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Damage to the uterus, the fallopian tubes and the ovaries
Published in David J Cahill, Practical Patient Management in Reproductive Medicine, 2019
Fibroids are common and estimates of their frequency vary from 30% on clinical assessment and 50% on ultrasound (6). When hysterectomy samples were examined (hysterectomies for all reasons: heavy periods, pain, etc.), fibroids were found in more than 70% of samples (7). Fibroids are generally found in women of reproductive years, giving rise to the theory that they are initiated and/or maintained by stimuli from oestradiol and progesterone (8). It is more complex than that, of course, and various proteins and growth factors are likely to be implicated. Other aetiological mechanisms have been postulated, including infection-related oncogenesis, abnormal cervical cytology, the use of genital talc, the use of intrauterine devices and sexually transmitted diseases. The National Institute of Environmental Health Sciences Uterine Fibroid Study surveyed more than 1000 women, examining these putative factors. The study found no link with most infections, including latent Chlamydia, but it found an inverse association between fibroids and abnormal cervical cytology (9). This was a well-conducted study which helped to clarify important questions, and the inverse relationship of abnormal cervical cytology and fibroids prompts further speculation. Human papilloma virus (HPV), the most common cause of abnormal cervical cytology, is known to be inserted at chromosome 12q14-15 in cervical cancer. That region on chromosome 12 is also the region of a translocation seen in fibroid tumours which have reached a larger size. The HPV insertion site is 50–100,00 base pairs (that's very close) from the HMGA-2 gene which can be overexpressed in fibroids. The inverse relationship described above suggests that HPV insertion may stabilise the region and reduce translocations, thus limiting fibroid growth. This area of work needs further exploration to test the hypothesis, but, if fruitful, there is the exciting potential that it could generate a vaccine to protect against fibroids in at-risk women.
Medical Options for Uterine Fibroids in the Context of Reproduction
Published in Botros R.M.B. Rizk, Yakoub Khalaf, Mostafa A. Borahay, Fibroids and Reproduction, 2020
Hoda Elkafas, Mona Al Helou, Qiwei Yang, Ayman Al-Hendy
Uterine fibroids are the most common benign myometrial tumors affecting 70%–80% of women during their lifetime [1–3]. In the United States, the annual economic burden of these tumors is evaluated to be $34.4 billion [4]. The rate of this disease can be affected by many factors, including race, body mass index, family history, and ethnicities. Although uterine fibroids are benign tumors, they can cause heavy menstrual bleeding (HMB), pelvic pain, preterm labor, recurrent abortion, urinary incontinence, and infertility. In addition to myomectomy and hysterectomy, which are the primary surgical treatments for fibroids, the current treatment also includes gonadotropin-releasing hormone (GnRH) agonist, which decreases tumor size by 40% in 3 months. Unfortunately, GnRH agonists have limited use due to their hypoestrogenic side effects [2,5]. Uterine fibroids are monoclonal tumors that arise from uterine smooth muscle (myometrium), and one of their characteristic features is their dependency on the ovarian steroids estrogen (E2) and progesterone (P4) [6]. Hormonal fluctuations influence fibroid growth during the pregnancy and postpartum periods. In addition to the hormonal response, these lesions are influenced by genetic aberrations [7,8]. The monoclonal origin of fibroids implies mutations of myometrial cells as the origin of the disease. Clonal chromosomal aberrations are detected in approximately 20% of the fibroids. Of these, recurrent chromosomal translocations, including chromosomal regions 12q1415 or 6p21, respectively, that report for the most of cytogenetic deviations, lead to transcriptional upregulation of the human high mobility group AT-hook (HMGA) genes following by activation of the p14Arf–p53 network. It is well studied that fibroids can be subdivided based on the presence of clonal chromosomal aberrations as, e.g., deletions of the long arm of chromosome 7, trisomy 12 or chromosomal rearrangements targeting both of the two human HMGA genes [2,9,10]. Recently, research on a somatic mutation (c.131G > A) in the mediator complex subunit 12 gene (MED12) has been undertaken, as this is a primary subscriber to fibroid pathogenesis. Mutations in exon 2 of MED12 are present in approximately 85% of uterine fibroids [2]. Sex steroid hormones are also suggested to play a role in fibroid occurrence. Estrogen has a crucial role in fibroid growth and development, which explains the onset of symptoms at puberty and stops after menopause. Uterine fibroids have more estrogen and progesterone receptors than healthy myometrial cells. Progesterone's role in pathogenesis is still poorly understood, but studies showed that it affects fibroid growth. Early life exposure to endocrine-disrupting chemicals, such as diethylstilbestrol (DES), genistein, dioxin, and bisphenol-A (BPA), can change the function of the endocrine system by binding hormone receptors or by revising hormone synthesis and metabolism, leading to hyperresponsiveness to normal levels of estrogen, which increases the risk of fibroid development [11–13].
Targeting the intrinsically disordered architectural High Mobility Group A (HMGA) oncoproteins in breast cancer: learning from the past to design future strategies
Published in Expert Opinion on Therapeutic Targets, 2020
Silvia Pegoraro, Gloria Ros, Michela Sgubin, Sara Petrosino, Alberto Zambelli, Riccardo Sgarra, Guidalberto Manfioletti
The expression and function of HMGA in BC have been recently reviewed [15]; therefore, here, we summarized the most important aspects together with the most recently published relevant findings. HMGA1 and HMGA2 have been investigated in several studies using RT-PCR or immunohistochemistry [see [15] for a comprehensive discussion], and in general, they are absent or expressed at very low levels in normal tissues while they are overexpressed in BC. HMGA1 and HMGA2 mRNA expression was analyzed using a dataset from BC patients showing that HMGA1 is enriched in the basal and HER2 subtypes compared to the others, in ER-negative, and in advanced grade tumors [15]. On the other hand, the same analysis evidenced that HMGA2 mRNA expression did not show any enrichment in any subtype, status or grade, probably because it is mainly regulated post-transcriptionally by miRNA, particularly through let-7 [15,16]. Indeed, post-transcriptional mechanisms play a relevant role in the control of HMGA gene expression, particularly HMGA2 [16]. The recent finding that Fra-1, bound to an intragenic enhancer region, is required for RNA Pol II recruitment at the HMGA1 promoter in TNBC [42] further supports the notion that HMGA1 gene expression is controlled mainly by TFs acting at the promoter/enhancer level [15]. Despite the relevance of HMGA2 post-transcriptional mechanism of regulation, it is worthwhile to show that HMGA2 transcription is under the direct control of the Wnt/beta-catenin and TGF-beta/SMAD pathways [43–48] which play a fundamental role in BC and represent potential targets for TNBC patients [49].
Effects of Fatty Acids on Hematological Neoplasms: A Mini Review
Published in Nutrition and Cancer, 2022
Silvia Giannattasio, Maria Dri, Giuseppe Merra, Giovanna Caparello, Tiziana Rampello, Laura Di Renzo
Another nontoxic group of molecules recently used is high mobility group AT‐Hook (HMGA) proteins, a family of nonhistone chromatin remodeling proteins known as “architectural transcriptional factors”. These molecules seem to be crucial in tumor progression, and in malignant hematopoiesis growth. HMGA proteins interact with the transcription pathways, modifying chromatin manufacturing and regulating gene expression. Overexpression of HMGA genes have found in human malignant neoplasia (57).