mdm2 gene amplification is associated with luminal breast cancer progression in humanized PDX mice and a worse outcome of estrogen receptor positive disease

It has been suggested that activation of estrogen receptor α (ER α) stimulates cell proliferation. In contrast, estrogen receptor β (ER β) has anti-proliferative and pro-apoptotic activity. Although the role of estrogens in estrogen receptor-positive breast cancer progression has been well established, the mechanism of their effect on apoptosis is not fully understood. It has been considered that ER status of breast cancer cells and estrogen availability might determine proline dehydrogenase/proline oxidase (PRODH/POX)-dependent apoptosis. PRODH/POX is a mitochondrial enzyme that converts proline into pyrroline-5-carboxylate (P5C). During this process, ATP (adenosine triphosphate) or ROS (reactive oxygen species) are produced, facilitating cell survival or death, respectively. However, the critical factor in driving PRODH/POX-dependent functions is proline availability. The amount of this amino acid is regulated at the level of prolidase (proline releasing enzyme), collagen biosynthesis (proline utilizing process), and glutamine, glutamate, α-ketoglutarate, and ornithine metabolism. Estrogens were found to upregulate prolidase activity and collagen biosynthesis. It seems that in estrogen receptor-positive breast cancer cells, prolidase supports proline for collagen biosynthesis, limiting its availability for PRODH/POX-dependent apoptosis. Moreover, lack of free proline (known to upregulate the transcriptional activity of hypoxia-inducible factor 1, HIF-1) contributes to downregulation of HIF-1-dependent pro-survival activity. The complex regulatory mechanism also involves PRODH/POX expression and activity. It is induced transcriptionally by p53 and post-transcriptionally by AMPK (AMP-activated protein kinase), which is regulated by ERs. The review also discusses the role of interconversion of proline/glutamate/ornithine in supporting proline to PRODH/POX-dependent functions. The data suggest that PRODH/POX-induced apoptosis is dependent on ER status in breast cancer cells.

Download Full-text

The SMRT Coregulator Enhances Growth of Estrogen Receptor-α-Positive Breast Cancer Cells by Promotion of Cell Cycle Progression and Inhibition of Apoptosis

Endocrinology ◽

10.1210/en.2014-1002 ◽

2014 ◽

Vol 155 (9) ◽

pp. 3251-3261 ◽

Cited By ~ 10

Author(s):

Julia K. Blackmore ◽

Sudipan Karmakar ◽

Guowei Gu ◽

Vaishali Chaubal ◽

Liguo Wang ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Estrogen Receptor ◽

Cancer Cells ◽

Cancer Progression ◽

Breast Cancer Cells ◽

Estrogen Receptor Α ◽

Breast Cancer Progression ◽

Apoptotic Genes ◽

Mcf 7

Abstract The SMRT coregulator functions as a dual coactivator and corepressor for estrogen receptor-α (ERα) in a gene-specific manner, and in several studies its elevated expression correlates with poor outcome for breast cancer patients. A specific role of SMRT in breast cancer progression has not been elucidated, but SMRT knock-down limits estradiol-dependent growth of MCF-7 breast cancer cells. In this study, small-interfering RNA (siRNA) and short-hairpin RNA (shRNA) approaches were used to determine the effects of SMRT depletion on growth of ERα-positive MCF-7 and ZR-75–1 breast cancer cells, as well as the ERα-negative MDA-MB-231 breast cancer line. Depletion of SMRT inhibited growth of ERα-positive cells grown in monolayer but had no effect on growth of the ERα-negative cells. Reduced SMRT levels also negatively impacted the anchorage-independent growth of MCF-7 cells as assessed by soft agar colony formation assays. The observed growth inhibitions were due to a loss of estradiol-induced progression through the G1/S transition of the cell cycle and increased apoptosis in SMRT-depleted compared with control cells. Gene expression analyses indicated that SMRT inhibits apoptosis by a coordinated regulation of genes involved in apoptosis. Functioning as a dual coactivator for anti-apoptotic genes and corepressor for pro-apoptotic genes, SMRT can limit apoptosis. Together these data indicate that SMRT promotes breast cancer progression through multiple pathways leading to increased proliferation and decreased apoptosis.

Download Full-text

mTORC2 Drives ZFX-mediated Ganglioside Biosynthesis to Promote Breast Cancer Progression.

10.1101/2022.01.10.475595 ◽

2022 ◽

Author(s):

Kajal Rajput ◽

Mohammad Nafees Ansari ◽

Somesh Kumar Jha ◽

Pankaj Sharma ◽

Sudeshna Datta ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Mammalian Cells ◽

Zinc Finger Protein ◽

Cell Signalling ◽

Dna Methyltransferases ◽

Breast Cancer Progression ◽

Regulatory Subunit ◽

Luminal Breast Cancer ◽

Invasion And Migration

Sphingolipid and ganglioside metabolic pathways are crucial components of cell signalling, having established roles in tumor cell proliferation, invasion, and migration. However, regulatory mechanisms controlling sphingolipid and ganglioside synthesis in mammalian cells is less known. Here, we show that RICTOR, the regulatory subunit of mTORC2, regulates the synthesis of sphingolipids and gangliosides in Luminal breast cancer-specific MCF-7 cells through transcriptional and epigenetic mechanisms. RICTOR regulates glucosylceramide levels by modulating the expression of UDP-Glucose Ceramide Glucosyl transferase (UGCG). We identify Zinc Finger protein X-linked (ZFX) as a RICTOR-responsive transcription factor whose recruitment to the UGCG promoter is regulated by DNA methyltransferases and histone demethylase (KDM5A) that are known AKT substrates. We further demonstrate that RICTOR regulates the synthesis of GD3 gangliosides through ZFX and UGCG, and triggers the activation of the EGFR signalling pathway, thereby promoting tumor growth. In line with our findings in cell culture and mice models, we observe an elevated expression of RICTOR, ZFX, and UGCG in Indian Luminal breast cancer patient samples, and in TCGA and METABRIC datasets. Together, we establish a key regulatory circuit, RICTOR-AKT-ZFX-UGCG-Ganglioside-EGFR-AKT, and elucidate its contribution to breast cancer progression.

Download Full-text

Abstract 144: MicroRNA-190, regulated by estrogen receptor signaling, suppresses expression of the metastasis-promoting genePAR-1and is associated with breast cancer progression

10.1158/1538-7445.am2012-144 ◽

2012 ◽

Author(s):

Hou-Wei Chu ◽

Chun-Wen Cheng ◽

Wen-Cheng Chou ◽

Ling-Yueh Hu ◽

Hsiao-Wei Wang ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Cancer Progression ◽

Breast Cancer Progression ◽

Receptor Signaling ◽

Estrogen Receptor Signaling

Download Full-text

Abstract 949: Progesterone receptor/IRS-1 cooperation promotes stem cell outgrowth and endocrine resistance in estrogen receptor-positive luminal breast cancer

10.1158/1538-7445.am2018-949 ◽

2018 ◽

Author(s):

Amy R. Dwyer ◽

Deepali Sachdev ◽

Carol A. Lange

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Stem Cell ◽

Progesterone Receptor ◽

Endocrine Resistance ◽

Luminal Breast Cancer ◽

Cell Outgrowth ◽

Estrogen Receptor Positive

Download Full-text

Expression of Annexin A2 Promotes Cancer Progression in Estrogen Receptor Negative Breast Cancers

Cells ◽

10.3390/cells9071582 ◽

2020 ◽

Vol 9 (7) ◽

pp. 1582 ◽

Cited By ~ 2

Author(s):

Amira F. Mahdi ◽

Beatrice Malacrida ◽

Joanne Nolan ◽

Mary E. McCumiskey ◽

Anne B. Merrigan ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Cell Lines ◽

Cancer Progression ◽

Annexin A2 ◽

Breast Cancer Progression ◽

Migration And Invasion ◽

Breast Cancer Cell Lines ◽

Cancer Subtypes ◽

Estrogen Receptor Negative

When breast cancer progresses to a metastatic stage, survival rates decline rapidly and it is considered incurable. Thus, deciphering the critical mechanisms of metastasis is of vital importance to develop new treatment options. We hypothesize that studying the proteins that are newly synthesized during the metastatic processes of migration and invasion will greatly enhance our understanding of breast cancer progression. We conducted a mass spectrometry screen following bioorthogonal noncanonical amino acid tagging to elucidate changes in the nascent proteome that occur during epidermal growth factor stimulation in migrating and invading cells. Annexin A2 was identified in this screen and subsequent examination of breast cancer cell lines revealed that Annexin A2 is specifically upregulated in estrogen receptor negative (ER-) cell lines. Furthermore, siRNA knockdown showed that Annexin A2 expression promotes the proliferation, wound healing and directional migration of breast cancer cells. In patients, Annexin A2 expression is increased in ER- breast cancer subtypes. Additionally, high Annexin A2 expression confers a higher probability of distant metastasis specifically for ER- patients. This work establishes a pivotal role of Annexin A2 in breast cancer progression and identifies Annexin A2 as a potential therapeutic target for the more aggressive and harder to treat ER- subtype.

Download Full-text