Tamoxifen Represses Breast Cancer Cell Growth by Interacting with SKI-interacting Protein (SKIP)

Abstract

Tamoxifen is the most common choice of anti-cancer drug for breast cancer in pre-menopausal women. Tamoxifen antagonizes the estrogen proliferative effect by interacting with estrogen receptor. Despite the fact that this treatment has showed a tremendous effect on the survival of patients, resistance to the treatment frequently occurs. Several mechanisms of tamoxifen resistance have been already described. However, the precise understanding of how tamoxifen prevents tumor growth has not been elucidated yet. The initial objective was to identify a secondary target of tamoxifen in order to enhance the efficiency of the treatment and improve the survival of breast cancer patients. In this study, an additional secondary target of tamoxifen had been identified. In particular, the role of tamoxifen in the interaction of SKI-interacting Protein (SKIP) with SMADs in TGF-β/SMAD signaling pathway has been investigated. The interaction of SKIP with tamoxifen represses breast cancer cell growth. The interactions of SKIP with estrogen receptor and vitamin D receptor under tamoxifen and TGF-β treatments have also been studied. The binding of SKIP and SMAD3 to the chromatin induces the transcription of TGF-β target genes. The differential expression of genes regulated by SKIP under various treatment conditions and their associated pathways were also studied. Hence, the study postulates that tamoxifen and TGF-β act in a synergic manner on cell growth inhibition, and that the expression of SKIP predicted response to tamoxifen in breast cancer patients.

Popular Abstract

SKIP – The Promising Interaction Partner

Have you ever wondered why there are a lot of pretty women dying of breast cancer? Haven’t they wished to be alive healthy and happy with their families. Unfortunately, when the normal breast cells acquire certain changes in their DNA, they may become cancerous. Breast cancer is a very heterogeneous disease because of the different subtypes. Among the subtypes, hormone receptor expressing luminal subtypes account for 64.3% of the tumors. It is highly surprising that one in twelve Norwegian women being diagnosed with breast cancer before they reach the age of 75. The numbers are huge not only in Norway but in the entire Scandinavia and worldwide.

Wouldn’t the patients have fought for their life? Of course, yes. The most common endocrine therapy in pre-menopausal women with breast cancer is the administration of the drug tamoxifen. Postmenopausal women are usually treated with aromatase inhibitors. Estrogen, the female sex hormone has a role in development and maintenance of female characteristics of the body mainly in reproduction and menstrual cycle processes. Despite being a crucial hormone for women, it can induce cancer by the action of its hormonal receptor called estrogen receptor.

Although tamoxifen had been a propitious treatment, downside still exist. Wouldn’t it be great if there is a possibility for alternative treatment options to improve the efficiency of the existing therapy and increase the survival of breast cancer patients? Hence using a proteomics approach, we identified that tamoxifen could have a secondary target named SKI-interacting Protein (SKIP). This particular protein is an essential transcriptional coactivator for many of the induced genes and it modulates a biological pathway called TGF-β signaling pathway. An inducible over expressing SKIP breast cancer cell line named MCF-7 was made and used in our project to mimic and understand the actual molecular mechanisms occurring inside a breast cancer patient.

The mechanism by which tamoxifen plays a role in the interaction of SKIP with a transcription factor called SMADs in the pathway was unknown. Our first objective was to identify the potential of SKIP-tamoxifen interaction in TGF-β signaling pathway. It was observed that overexpression of SKIP was able to lower the vigorous growth of cancer cells to a certain extent. However, it works better when there is a mutual interaction with tamoxifen and TGF-β. In our study we used proteomics and genomics methodologies to investigate the interactions of SKIP with SMADs in the TGF-β pathway and the influence of tamoxifen. Interestingly, the interaction of SKIP with SMADs seemed to be influenced by tamoxifen.

In order to achieve a deeper understanding of the mechanisms, it is highly important to know where the transcription factors bind the DNA and how the genes are regulated. Hence, we also studied the binding of SKIP and SMAD3 to the chromatin which eventually induces the transcription of TGF-β target genes. The differential expression of genes regulated by SKIP under various treatment conditions and their associated pathways were also explored. Hence, the study postulates that the interaction between SKIP and SMADs under the influence of the factors tamoxifen and TGF-β could lead to exhibit a synergic effect in inhibiting the cancer cell growth.

Master’s Degree Project in Biology/Molecular Biology/Molecular Genetics and Biotechnology credits 60 Department of Biology, Lund University

Advisor: Dr. Antoni Hurtado Rodriguez
Department: Hurtado Group, Centre for Molecular Medicine, Nordic EMBL Partnership, Norway

• author: Manivannan, Madhuri
• supervisor: Antoni Hurtado; Marita Cohn
• organization: Degree Projects in Molecular Biology
• course: MOBN03 20172
• year: 2018
• type: H2 - Master's Degree (Two Years)
• subject: Biology and Life Sciences
• language: English
• id: 8958677
• date added to LUP: 2018-09-14 10:04:36
• date last changed: 2018-09-14 10:04:36