Biology subjects

Rakha, E.

Publications and source records attributed to Rakha, E..

6 recordsLinked to original sources

bioRxiv2024

Predictive biomarkers of breast ductal carcinoma in situ may underestimate the risk of recurrence due to de novo ipsilateral breast carcinoma development

Development of ipsilateral breast carcinoma following diagnosis of breast ductal carcinoma in situ (DCIS) has been assumed to represent recurrence of the primary tumour. However, this may not be the case and it is important to know how often recurrences are new tumours. Ipsilateral primary-recurrence pairs (n=78) were sequenced to test their clonal relatedness. Shared genetic events were identified from whole exome sequencing (n=54 pairs) using haplotype-specific copy number and phylogenetic analysis. The remaining pairs were sequenced by a targeted panel or low-coverage whole genome sequencing. We included 32 non-recurrent DCIS to compare recurrent and non-recurrent disease. We found that 7% of DCIS recurrences were non-clonal by whole exome sequencing, indicative of a new breast carcinoma. Lower resolution methods detected a higher non-clonality rate (29%). Comparing primary DCIS with their recurrences found that evolution of DCIS to invasive disease was associated with increased ploidy and copy number events. TP53 mutations were enriched in DCIS with clonal recurrence compared with non-recurrent DCIS. Our results verify that de novo "recurrent tumours" of independent origin occur in patients who may be at high risk.

cancer biology↗

bioRxiv2023

An Nav1.5-dependent feedback mechanism driving glycolytic acidification in breast cancer metastasis

Solid tumours have abnormally high intracellular [Na+]. The activity of various Na+ channels may underlie this Na+ accumulation. Voltage-gated Na+ channels (VGSCs) have been shown to be functionally active in cancer cell lines, where they promote invasion. However, the mechanisms involved, and clinical relevance, are incompletely understood. Here, we show that protein expression of the Nav1.5 VGSC subtype strongly correlates with increased metastasis and shortened cancer-specific survival in breast cancer patients. In addition, VGSCs are functionally active in patient-derived breast tumour cells, cell lines, and cancer-associated fibroblasts. Knock down of Nav1.5 in a mouse model of breast cancer suppresses expression of invasion-regulating genes. Nav1.5 activity increases glycolysis in breast cancer cells, likely by up-regulating activity of the Na+/K+ ATPase, thus promoting H+ production and extracellular acidification. The pH of murine xenograft tumours is lower at the periphery than in the core, in regions of higher proliferation and lower apoptosis. In turn, acidic extracellular pH elevates persistent Na+ influx through Nav1.5 into breast cancer cells. Together, these findings show positive feedback between extracellular acidification and movement of Na+ into cancer cells which can facilitate invasion. These results highlight the clinical significance of Nav1.5 activity as a potentiator of breast cancer metastasis and provide further evidence supporting the use of VGSC inhibitors in cancer treatment.

cancer biology↗

bioRxiv2022

EHD2 overexpression promotes tumorigenesis and metastasis in triple-negative breast cancer by regulating store-operated calcium entry

With nearly all cancer deaths a result of metastasis, elucidating novel pro-metastatic cellular adaptations could provide new therapeutic targets. Here, we show that overexpression of the EPS15-Homology Domain-containing 2 (EHD2) protein in a large subset of breast cancers (BCs), especially the triple-negative (TNBC) and HER2+ subtypes, correlates with shorter patient survival. The mRNAs for EHD2 and Caveolin-1/2, structural components of caveolae, show co-overexpression across breast tumors, predicting shorter survival in basal-like BC. EHD2 shRNA knockdown and CRISPR-Cas9 knockout of EHD2, together with mouse EHD2 rescue, in TNBC cell line models demonstrate a major positive role of EHD2 in promoting tumorigenesis and metastasis. Mechanistically, we link these roles of EHD2 to store-operated calcium entry (SOCE), with EHD2-dependent stabilization of plasma membrane caveolae ensuring high cell surface expression of the SOCE-linked calcium channel Orai1. The novel EHD2-SOCE oncogenic axis represents a potential therapeutic target in EHD2 and CAV1/2-overexpressing BC.

cancer biology↗

bioRxiv2021

RANK is an independent biomarker of poor prognosis in estrogen receptor-negative breast cancer and a therapeutic target in patient-derived xenografts

Despite strong preclinical data, the therapeutic benefit of the RANKL inhibitor denosumab in BC patients, beyond its bone-related effects, is unclear. Here, we investigated the prognostic value of RANK expression and its functionality in human BC. We analyzed RANK and RANKL expression in more than 1500 BC cases (777 being estrogen receptor-negative (ER-)) from four independent cohorts. We confirmed that RANK is more frequently expressed in ER- tumors, but it is also found in a subset of ER+ tumors. In ER- BC, RANK expression was independently associated with poor outcome, especially in postmenopausal patients and those who received adjuvant chemotherapy. Gene expression analyses unraveled distinct biology associated with RANK in relation to ER expression and menopause, and evidenced enhanced RANK activation in ER- postmenopausal tumors, together with regulation of metabolic pathways. Functional studies and transcriptomic analyses in ER- RANK+ patients-derived orthoxenografts demonstrated that activation of RANK signaling pathway promotes tumor cell proliferation and stemness, and regulates multiple biological processes including tumor immune surveillance and metabolism. Our results demonstrate that RANK expression is an independent poor prognosis biomarker in postmenopausal ER- BC patients and support the rational of using RANK pathway inhibitors in combination with chemotherapy in ER- BC.

cancer biology↗

bioRxiv2020

VGLL1-directed TEAD activation drives endocrine therapy resistance in estrogen receptor positive breast cancer

Resistance to endocrine therapies (ET) is common in estrogen receptor (ER) positive breast cancer and most relapsed patients die with ET-resistant disease. While genetic mutations provide explanations for some relapsed patients1, mechanisms of resistance remain undefined in many cases. Drug-induced epigenetic reprogramming provides possible routes to resistance2. By analysing histone H3 lysine 27 acetylation (H3K27ac) profiles in models of ET resistance, we discovered that selective ER down-regulators (SERDs) such as fulvestrant promote epigenetic activation of VGLL1, a co-activator for TEAD transcription factors. We show that VGLL1, acting via TEADs, promotes expression of genes that drive growth of fulvestrant-resistant breast cancer cells. Pharmacological disruption of VGLL1/TEAD4 interaction inhibits VGLL1/TEAD transcriptional programmes to block growth of the resistant cells and prevents growth. Among the VGLL1/TEAD-regulated genes, we identify EGFR, whereby VGLL1-directed EGFR upregulation sensitises fulvestrant-resistant breast cancer cells to EGFR inhibitors. Taken together, our findings identify VGLL1 as a transcriptional driver in ET resistance and advance new therapeutic possibilities for relapsed ER+ breast cancer patients.

cancer biology↗

bioRxiv2019

Outcome of radial scar/complex sclerosing lesion associated with epithelial proliferations with atypia diagnosed on breast core biopsy - Results from a multicentric UK based study

AIMS: The clinical significance of radial scar/complex sclerosing lesion (RS/CSL) with high risk lesions (epithelial atypia) diagnosed on needle core biopsy (NCB) is not well defined. We aimed at assessing the upgrade rate to carcinoma in-situ (DCIS) and invasive on the surgical excision specimen in a large cohort of RS/CSL associated with atypia. METHODS: 161 women with NCB diagnosis of a RS/CSL with atypia and follow-up histology were studied. Histological findings including different forms of the atypical lesions and final histological outcome in the excision specimens were retrieved and analysed and the upgrade rate for malignancy and invasive carcinoma calculated. RESULTS: 76% of the cases were associated with an atypical ductal hyperplasia (ADH) whereas lobular neoplasia was seen in 24%. On final histology 38 cases were malignant (overall upgrade rate of 25%); 12 invasive and 27 DCIS. The upgrade differed according to the type of atypia and was highest for ADH (35%). When associated with lobular neoplasia the upgrade rate was 12%. The upgrade rates variability was also considerably lower and showing less variability when considering the upgrade to invasive carcinoma alone. CONCLUSION: The upgrade rate for ADH diagnosed on NCB with RS is similar to that of ADH without RS and therefore should be managed similarly. RS associated with LN is less frequently associated with malignant outcome. Most lesions exhibiting some degree of atypia showed similar upgrade rate to invasive carcinoma. Management of RS should be based on the concurrent atypical lesion.

pathology↗