Oestradiol Regulation of Lipid Metabolism in Gynaecological Cancers

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Amira Hajirah Abd Jamil	--	1872	2022-05-11 17:23:17	\|
2	format correct	Catherine Yang	Meta information modification	1872	2022-05-12 02:59:20	\|

This entry is adapted from the peer-reviewed paper 10.3390/metabo12040350

Cancer cells undergo metabolic reprogramming to support cell proliferation, growth, and dissemination, a trait now considered a hallmark of cancer. Alterations in lipid metabolism, and specifically, the uptake and synthesis of fatty acids (FAs), constitute one well-documented aspect of this reprogramming. Fatty acids (FAs) are carboxylic acids, consisting of hydrocarbon chains with varying degrees of length, branching and saturation. They act as primary building blocks for lipid species, such as phospholipids, sphingolipids and triglycerides, all of which participate in a wide array of biological processes. In addition to these roles, FAs are also well established as having a critical role in altering gene transcription by regulating the activity of FA-sensitive transcription factors, particularly sterol-regulatory element-binding protein (SREBP) and peroxisome proliferator-activated receptors (PPARs). More recently, dysregulated FA metabolism has been reported and studied in many cancer types, including gynaecological cancers. FA metabolism supports tumorigenesis and cancer progression through a range of processes, including membrane biosynthesis, energy storage and production, and generation of signalling intermediates. Female sex hormones, specifically oestradiol, play a crucial role in regulating FA metabolism and are also implicated in promoting the risk of gynaecological cancers. The increased risk for these cancers and their pathogenesis has been epidemiologically linked to abnormally high levels of serum oestradiol. Emerging evidence indicates aberrant FA metabolism is postulated to be mediated by the action of oestradiol, either directly via their classical, oestrogen receptor (ER)-mediated pathways, or indirectly through the insulin-like growth factor I (IGFI) receptors (IGIFR), with the levels of serum oestradiol and the IGFIR pathway both dysregulated, not only in gynaecological cancers but also in obesity. However, the mechanisms linking oestradiol to the dysregulation of FA metabolism in these cancer types are still underexplored.

Fatty acid metabolism Oestradiol gynaecological cancer

1. Oestrogen Receptor Pathway

Oestradiol canonically binds to oestrogen receptors (ER), through which signalling plays a critical role in the development and maintenance of female reproductive function ^[1], by regulating a myriad of cellular activities, including FA metabolism ^[2]. Given this role, it is not surprising that the dysregulation of ER is implicated in the progression of gynaecological cancers, notably breast cancer. Activated ER, apart from binding to its response elements as transcription factors, forms multi-protein complexes by recruiting coregulators to dynamically adjust its transcriptional activity, through specific, coregulator-dependent histone modifications ^[3].

Kristiansen et al., found that, in breast cancer tissues, oestradiol suppressed the expression of both ER and non-muscle myoglobin (Mb) ^[4], a well-known mobile carrier of oxygen, with emerging evidence of its role as an oncogene ^[5]^[6]. Mb is also found to strongly co-localise with both ER and FASN, suggesting a potential binding between Mb, with both ER and FASN ^[4]. Owing to the FA-binding properties of non-muscle Mb ^[7], oestradiol could enhance intracellular FA availability in gynaecological cancers by disrupting FASN-Mb/ER binding through lowering Mb and ER expression (Figure 1). The increased FA availability allows FASN-produced FAs to be used by the cancer cells instead of being sequestered through Mb/ER binding. Interestingly, in endometrial cancer cell lines, the growth of high-ER-expressing Ishikawa cells was more retarded by FASN inhibition than that of low-ER-expressing HEC1B cells ^[8]. Thus, the degree to which gynaecological cancers depend on FA synthesis for growth appears to be dependent to oestradiol via ER signalling.

Figure 1. Oestradiol dysregulates the activity of FA metabolism enzymes in gynaecological cancers via the ER and possibly also the IGFIR and IR pathway. Solid lines with an arrowhead represent positive interaction whereas crossbars represent negative interaction. Question marks (?) represent interactions suggested indirectly by current evidence, but more direct evidence is needed to establish their existence. MEDA-4, Mesenteric oestrogen-dependent adipose 4, IGFI, Insulin-like growth factor 1; IGFIR, Insulin-like growth factor 1 receptor; mTORC, Mammalian target of rapamycin complex 1; Mb, Myoglobin; IR, Insulin receptor; ER, Oestrogen receptor; PRLR, Prolactin receptor; AMPK, 5’ adenosine monophosphate-activated protein kinase; SREBP, Sterol-regulatory element binding protein; ACLY, ATP-citrate lyase; ACC, Acetyl-CoA carboxylase; FASN, Fatty acid synthase; ACS, Acyl-CoA synthetase; CPTI, Carnitine palmitoyltransferase I.

The ER pathway is also known to crosstalk with other signalling pathways, notably the prolactin receptor (PRLR) pathway ^[9]^[10]. Prolactin has an important role in lactation but has since expanded to encompass an array of functions, ranging from metabolic homeostasis to maternal behaviour ^[11]. In gynaecological cancers, prolactin is implicated in ovarian and endometrial cancer, where PRLR is found to be upregulated ^[12]. Linher-Melville et al., found prolactin stimulated the expression and activity of CPTIA in MDA-MB-231 cells, in an AMPK-dependent manner. Prolactin also partially restored FA oxidation when CPTIA and AMPK were knocked down, demonstrating the crucial role prolactin plays in promoting FA oxidation in breast cancer. Apart from the signalling interaction between ER and PRL pathway, the oestradiol–ER complex has been reported to transcriptionally upregulate both prolactin and PRLR in breast cancer ^[13]. This evidence describes an indirect way oestradiol could upregulate CPTI and enhance FA oxidation in breast cancer through the ER-PRLR crosstalk and direct upregulation of the PRLR pathway by oestradiol.

Mesenteric oestrogen-dependent adipose (MEDA-4) regulates adipogenesis, adipocyte differentiation and lipid accumulation, serving as a key protein in oestradiol-regulated region-specific fat deposition ^[14]. Li et al., recently showed MEDA-4 expression negatively correlated with breast cancer patient survival and confirmed the role of MEDA-4 in promoting epithelial-to-mesenchymal transition (EMT), in an AKT-dependent manner, using breast cancer cell lines ^[15], showing the importance of MEDA-4 in breast cancer pathogenesis. These results, however, were obtained without investigating the role of oestradiol and MEDA-4 in FA metabolism. More relevantly, oestradiol is known to downregulate MEDA-4, most likely through the ER pathway ^[11]^[16]^[17]^[18]^[19]^[20]^[21]^[22], subsequently lowering CD36 expression levels in adipocytes ^[14]. Given oestradiol induces proliferation and downregulates CD36 in several breast cancer cell lines ^[23], a mechanism similar to this might also be operating in breast cancer (Figure 1), suggesting oestradiol could promote the malignancy of breast cancer in a CD36-dependent manner, by downregulating MEDA-4. Nevertheless, more studies are needed to unravel, in breast cancer pathogenesis, the mechanism linking oestradiol-regulated MEDA-4 and CD36, specifically its FA-uptake role, given its multifaceted properties of being both pro- and anti-carcinogenic, through a multitude of mechanisms ^[24].

Notably, ER itself can be regulated by ACSL4, as ER expressions were reduced in MCF-7 Tet-Off/ACSL4 and restored upon treatment with doxycycline, suggesting ACSL4 negatively controls ER expression and mechanistically determines ER status in breast cancer along with its dependency on oestradiol ^[25]. Further, in breast cancer, knocking down FASN dramatically lowered (by >100 fold) the amount of oestradiol needed to activate ER transcriptional activity, and pharmacologically inhibiting FASN in ER-negative breast cancer cells, stably transfected with ER, increased oestradiol-induced ER-mediated transcriptional activity ^[26]. Therefore, given the potential impact on treatment approach, the possibility of mutual regulation between ER and FA metabolism enzymes should be considered.

2. Insulin-like Growth 1 Receptor Pathway

Apart from ER, current evidence strongly suggests that oestradiol could also bind to other surface receptors, traditionally associated with other ligands. Yang et al., investigated the effect of oestradiol on the progression of ER- metastatic breast cancer using 4T1 tumour mammary cells. Despite lacking ER, oestradiol-treated 4T1 had greater invasiveness in vitro and metastasised to the lungs faster in vivo ^[27]. In line with this, a case-control study within the EPIC cohort (European Prospective Investigation into Cancer and Nutrition) found that oestradiol positively correlated with not only ER+ breast cancer types, but also ER- ones (OR = 2.11) ^[28]. These results suggest that oestradiol could be promoting the carcinogenesis of ER- gynaecological cancers in an ER-independent manner. Indeed, Zhu et al., examined the potential of oestradiol to induce DNA synthesis through the IGFI pathway in uterine epithelial cells. Treatment with IGFIR inhibitor picropodophyllin (PPP) inhibited not only oestradiol-induced DNA synthesis, but also oestradiol-stimulated IGFIR phosphorylation ^[29]. Interestingly, they also found that oestradiol-stimulated IGFIR signalling on DNA synthesis is independent of the action of oestradiol through ER signalling ^[29], further suggesting that oestradiol acts as a ligand for IGFIR to instigate IGFIR signalling and its subsequent downstream effects, which could also include those related to FA metabolism.

IGFIR signalling has been reported to dysregulate FA metabolism in gynaecological cancers, contributing to their development and progression. In a study by Chen et al., IGFI was shown to rapidly induce ACLY Ser-455 phosphorylation, a post-translational modification crucial for regulating lipid metabolism in breast cancer. This phosphorylation promoted glucose-to-lipid conversion, both of which were reduced in the presence of the mTORC1/2 dual inhibitor WYE-132 ^[30]. Additionally, transfecting various ACL phospho-mutants into MDA-MB-453 inhibited its growth, which was rescued using shRNA-resistant constructs ^[30]. Overall, this evidence suggests that IGFI promotes the growth of gynaecological cancers, at least in breast cancer. This carcinogenic effect of IGFI is achieved via mTORC-dependent phosphorylation of ACLY Ser-455 to enhance ACLY function for glucose-derived lipid synthesis, probably including FAs too. Furthermore, Balaban et al., found IGFI induced the de-phosphorylation of pACC by inhibiting the physical interaction between pACC and BRCA1. Silencing BRCA1 in MCF7 lowered pACC levels and increased MCF7 proliferation ^[31], suggesting a IGFI-induced reduction in pACC is involved in retarding the growth of gynaecological cancers. However, other investigators found lowered pACC to be anti-carcinogenic in breast cancer patients treated with metformin, a type 2 diabetes mellitus drug, with accumulating evidence showing its strong potential as an anti-cancer agent ^[32].

Moreover, the ER- breast cancer subtype TNBC was found to not only have higher IGFIR signalling activity than ER+ breast cancers ^[29], but also exhibited greater FA elongation and uptake ^[33]^[34]. More conclusive data on the metabolic differences between ER+ and ER- breast cancers are, however, needed, as these metabolic studies rely on mRNA expression of a panel of metabolic proteins involved in FA metabolism, which do not necessarily reflect overall metabolic activity ^[35], to infer the metabolic trends of the various breast cancer subtypes. Nevertheless, this evidence strongly suggests oestradiol may also alter the FA metabolism of gynaecological cancers by dysregulating enzymes, such as ACLY and ACC, through the IGFIR signalling pathway, probably by serving as an IGFIR ligand. More studies, however, are needed to determine if direct oestradiol-IGFIR binding does exist and, if so, the specific kinetics of such binding. Nevertheless, it is highly possible for such binding to occur, since oestradiol is found to directly bind to insulin receptors (IR), with which IGFIR shares up to 65% homology in the ligand-binding domain and up to 85% in the tyrosine kinase and substrate recruitment domain ^[7]^[36]. In addition, Huang et al., found insulin-stimulated FASN expression in breast cancer cells, with a concomitant increase in SREBP expression and pAkt/Akt ratio. Reducing these with docosahexaenoic acid (DHA) abrogated insulin-stimulated FASN expression, suggesting insulin promotes FASN expression in breast cancer by upregulating SREBP through the Akt pathway ^[37]. The high degree of homology in IR and IGFIR could also indicate possible activation of IR signalling by oestradiol, further suggesting another non-ER signalling pathway, through which oestradiol may dysregulate FA metabolism in gynaecological cancers.

There is still much to be investigated as to the exact pathways in which oestradiol, upon binding to ER, dysregulates FA metabolism in gynaecological cancers. Furthermore, emerging evidence strongly indicates oestradiol could influence FA metabolism in these cancer types, through not only the classical ER pathway, but also non-ER pathways, such as the IGIFR pathway. Therefore, subsequent research focus should be expanded to encompass not only investigating the key molecular players of the ER pathway, but possibly those of the non-ER pathways too, such as the IGFIR pathway, in understanding oestradiol-induced FA dysregulation in gynaecological cancers, diversifying the potential candidates to be pharmacologically targeted in treating these cancer types.

References

Lee, H.-R.; Kim, T.-H.; Choi, K.-C. Functions and physiological roles of two types of estrogen receptors, ERα and ERβ, identified by estrogen receptor knockout mouse. Lab. Anim. Res. 2012, 28, 71–76.
Faulds, M.H.; Zhao, C.; Dahlman-Wright, K.; Gustafsson, J.-Å. The diversity of sex steroid action: Regulation of metabolism by estrogen signaling. J. Endocrinol. 2012, 212, 3–12.
Saha Roy, S.; Vadlamudi, R.K. Role of Estrogen Receptor Signaling in Breast Cancer Metastasis. Int. J. Breast Cancer 2012, 2012, 654698.
Kristiansen, G.; Rose, M.; Geisler, C.; Fritzsche, F.R.; Gerhardt, J.; Lüke, C.; Ladhoff, A.M.; Knüchel, R.; Dietel, M.; Moch, H.; et al. Endogenous myoglobin in human breast cancer is a hallmark of luminal cancer phenotype. Br. J. Cancer 2010, 102, 1736–1745.
Bicker, A.; Nauth, T.; Gerst, D.; Aboouf, M.A.; Fandrey, J.; Kristiansen, G.; Gorr, T.A.; Hankeln, T. The role of myoglobin in epithelial cancers: Insights from transcriptomics. Int. J. Mol. Med. 2020, 45, 385–400.
Bicker, A.; Brahmer, A.M.; Meller, S.; Kristiansen, G.; Gorr, T.A.; Hankeln, T. The Distinct Gene Regulatory Network of Myoglobin in Prostate and Breast Cancer. PLoS ONE 2015, 10, e0142662.
Sriram, R.; Kreutzer, U.; Shih, L.; Jue, T. Interaction of fatty acid with myoglobin. FEBS Lett. 2008, 582, 3643–3649.
Rahman, M.T.; Nakayama, K.; Ishikawa, M.; Rahman, M.; Katagiri, H.; Katagiri, A.; Ishibashi, T.; Iida, K.; Miyazaki, K. Fatty Acid Synthase Is a Potential Therapeutic Target in Estrogen Receptor-/Progesterone Receptor-Positive Endometrioid Endometrial Cancer. Oncology 2013, 84, 166–173.
Xiao, Z.; Yang, X.; Zhang, K.; Liu, Z.; Shao, Z.; Song, C.; Wang, X.; Li, Z. Estrogen receptor α/prolactin receptor bilateral crosstalk promotes bromocriptine resistance in prolactinomas. Int. J. Med. Sci. 2020, 17, 3174–3189.
Barcus, C.E.; Holt, E.C.; Keely, P.J.; Eliceiri, K.W.; Schuler, L.A. Dense Collagen-I Matrices Enhance Pro-Tumorigenic Estrogen-Prolactin Crosstalk in MCF-7 and T47D Breast Cancer Cells. PLoS ONE 2015, 10, e0116891.
Gonzalez-Guerrico, A.M.; Espinoza, I.; Schroeder, B.; Park, C.H.; Kvp, C.M.; Khurana, A.; Corominas-Faja, B.; Cuyàs, E.; Alarcón, T.; Kleer, C.; et al. Suppression of endogenous lipogenesis induces reversion of the malignant phenotype and normalized differentiation in breast cancer. Oncotarget 2016, 7, 71151–71168.
Sethi, B.K.; Chanukya, G.V.; Nagesh, V.S. Prolactin and cancer: Has the orphan finally found a home? Indian J. Endocrinol. Metab. 2012, 16, S195–S198.
Dong, J.; Tsai-Morris, C.H.; Dufau, M.L. A novel estradiol/estrogen receptor alpha-dependent transcriptional mechanism controls expression of the human prolactin receptor. J. Biol. Chem. 2006, 281, 18825–18836.
Zhang, H.; Chen, X.; Sairam, M.R. Novel genes of visceral adiposity: Identification of mouse and human mesenteric estrogen-dependent adipose (MEDA)-4 gene and its adipogenic function. Endocrinology 2012, 153, 2665–2676.
Li, Z.; Li, C.; Wu, Q.; Tu, Y.; Wang, C.; Yu, X.; Li, B.; Wang, Z.; Sun, S.; Sun, S. MEDAG enhances breast cancer progression and reduces epirubicin sensitivity through the AKT/AMPK/mTOR pathway. Cell Death Dis. 2021, 12, 97.
Pizer, E.S.; Thupari, J.; Han, W.F.; Pinn, M.L.; Chrest, F.J.; Frehywot, G.L.; Townsend, C.A.; Kuhajda, F.P. Malonyl-coenzyme-A is a potential mediator of cytotoxicity induced by fatty-acid synthase inhibition in human breast cancer cells and xenografts. Cancer Res. 2000, 60, 213–218.
Corominas-Faja, B.; Vellon, L.; Cuyas, E.; Buxo, M.; Martin-Castillo, B.; Serra, D.; Garcia, J.; Lupu, R.; Menendez, J.A. Clinical and therapeutic relevance of the metabolic oncogene fatty acid synthase in HER2+ breast cancer. Histol. Histopathol. 2017, 32, 687–698.
Alli, P.M.; Pinn, M.L.; Jaffee, E.M.; McFadden, J.M.; Kuhajda, F.P. Fatty acid synthase inhibitors are chemopreventive for mammary cancer in neu-N transgenic mice. Oncogene 2005, 24, 39–46.
Zhou, W.; Simpson, P.J.; McFadden, J.M.; Townsend, C.A.; Medghalchi, S.M.; Vadlamudi, A.; Pinn, M.L.; Ronnett, G.V.; Kuhajda, F.P. Fatty acid synthase inhibition triggers apoptosis during S phase in human cancer cells. Cancer Res. 2003, 63, 7330–7337.
Kuhajda, F.P.; Jenner, K.; Wood, F.D.; Hennigar, R.A.; Jacobs, L.B.; Dick, J.D.; Pasternack, G.R. Fatty acid synthesis: A potential selective target for antineoplastic therapy. Proc. Natl. Acad. Sci. USA 1994, 91, 6379–6383.
Pizer, E.S.; Jackisch, C.; Wood, F.D.; Pasternack, G.R.; Davidson, N.E.; Kuhajda, F.P. Inhibition of fatty acid synthesis induces programmed cell death in human breast cancer cells. Cancer Res. 1996, 56, 2745–2747.
Vazquez-Martin, A.; Colomer, R.; Brunet, J.; Lupu, R.; Menendez, J.A. Overexpression of fatty acid synthase gene activates HER1/HER2 tyrosine kinase receptors in human breast epithelial cells. Cell Prolif. 2008, 41, 59–85.
Uray, I.P.; Liang, Y.; Hyder, S.M. Estradiol down-regulates CD36 expression in human breast cancer cells. Cancer Lett. 2004, 207, 101–107.
Jiménez, B.; Volpert, O.V.; Crawford, S.E.; Febbraio, M.; Silverstein, R.L.; Bouck, N. Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1. Nat. Med. 2000, 6, 41–48.
Orlando, U.D.; Garona, J.; Ripoll, G.V.; Maloberti, P.M.; Solano, A.R.; Avagnina, A.; Gomez, D.E.; Alonso, D.F.; Podesta, E.J. The Functional Interaction between Acyl-CoA Synthetase 4, 5-Lipooxygenase and Cyclooxygenase-2 Controls Tumor Growth: A Novel Therapeutic Target. PLoS ONE 2012, 7, 14.
Menendez, J.A.; Lupu, R. Fatty acid synthase regulates estrogen receptor-α signaling in breast cancer cells. Oncogenesis 2017, 6, e299.
Yang, X.; Belosay, A.; Du, M.; Fan, T.M.; Turner, R.T.; Iwaniec, U.T.; Helferich, W.G. Estradiol increases ER-negative breast cancer metastasis in an experimental model. Clin. Exp. Metastasis 2013, 30, 711–721.
James, R.E.; Lukanova, A.; Dossus, L.; Becker, S.; Rinaldi, S.; Tjønneland, A.; Olsen, A.; Overvad, K.; Mesrine, S.; Engel, P.; et al. Postmenopausal Serum Sex Steroids and Risk of Hormone Receptor–Positive and -Negative Breast Cancer: A Nested Case–Control Study. Cancer Prev. Res. 2011, 4, 1626–1635.
Zhu, L.; Pollard, J.W. Estradiol-17beta regulates mouse uterine epithelial cell proliferation through insulin-like growth factor 1 signaling. Proc. Natl. Acad. Sci. USA 2007, 104, 15847–15851.
Chen, Y.; Qian, J.; He, Q.; Zhao, H.; Toral-Barza, L.; Shi, C.; Zhang, X.; Wu, J.; Yu, K. mTOR complex-2 stimulates acetyl-CoA and de novo lipogenesis through ATP citrate lyase in HER2/PIK3CA-hyperactive breast cancer. Oncotarget 2016, 7, 25224–25240.
Koobotse, M.; Holly, J.; Perks, C. Elucidating the novel BRCA1 function as a non-genomic metabolic restraInt. in ER-positive breast cancer cell lines. Oncotarget 2018, 9, 33562–33576.
Kasznicki, J.; Sliwinska, A.; Drzewoski, J. Metformin in cancer prevention and therapy. Ann. Transl. Med. 2014, 2, 57.
Monaco, M.E. Fatty acid metabolism in breast cancer subtypes. Oncotarget 2017, 8, 29487–29500.
Yamashita, Y.; Nishiumi, S.; Kono, S.; Takao, S.; Azuma, T.; Yoshida, M. Differences in elongation of very long chain fatty acids and fatty acid metabolism between triple-negative and hormone receptor-positive breast cancer. BMC Cancer 2017, 17, 589.
Koussounadis, A.; Langdon, S.P.; Um, I.H.; Harrison, D.J.; Smith, V.A. Relationship between differentially expressed mRNA and mRNA-protein correlations in a xenograft model system. Sci. Rep. 2015, 5, 10775.
Root-Bernstein, R.; Podufaly, A.; Dillon, P.F. Estradiol Binds to Insulin and Insulin Receptor Decreasing Insulin Binding in vitro. Front. Endocrinol. 2014, 5, 118.
Huang, L.-H.; Chung, H.-Y.; Su, H.-M. Docosahexaenoic acid reduces sterol regulatory element binding protein-1 and fatty acid synthase expression and inhibits cell proliferation by inhibiting pAkt signaling in a human breast cancer MCF-7 cell line. BMC Cancer 2017, 17, 890.

© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.

Upload a video for this entry

Information

Subjects: Biochemistry & Molecular Biology; Obstetrics & Gynaecology

Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

Amira Abd Jamil

View Times: 636

Update Date: 12 May 2022

Table of Contents

Video Upload Options

Confirm

1. Oestrogen Receptor Pathway

2. Insulin-like Growth 1 Receptor Pathway

References