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Mahmoud, Rinad (2021) The role of HOXA5 in triple-negative breast cancer (TNBC). MRes thesis, University of Nottingham.

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Abstract

Breast cancer (BC) accounts for about 15% of all cancer types in the UK and is considered the most common malignancy among females. Triple-negative breast cancer (TNBC) subtype accounts for 10-20% of all BC subtypes. TNBC is known for its aggressive clinical course and poor patient outcome compared to other BC types. There is an urge to further understand the pathology and identify novel effective treatments for TNBC. Recently, the enrichment of TNBC tumours with cancer stem cells has been recognized as a key for their oncogenic properties. However, the specific mechanisms that regulate TNBC self-renewal, cellular differentiation, and proliferation and consequently their progression and migration ability is still unclear. Dysregulations in HOX gene family expression including HOXA5 transcription factor has been associated with cancer in many ways due to their role in cellular differentiation. However, the role of HOXA5 in stemness and cellular differentiation in TNBC is not clear. Hence, in this study, we aim to define HOXA5 specific role in stemness, cellular differentiation and proliferation in the different TNBC subtypes.



We generated lentivirus modified HOXA5 expressing and knockdown TNBC cells to investigate HOXA5 elicited transcriptomic and protein expression changes. We tested the effects of HOXA5 on a selected set of markers (proliferation, stemness, differentiation markers) using RT-qPCR. We also tested changes in cellular survival using clonogenic assay and assessed HOXA5 effect on cellular migration using wound-healing assay. Moreover, we investigated HOXA5 effects on TNBC stemness capacity through mammosphere formation assays. Our study also aims to identify the ability of retinoids to modulate HOXA5 expression and its subsequent effect on TNBC cellular phenotype and proliferation. Therefore, we tested retinoid as short- and long-term treatment regimens and tested the treatment effects on HOXA5 levels and the selected proliferation marker using RT-qPCR. Our study identified HOXA5 as an important regulator of cancer stem cells in TNBC. Our data demonstrate that HOXA5 is relevant for survival and stemness in TNBC. This may also correspond to the different subtypes, where this effect is further evoked in the M and MSL TNBC subtypes. We also believe that HOXA5 stimulates cellular invasion and migration in TNBC. Our data suggest that HOXA5 elicit these effects through modulating the expression of a set of genes involved in cancer cells stemness and proliferation (ALDH1 family members ALDH1A1 and ALDH1A3), adhesion and phenotypic changes (CDH1 and KRT14), invasion and proliferation (YAP target genes; TACSTD2, CTGF, and CYR61). Our study also showed that retinoids induce stemness in TNBC and suggest that HOXA5 could play an important role in retinoid induced stemness traits and maintenance in TNBC. The study added to the understanding of the stemness and differentiation process in TNBC tissue. It also provided evidence of HOXA5 playing an oncogenic role in TNBC despite its beneficial effect in other breast cancer subtypes.

Item Type:	Thesis (University of Nottingham only) (MRes)
Supervisors:	Ordonez Moran, Paloma Shams Nateri, Abdolrahman
Keywords:	HOXA5, Cancer Stem Cells (CSCs), Breast cancer
Subjects:	W Medicine and related subjects (NLM Classification) > WP Gynecology
Faculties/Schools:	UK Campuses > Faculty of Medicine and Health Sciences > School of Medicine
Item ID:	67232
Depositing User:	Mahmoud, Rinad
Date Deposited:	14 Jan 2022 08:51
Last Modified:	14 Jan 2022 08:51
URI:	https://eprints.nottingham.ac.uk/id/eprint/67232

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