Interplay between BRCA1 and RHAMM Regulates Epithelial Apicobasal Polarization and May Influence Risk of Breast Cancer

Maxwell, Christopher A.; Benı́tez, Javier; Gómez-Baldó, Laia; Osorio, Ana; Bonifaci, Núria; Fernández-Ramires, Ricardo; Costes, Sylvain V.; Guinó, Elisabet; Chen, Helen; Evans, Gareth J. R.; Mohan, Pooja; Català, Isabel; Petit, Audrey; Aguilar, Helena; Villanueva, Alberto; Aytés, Álvaro; Serra-Musach, Jordi; Rennert, Gad; Lejbkowicz, Flavio; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Ripamonti, Carla; Bonanni, Bernardo; Viel, Alessandra; Allavena, Anna; Bernard, Loris; Radice, Paolo; Friedman, Eitan; Kaufman, Bella; Laitman, Yael; Dubrovsky, Maya; Milgrom, Roni; Jakubowska, Anna; Cybulski, Cezary; Górski, Bohdan; Jaworska, Katarzyna; Durda, Katarzyna; Sukiennicki, Grzegorz; Lubiński, Jan; Shugart, Yin Yao; Domchek, Susan M.; Letrero, Richard; Weber, Barbara; Hogervorst, Frans B.L.; Rookus, Matti A.; Collée, J. Margriet; Devilee, Peter; Ligtenberg, Marjolijn J. L.; Luijt, Rob B. van der; Aalfs, Cora M.; Waisfisz, Quinten; Wijnen, Juul T.; Roozendaal, C. E. P. van; Easton, Douglas F.; Peock, Susan; Cook, Margaret; Oliver, Clare; Frost, Debra; Harrington, Patricia; Evans, D. Gareth; Lalloo, Fiona; Eeles, Rosalind; Izatt, Louise; Chu, Carol; Eccles, Diana; Douglas, Fiona; Brewer, Carole; Nevanlinna, Heli; Heikkinen, Tuomas; Couch, Fergus J.; Lindor, Noralane M.; Wang, Xianshu; Godwin, Andrew K.; Caligo, Maria A.; Lombardi, Grazia; Loman, Niklas; Karlsson, Per; Ehrencrona, Hans; Wachenfeldt, Anna von; Barkardóttir, Rósa B.; Hamann, Ute; Rashid, Muhammad Usman; Lasa, Adriana; Caldés, Trinidad; Andrés, Raquel; Schmitt, Michael; Assmann, Volker; Stevens, Kristen N.; Offit, Kenneth; Curado, João; Tilgner, Hagen; Guigó, Roderic; Aiza, Gemma; Brunet, Joan; Castellsague, Joan; Martrat, Griselda; Urruticoechea, Ander; Blanco, Ignacio; Tihomirova, Laima; Goldgar, David E.; Buys, Saundra S.; John, Esther M.; Miron, Alexander; Southey, Melissa C.; Daly, Mary B.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Meindl, Alfons; Arnold, Norbert; Deissler, Helmut; Varon-Mateeva, Raymonda; Sutter, Christian; Niederacher, Dieter; Imyamitov, Evgeny; Sinilnikova, Olga M.; Stoppa-Lyonne, Dominique; Mazoyer, Sylvie; Verny-Pierre, Carole; Castéra, Laurent; Pauw, Antoine de; Bignon, Yves‐Jean; Uhrhammer, Nancy; Peyrat, Jean‐Philippe; Vennin, Philippe; Ferrer, Sandra Fert; Collonge‐Rame, Marie‐Agnès; Mortemousque, Isabelle; Spurdle, Amanda B.; Beesley, Jonathan; Chen, Xiaoqing; Healey, Sue; Barcellos‐Hoff, Mary Helen; Vidal, Marc; Gruber, Stephen B.; Lázaro, Conxi; Capellà, Gabriel; McGuffog, Lesley; Nathanson, Katherine L.; Antoniou, Antonis C.; Chenevix-Trench, Georgia; Fleisch, Markus; Moreno, Vı́ctor; Pujana, Miguel Ángel

doi:10.1371/journal.pbio.1001199

Cited by 93 publications

(128 citation statements)

References 76 publications

(129 reference statements)

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“…Unraveling the molecular and cellular mechanisms underlying breast cancer progression and metastasis is critical for development of therapeutic agents to treat this deadly disease. Receptor for hyaluronan (HA)-mediated motility (RHAMM), also known as HMMR, IHABP, or CD168, has been identified as a breast cancer susceptibility gene (2,3), with dual oncogenic functions as HA receptor and mitotic spindle binding protein (4,5). RHAMM is generally not detected in homeostatic tissues, and is transiently produced during wound repair, but its hyperexpression is associated with tumor development, progression, and metastasis (2,6).…”

mentioning

confidence: 99%

Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility

Wang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

277

284

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Expression of receptor for hyaluronan-mediated motility (RHAMM), a breast cancer susceptibility gene, is tightly controlled in normal tissues but elevated in many tumors, contributing to tumorigenesis and metastases. However, how the expression of RHAMM is regulated remains elusive. Statins, inhibitors of mevalonate metabolic pathway widely used for hypercholesterolemia, have been found to also have antitumor effects, but little is known of the specific targets and mechanisms. Moreover, Hippo signaling pathway plays crucial roles in organ size control and cancer development, yet its downstream transcriptional targets remain obscure. Here we show that RHAMM expression is regulated by mevalonate and Hippo pathways converging onto Yes-associated protein (YAP)/TEAD, which binds RHAMM promoter at specific sites and controls its transcription and consequently breast cancer cell migration and invasion (BCCMI); and that simvastatin inhibits BCCMI via targeting YAP-mediated RHAMM transcription. Required for ERK phosphorylation and BCCMI, YAP-activated RHAMM transcription is dependent on mevalonate and sensitive to simvastatin, which modulate RHAMM transcription by modulating YAP phosphorylation and nuclear-cytoplasmic localization. Further, modulation by mevalonate/simvastatin of YAP-activated RHAMM transcription requires geranylgeranylation, Rho GTPase activation, and actin cytoskeleton rearrangement, but is largely independent of MST and LATS kinase activity. These findings from in vitro and in vivo investigations link mevalonate and Hippo pathways with RHAMM as a downstream effector, a YAP-transcription and simvastatin-inhibition target, and a cancer metastasis mediator; uncover a mechanism regulating RHAMM expression and cancer metastases; and reveal a mode whereby simvastatin exerts anticancer effects; providing potential targets for cancer therapeutic agents.

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mentioning

confidence: 99%

Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility

Wang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

277

284

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“…This distinctive biology led to the hypothesis that BRCA1 functions as a stem cell regulator in the breast (47). Aberrant lineage commitment is a unique feature of the BRCA1-deficient breast epithelium as shown by several laboratories using different approaches, including marker characteristics, molecular analysis, cell surface antigens, and functional assays (48)(49)(50)(51)(52)(53). Knockdown of BRCA1 in primary breast epithelial cells increases cells displaying aldehyde dehydrogenase (AldH) and decreases cells expressing luminal epithelial markers and ER (52).…”

Section: Introductionmentioning

confidence: 99%

Does Microenvironment Contribute to the Etiology of Estrogen Receptor–Negative Breast Cancer?

Barcellos‐Hoff

2013

Clinical Cancer Research

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What dictates the prevalence of certain types of breast cancer, which are classified by markers, particularly estrogen receptor (ER), expression profiles such as basal or luminal, and genetic alterations such as HER2 amplification, in particular populations is not well understood. It is increasingly evident that microenvironment disruption is highly intertwined with cancer progression. Here, the idea that microenvironment shapes the course of carcinogenesis, and hence breast cancer subtype, is discussed. Aggressive, basal-like, ER-negative breast tumors occur in younger women, African-American women, women who carry BRCA1 mutation, and women exposed to ionizing radiation. Recent experimental studies using ionizing radiation, a well-documented environmental exposure, suggest that certain processes in the microenvironment strongly favor the development of ER-negative tumors. Understanding the contribution of tissue microenvironment during carcinogenesis could lead to prevention strategies that are personalized to age, agent, and exposure to reduce the risk of aggressive breast cancer.

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“…Frequently, the loss of expression or mislocalization of the molecules of polarity complex such as SCRIB, Crumbs, and PAR has been implicated in the carcinogenesis of the breast [40][41][42]. Recently, BRCA1 has been reported to play a key role in the cytoskeletal organization and polarity of the breast tissue [43]. Probably, the loss of polarity in BRCA1-mutated breast tumors results in the loss of cell-cell adhesion and, hence, the movement of cancer cells from the primary to the distant site.…”

Section: Brca1 and Apicobasal Polaritymentioning

confidence: 99%

“…Mechanistically, BRCA1 regulates the polarity and, hence, the differentiation of breast cancer cells by regulating the expression of Hyaluronan-Mediated Motility Receptor (HMMR), a lowpenetrance breast cancer susceptibility gene product that is usually over expressed in BRCA1-related tumors and results in poor prognosis [43][44][45]. The early report comes from a linkage association study where the genetic variation at chromosome 5q33-34, which is actually the gene location of HMMR, is clearly associated with the risk of breast cancer among BRCA1 mutation carriers [46].…”

Section: Brca1 and Apicobasal Polaritymentioning

confidence: 99%

“…For instance, the cytoskeletal molecule vimentin is increased, and CCD49f is decreased upon BRCA1 knockdown. Maxwell et al (2011) have shown that BRCA1, through the non-centrosome-dependent assembly of microtubules, maintains the polarity of the breast epithelium and the loss of BRCA1 clearly impair the cytoskeletal reorganization, as observed by increased levels of intermediate filament proteins such as vimentin. Furthermore, BRCA1 is reported to maintain the polarization of breast epithelium by directing the proteosome-mediated degradation of the BRCA1 target, HMMR [47].…”

Section: Brca1 and Apicobasal Polaritymentioning

confidence: 99%

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Role of BRCA1 in Breast Cancer Metastasis

Kumar¹,

Sreelatha²,

Nadhan³

et al. 2016

Gynecologic Cancers - Basic Sciences, Clinical and Therapeutic Perspectives

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The role of BRCA1 in breast cancer metastasis is a less explored area that might have importance in increased aggressiveness of BRCA1 defective triple negative cancers.The possible influence of BRCA1 on apico basal polarity and ezrin, radixin and meosin (ERM) proteins are discussed in this review as a reason for cell metastasis. This might help in developing antimetastatic drugs that could help for better prognosis in BRCA1 defective breast cancers.

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Interplay between BRCA1 and RHAMM Regulates Epithelial Apicobasal Polarization and May Influence Risk of Breast Cancer

Abstract: Genetic analysis identifies the HMMR gene as a modifier of the breast cancer risk associated with BRCA1 gene mutation, while cell biological analysis of the protein product suggests a function in regulating development of the mammary gland.

Cited by 93 publications

References 76 publications

Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility

Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility

Does Microenvironment Contribute to the Etiology of Estrogen Receptor–Negative Breast Cancer?

Role of BRCA1 in Breast Cancer Metastasis

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