Hormone-induced DNA damage response and repair mediated by cyclin D1 in breast and prostate cancer

Abstract

Cell cycle control proteins govern events that leads to the production of two identical daughter cells. Distinct sequential temporal phases, Gap 1 (G1), Gap 0 (G0), Synthesis (S), Gap 2 (G2) and Mitosis (M) are negotiated through a series of check points during which the favorability of the local cellular environment is assessed, prior to replicating DNA [1]. Cyclin D1 has been characterized as a key regulatory subunit of the holoenzyme that promotes the G1/S-phase transition through phosphorylating the pRB protein. Cyclin D1 overexpression is considered a driving force in several types of cancers and cdk inhibitors are being used effectively in the clinic for treatment of ERα+ breast cancer [1, 2]. Genomic DNA is assaulted by damaging ionizing radiation, chemical carcinogens, and reactive oxygen species (ROS) which are generated by cellular metabolism. Furthermore, specific hormones including estrogens [3, 4] and androgens [5] govern pathways that damage DNA. Defects in the DNA Damage Response (DDR) pathway can lead to genomic instability and cancer. Evidence is emerging that cyclin D1 bind proteins involved in DNA repair including BRCA1 [6], RAD51 [7], BRCA2 [8] and is involved in the DNA damage and DNA repair processes [7, 8]. Because the repair of damaged DNA appears to be an important and unexpected role for cyclin D1, and inhibitors of cyclin D1-dependent kinase activity are being used in the clinic, the latest findings on the role of cyclin D1 in mediating the DDR including the DDR induced by the hormones estrogen [9] and androgen [10, 11] is reviewed.

miR‑9 depletion suppresses the proliferation of osteosarcoma cells by targeting p16

“…Cyclin D1 combines and activates the cyclin-dependent kinase 4 (CDK4) specific to the G1 phase, the inhibitor protein (Rb) of which is therefore phosphorylated. The phosphorylated Rb protein dissociates from its E2F transcription factor, and the E2F transcriptional factor begins to transcribe the gene of the living cell cycle, thereby promoting the cell cycle into the S phase from the G1 phase (43). Cyclin A mainly activates CDK2 and CDK1 to regulate chromosome replication and mitosis (44,45).…”

The membrane-associated form of cyclin D1 enhances cellular invasion

“…The estrogen receptor α (ERα) is known to convey both genomic and extra genomic activities 37 . The extranuclear estrogen signaling pathway is thought to involve a membrane-associated ERα, which activates PI3-kinase and thereby Akt signaling 38 . Maximal activation of Akt requires phosphorylation on the carboxy-terminal site, S473, by mTORC2 39,40 .…”

In vitro cytotoxic and antiproliferative effects of usnic acid on hormone‐dependent breast and prostate cancer cells

“…The main therapeutic strategy for these cancer types are similar and are called “endocrine or hormone therapy” targeting to block related hormone synthesis or hormone receptor activity . Although hormone therapy gives effective results at the beginning of treatment, acquired therapy resistance is known to develop in later period . Additionally, hormone therapy is not fully selective for cancer cells and can also damage normal cells of the affected tissue .…”