [27], BRCA1 [14, 28], TGF-β [29], RAR/RXR [30] and the vitamin D receptor [31]. In addition to expression of p21, cellular localization of p21 is also related to the therapeutic resistance [32].…”