KIBRA; a novel biomarker predicting recurrence free survival of breast cancer patients receiving adjuvant therapy

Mudduwa, Lakmini; Peiris, Harshini; Abeysiriwardhana, Deepthika; Liyanage, N. D. L.; Rayala, Suresh K.; Liyanage, Thusharie

doi:10.1186/s12885-018-4491-6

Cited by 10 publications

(16 citation statements)

References 17 publications

(26 reference statements)

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“…While WWC1 has been primarily linked to episodic memory and Alzheimer's disease, a recent candidate gene study observed an association between WWC1 variants and risk of estrogen‐receptor positive breast cancer in women of African ancestry. Likewise, WWC1/KIBRA has been linked to breast cancer outcomes, including recurrence‐free survival and metastasis . In the current study, we found an association with ER negative breast cancer for the SNP nearest to the WWC1 gene.…”

Section: Discussionsupporting

confidence: 60%

“…Likewise, WWC1/KIBRA has been linked to breast cancer outcomes, including recurrence-free survival and metastasis. 32,33 In the current study, we found an association with ER negative breast cancer for the SNP nearest to the WWC1 gene. To our knowledge, the other two loci associated with EOC in women of African descent at the suggestive threshold, LOC101927394 and UGT2A2, have not been reported in association with cancer or other diseases.…”

Section: Discussionsupporting

confidence: 57%

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Identification of novel epithelial ovarian cancer loci in women of African ancestry

Manichaikul

Peres

Wang

et al. 2019

Intl Journal of Cancer

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Women of African ancestry have lower incidence of epithelial ovarian cancer (EOC) yet worse survival compared to women of European ancestry. We conducted a genome‐wide association study in African ancestry women with 755 EOC cases, including 537 high‐grade serous ovarian carcinomas (HGSOC) and 1,235 controls. We identified four novel loci with suggestive evidence of association with EOC (p < 1 × 10−6), including rs4525119 (intronic to AKR1C3), rs7643459 (intronic to LOC101927394), rs4286604 (12 kb 3′ of UGT2A2) and rs142091544 (5 kb 5′ of WWC1). For HGSOC, we identified six loci with suggestive evidence of association including rs37792 (132 kb 5′ of follistatin [FST]), rs57403204 (81 kb 3′ of MAGEC1), rs79079890 (LOC105376360 intronic), rs66459581 (5 kb 5′ of PRPSAP1), rs116046250 (GABRG3 intronic) and rs192876988 (32 kb 3′ of GK2). Among the identified variants, two are near genes known to regulate hormones and diseases of the ovary (AKR1C3 and FST), and two are linked to cancer (AKR1C3 and MAGEC1). In follow‐up studies of the 10 identified variants, the GK2 region SNP, rs192876988, showed an inverse association with EOC in European ancestry women (p = 0.002), increased risk of ER positive breast cancer in African ancestry women (p = 0.027) and decreased expression of GK2 in HGSOC tissue from African ancestry women (p = 0.004). A European ancestry‐derived polygenic risk score showed positive associations with EOC and HGSOC in women of African ancestry suggesting shared genetic architecture. Our investigation presents evidence of variants for EOC shared among European and African ancestry women and identifies novel EOC risk loci in women of African ancestry.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionsupporting

confidence: 57%

Identification of novel epithelial ovarian cancer loci in women of African ancestry

Manichaikul

Peres

Wang

et al. 2019

Intl Journal of Cancer

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“…The third most significant master regulator, the WW and C2 domain-containing 1 ( WWC1 ) gene, produces a phosphoprotein. It has functions in restricting proliferation and promoting apoptosis, as well as in regulating transcription of estrogen receptor α ( ESR1 ) [ 82 ]. The WWC1 gene is part of the hippo pathway, which also regulates cell proliferation and apoptosis and plays a role in position sensing and lineage specification in preimplantation embryos [ 83 , 84 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of Loci and Pathways Associated with Heifer Conception Rate in U.S. Holsteins

Galliou

Kiser

Oliver

et al. 2020

Genes

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Heifer conception rate (HCR) is defined as the percentage of inseminated heifers that become pregnant at each service. The genome-wide association analyses in this study focused on identifying the loci associated with Holstein heifer (n = 2013) conception rate at first service (HCR1) and the number of times bred (TBRD) to achieve a pregnancy. There were 348 unique loci associated (p < 5 × 10−8) with HCR1 and 615 unique loci associated (p < 5 × 10−8) with TBRD. The two phenotypes shared 302 loci, and 56 loci were validated in independent cattle populations. There were 52 transcription factor binding sites (TFBS) and 552 positional candidate genes identified in the HCR1- and TBRD-associated loci. The positional candidate genes and the TFBS associated with HCR1 and TBRD were used in the ingenuity pathway analysis (IPA). In the IPA, 11 pathways, 207 master regulators and 11 upstream regulators were associated (p < 1.23 × 10−5) with HCR1 and TBRD. The validated loci associated with both HCR1 and TBRD make good candidates for genomic selection and further investigations to elucidate the mechanisms associated with subfertility and infertility.

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“…Furthermore, we show that decreased KIBRA expression correlates with reduced BC patients’ OS and RFS. Notably, during the period our manuscript was under review, it was reported that luminal BC patients with endocrine therapy and KIBRA-low expression had an RFS disadvantage over those who were positive for KIBRA [ 39 ]. Accordingly, the correlation between expression of WWC2/WWC3 and clinical features of breast cancer must be further determined.…”

Section: Discussionmentioning

confidence: 99%

Loss of KIBRA function activates EGFR signaling by inducing AREG

et al. 2018

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The Hippo signaling pathway is a central regulator of organ size, tissue homeostasis, and tumorigenesis. KIBRA is a member of the WW domain-containing protein family and has recently been reported to be an upstream protein in the Hippo signaling pathway. However, the clinical significance of KIBRA deregulation and the underlying mechanisms by which KIBRA regulates breast cancer (BC) initiation and progression remain poorly understood. Here, we report that KIBRA knockdown in mammary epithelial cells induced epithelial-to-mesenchymal transition (EMT) and increased cell migration and tumorigenic potential. Mechanistically, we observed that inhibiting KIBRA induced growth factor-independent cell proliferation in 2D and 3D culture due to the secretion of amphiregulin (AREG), an epidermal growth factor receptor (EGFR) ligand. Also, we show that AREG activation in KIBRA-knockdown cells depended on the transcriptional coactivator YAP1. Significantly, decreased expression of KIBRA is correlated with recurrence and reduced BC patient survival. In summary, this study elucidates the molecular events that underpin the role of KIBRA in BC. As a result, our work provides biological insight into the role of KIBRA as a critical regulator of YAP1-mediated oncogenic growth, and may have clinical potential for facilitating patient stratification and identifying novel therapeutic approaches for BC patients.

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KIBRA; a novel biomarker predicting recurrence free survival of breast cancer patients receiving adjuvant therapy

Cited by 10 publications

References 17 publications

Identification of novel epithelial ovarian cancer loci in women of African ancestry

Identification of novel epithelial ovarian cancer loci in women of African ancestry

Identification of Loci and Pathways Associated with Heifer Conception Rate in U.S. Holsteins

Loss of KIBRA function activates EGFR signaling by inducing AREG

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