Vicious Cycle of Obesity, Inflammation, and Breast Cancer

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1		Lauren Gollahon	--	3925	2022-04-07 21:13:50	\|
2	Adjust the reference format	Lindsay Dong	Meta information modification	3925	2022-04-08 08:44:15	\|

This entry is adapted from the peer-reviewed paper 10.3390/ijms23052480

Epidemiological studies refer to obesity-associated metabolic changes as a critical risk factor behind the progression of breast cancer. The plethora of signals arising due to obesity-induced changes in adipocytes present in breast tumor microenvironment, significantly affect the behavior of adjacent breast cells. Adipocytes from white adipose tissue are currently recognized as an active endocrine organ secreting different bioactive compounds. However, due to excess energy intake and increased fat accumulation, there are morphological followed by secretory changes in adipocytes, which make the breast microenvironment proinflammatory. This proinflammatory milieu not only increases the risk of breast cancer development through hormone conversion, but it also plays a role in breast cancer progression through the activation of effector proteins responsible for the biological phenomenon of metastasis.

obesity white adipose tissue breast cancer breast tumor microenvironment inflammation

1. Breast Cancer

1.1. Molecular Histotypes of Breast Cancer

Breast cancer is a highly heterogeneous disease. The aggressiveness of breast cancer varies according to its molecular subtypes. The different subtypes are derived from different cells of origin within the mammary glands ^[1]. They are classified into the following subtypes, luminal A, luminal B, human epidermal growth factor receptor 2 (HER2) positive, and basal type or triple negative breast cancer (TNBC), based on the presence of key protein receptors, namely estrogen receptor (ER), progesterone receptor (PR), and HER2 ^[2]. Each subtype has its own distinct set of risk factors, presentation, prognosis, and response to treatment (Table 1). TNBC (ER-/PR-/HER2-) has the worst prognosis of all the types and has the highest metastatic potential ^[2]. Inflammatory breast cancer (IBC) is another aggressive and rare form of breast cancer with poor prognosis.

Table 1. Distinct features of breast cancer based on molecular histotypes for U.S. women.

Molecular Subtypes	Luminal A	Luminal B	HER2 Positive	Triple Negative	Inflammatory Breast Cancer
% of Breast Cancers (U.S. Women) ^[3]	11%	73%	4%	12%	Unknown
Receptor Expression	ER+ PR+ HER2+	ER+ PR± HER2-	ER- PR- HER2+	ER- PR- HER2-	ER-, PR-, HER2+ TNBC
Histological Grade	Low	Intermediate	High	High	High
Prognosis	Good	Intermediate	Poor	Poor	Poor
Ki67 by IHC	Low	High	High	High	High
Response to Treatment	Endocrine therapy: anti-estrogen aromatase inhibitors—Anastrozole Exemestrozole Letrozole	Endocrine therapy: anti-estrogen aromatase inhibitors—Anastrozole Exemestrozole Letrozole	HER2-targeted drugs: Trastuzumab Pertuzumab Neratinib	Treatment: Taxanes— Paclitaxel Docetaxel Anthracyclines Doxorubicon 5-flurouracil	Treatment: HER2+ targeted therapy

1.2. Etiology and Ethnic Differences in Breast Cancer

In the biennial report by the American Cancer Society, certain factors were listed as contributing towards elevating the risk of breast cancer development. The inherited variation in the genetic sequence of BRCA1, BRCA2 genes accounts for 5% to 10% of all breast cancers and was identified primarily among Black and Hispanic breast cancer patients ^[4]. Other factors that contribute to the risk of developing invasive breast cancer include the use of hormonal contraceptives, menopausal hormone replacement therapy, nulliparity, childbirth at a late age, lack of breastfeeding, early menarche, and late menopause ^[4]. In addition, the increase in body mass index (BMI) due to changes in dietary behavior and physical inactivity also progressively aggravates the overall survival rates ^[4]. Excess weight gain and its likelihood for fueling the pathogenesis of breast cancer is mainly devastating for women who are above age 50 or who are postmenopausal ^[4]^[5]. This is because fat cells become the major source of estrogen post-menopause, subsequently increasing the risk of developing hormone-sensitive breast cancer in obese women ^[4]. Aging is another important variable that increases the susceptibility of breast cancer development. The most invasive breast cancers are reported in women who are >55 ^[6].

1.3. The Tumor Microenviroment

Several experimental studies suggest that the tumor microenvironment (TME) plays a role in determining the prognosis of breast cancer. Autocrine and paracrine signaling factors from the TME primarily stimulate the growth and proliferation of cancer cells during the earlier stage of tumorigenesis ^[7]. Invasive breast cancer usually presents as a solitary tumor. However, it has the distinct ability to spread to nearby organs as well as to distant areas across the body. This complex process of cancer spreading from its original, or primary, location to new areas is known as “secondary cancer” or “metastasis” ^[8]. Metastasis is one of the major reasons why breast cancer is still incurable ^[8].

Among the modifiable risk factors, obesity is the most alarming health issue, which increased the risk of several cancers, including breast cancer, by being a contributor to changing the normal homeostasis of the TME. It is reported to be responsible for 52% and 88% cancer-related mortality rates in males and females, respectively ^[9]. The strong association of obesity with several pathological conditions, such as type 2 diabetes, cardiovascular disease, and hypercholesterolemia, is well established. However, their link with cancer is still underappreciated ^[10]. Breast tissue is distinctive in nature due to the presence of a fat-rich connective tissue known as the mammary fat pad, of which white adipocytes constitute its major cellular component ^[11]. Epidemiological studies reported that obesity-associated changes in the metabolic profile and pro-inflammatory signaling of the adipose tissue disrupts the normal physiological homeostasis in local tissues and the systemic microenvironment. This, in conjunction with hypoxia, creates a critical modification in the TME that increases the risk of both the progression and pathogenesis of breast cancer in obese individuals ^[10].

1.4. Chronic Inflammation and Breast Cancer

As early as 1863, Rudolf Virchow was the first to hypothesize a link between chronic inflammation and cancer ^[7]. Obesity promotion, chronic inflammation, and endocrine changes in adipose tissue, act as intermediaries in building a “rapport” between obesity and cancer ^[12]. Adipose tissue is a non-trivial part of the breast fat pad where white adipose tissue (WAT) comprises the majority of the deposits ^[13]. WAT is heterogenic in nature and consists of a complex cellular arrangement that makes the TME dynamic in nature. The main function of WAT is to store fat in the form of triglycerides and release it in the form of fatty acids whenever there is a demand for energy or other metabolic needs. It is also an active endocrine organ that secretes more than 50 kinds of bioactive compounds ^[14]. Under normal physiological conditions, the breast’s luminal epithelial cells require an interaction with the mammary fat pad for ductal luminal cell morphogenesis and alveolar luminal cell differentiation into lactating alveoli ^[11]. Moreover, the presence of immune cells in healthy breast tissue maintains tissue homeostasis and an immune suppressive microenvironment by keeping track of apoptotic cells, angiogenesis, and extracellular matrix (ECM) remodeling ^[15]. However, due to increased fat accumulation as a result of obesity, white adipocytes undergo an increase in volume ^[16]. Adipocyte hypertrophy compromises the integrity of some adipocytes due to limited expandability. This overaccumulation of fat disrupts metabolic homeostasis and induces cell stresses, such as ER stress and oxidative stress, resulting in a chronic inflammatory microenvironment ^[14]^[16]^[17]. Such deregulation assists in facilitating different obesity-associated diseases, including breast cancer ^[5].

Obesity-induced chronic inflammation stimulates the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) ^[18]. This ensures tumorigenesis by inducing genetic mutations that activate protooncogenes, chromosome alterations, and the inactivation of tumor suppressor genes ^[18]. Inflammation also causes the infiltration of proinflammatory macrophages in response to chemotactic agents, which further secretes proinflammatory cytokines and chemokines in to the TME ^[19]. This, in turn, induces the activation of transcription factors, namely, the nuclear factor kappa-light-chain-enhancer (NF-kB), signal transducer, and activator of transcription factor 3 (STAT-3), signal transducer and activator of transcription factor 5 (STAT-5), and hypoxia inducible factor 1-alpha (HIF-1a), which activates signaling pathways progressing towards more aggressive breast cancer, and increasing the likelihood of metastasis ^[20]^[21].

2. Obesity, Inflammation, and Breast Cancer—A Vicious Cycle

2.1. Obesity-Associated Chronic Inflammation

Obesity-induced changes in WAT reprograms the TME in such a way that it becomes favorable for the growth and progression of breast cancer. Among the numerous mechanisms behind the risks associated with obesity-induced breast cancer, the role played by inflammation remains arguably at the forefront. Due to excess fat accumulation by WAT and the subsequent reduction in blood supply resulting in regional hypoxia and adipocyte stress ^[10]^[22], reduced tissue oxygenation causes changes in the transcriptional programming of adipocytes and other stromal cells, which leads to the excess deposition of fibrillar components in the ECM ^[13]. This makes the ECM stiff and generates tissue fibrosis ^[13]. Adipocytes, enclosed within this rigid ECM, face metabolic perturbations, which then impair their normal physiological functions and entail necrotic or pyroptosis-induced cell death ^[13]. Adipocyte cell death, due to a rupture in the cell membranes, accompanies the release of cellular contents, such as lipids, cytokines, ROS, RNS, the nucleic acid ^[10]. These adipocyte-released contents attract immune cells to the dying adipocytes ^[23]. Increased fatty acids released from the dysfunctional adipocytes are recognized by the Toll-like receptor 4 (TLR4) present on the cell surface of the resident macrophages ^[19]^[24]. This leads to the overproduction of proinflammatory cytokines via NF-kB activation, followed by the creation of a localized inflammation in the breast TME ^[19]^[22].

Inflammation is further intensified by the recruitment of macrophages. Obese dysfunctional adipocytes induce localized inflammation, increasing the level of monocyte chemoattractant protein (CCL2) expression by adipocytes in the breast TME. Additionally, cell-free DNA, released from the degenerated adipocytes, also increases the level of CCL2 protein ^[25].

2.2. Obesity-Associated Macrophage Corruption

The process of macrophage infiltration is positively associated with increased body weight and adipocyte size ^[26]. The enrichment of macrophages at the invasive front of the primary tumor site is reported in ^[27]. One in vivo research demonstrated the importance of CSF-1, a nutrient for macrophage survival and proliferation, by correlating its deletion with reduced macrophage density and delayed the metastatic progression of cancer ^[28]. Based on these experimental results, macrophages, recruited in the tumor microenvironment, are indirectly associated with tumor progression, and are identified as tumor-associated macrophages (TAMs) ^[29]^[30]. TAMs are responsible for breast tumor progression by fostering EMT, angiogenesis, extracellular matrix degradation, immunosuppression in response to the TME ^[30]. In addition to the recruited macrophages, there are also tissue-resident macrophages present in the breast TME ^[30]. However, they play contrasting roles. Tissue-resident macrophages are derived from hematopoietic progenitors present in the sac, which arises during embryonic development ^[31]. Colony stimulant factor 1 (CSF1) produced by local stroma maintains the in situ proliferation and self-renewal of local macrophages ^[31]. Under normal physiological conditions, they maintain tissue homeostasis and defend against pathogens ^[27].

Due to their high plasticity, macrophages can transform into different endotypes based on the cues released from the TME ^[31]. While classically activated tumor-associated macrophages (M1) restrain cancer development, alternatively activated tumor-associated macrophages (M2) promote cancer ^[29]. The hypoxic breast tumor microenvironment is very conducive for M2 polarization of tumor-associated macrophages ^[25].

2.3. Obesity-Associated Aromatase Expression

Apart from the interaction between adipocytes and macrophages in the breast TME, the availability of estrogen also increases, especially in postmenopausal breast cancer patients. Studies have observed a high prevalence of obesity correlated with increased serum concentrations of estrogen in postmenopausal breast cancer patients ^[26]. Estrogen is a sex steroid hormone that is mainly associated with hormone receptor-positive breast cancer. This hormone is primarily produced in the granulosa cells of the ovaries in premenopausal women ^[26]. Under normal physiological conditions, white adipocytes are also capable of producing sex steroid hormones. As a result, in postmenopausal women, when the ovaries stop producing estrogen, white adipocytes become the main source for its biosynthesis ^[15]. A total of 18 carbon steroid estrogens (e.g., estrone and estradiol) are mainly converted from 19 carbon steroids androgens (e.g., androstenedione and testosterone) in the presence of aromatase ^[26]^[32]. The obesity-associated increased release of proinflammatory cytokines in breast TME is accompanied by an increased expression of aromatase in white adipocytes, which then converts androgens to estrogens in the adipose tissue ^[26]. In addition to this, obesity-assisted hyperinsulinemia decreases the level of steroid sex hormone-binding globulin (SHBG) ^[33]. This increases the bioavailability of free estrogen, which then promotes mammary tumorigenesis.

2.4. Obesity-Associated Metabolic Remodeling

One of the several benefits of breast tumor cells having adipocytes in the microenvironment is the mobilization of stored fat for compensating higher metabolic requirements ^[11]. Cancer cells require constant supplies of nutrients for their metabolic growth and energy. Various in vitro and in vivo studies concluded that cancer cells offset this need by generating de novo synthetic pathways to generate fatty acids from blood-derived glucose ^[34]^[35]. The de novo biogenesis of fatty acid (FA) and cholesterol, under normoxic conditions, takes place through the conversion of glucose to pyruvate, which feeds into the tricarboxylic acid (TCA) cycle and generates citrate ^[34]^[36]. This mitochondrially produced citrate is converted to acetyl Co A, a substrate of fatty acid synthesis, with the help of ATP citrate lyase ^[37]. One molecule of Acetyl Co A, with seven molecules of malonyl Co A, in the presence of the fatty acid synthase (FASN) and reduced equivalent NADPH, generates the initial FA palmitate via serial condensation ^[35]^[36]. This saturated long chain fatty acid is then further modified and desaturates into complex membrane phospholipids and triglycerides (TAGs) along the way, due to the action of different enzymes ^[34]. In vivo and in situ studies reported an increased expression of FASN in breast cancer cells ^[38]^[39]. FASN-catalyzed FA biosynthesis is stimulated by a high-carbohydrate diet and is suppressed during fasting. Acetyl CoA is also the initial substrate for cholesterol synthesis following the mevalonate pathway. The sterol regulatory element-binding proteins (SREBPs), the master regulator or transcription factor controlling the expression of enzymes involved in fatty acid and cholesterol synthesis, is also overexpressed in cancer ^[35]^[36].

However, this fatty acid can also be supplied by the TME. In a proliferative TME, a lack of oxygen due to insufficient diffusion to an area distant from vasculature, causes hypoxia ^[40]. Hypoxia triggers cancer cells to compete with the resident stromal and immune cells for metabolic nutrients ^[41]. Under such conditions, cancer cells use aerobic glycolysis, where glucose-derived pyruvate is converted to lactate to generate ATP instead of using TCA cycle facilitated mitochondrial oxidative phosphorylation ^[41]. To compensate for the need of fatty acids, cells may switch to alternative sources, such as acetate or the glutamine pathway, to biosynthesize lipids ^[35]. However, in hypoxic conditions, the synthesis of monounsaturated fatty acids is compromised due to oxygen limitations, compromising the enzymatic reactions ^[42]. The unavailability of unsaturated fatty acids, in turn, raises endoplasmic reticulum stress and triggers the activation of the uncoupled protein response (UPR), due to the over-incorporation of saturated fatty acids into the ER membrane, leading to cell death ^[42].

The rapid hypertrophy of white adipocytes due to excess caloric intake coupled with a lack of energy expenditure results in increased fat storage ^[43]. Because free FAs are toxic at higher concentrations, they are stored in the cytosolic lipid droplets of white adipocytes in the form of triglycerides ^[40]. Triglyceride synthesis and storage in adipocytes takes place through the glycerol–phosphate pathway ^[9]. Free FAs, in the presence of acyl CoA synthetase, forms 2 molecules of fatty acyl CoA. This fatty acyl CoA is acylated and dephosphorylated to diacyl glycerol in a reaction with glycerol-3-phosphate ^[9]. Triglycerides are synthesized when a third molecules of fatty acyl CoA is added to the glycerol backbone in the presence of diacylglycerol transferase ^[9]. Moreover, in the obese condition, the expression of FASN also increases in adipose tissues, thus influencing the de novo lipogenesis of triglycerides and their storage in adipocytes ^[44]. This increased synthesis of triglycerides from free FAs and their accumulation as lipid droplets, results in adipocyte hypertrophy leading to obesity.

Although the average range of lipid droplets in other cells is 0.1 to 10 μm, in adipocytes they can accumulate up to 100 μm ^[40]. Due to the proximity, breast cancer cells use lipids from adipocytes as a source of energy ^[43]. Adipocytes can mobilize their stored lipids for breast cancer cell metabolic requirements through neutral lipolysis and autophagy. With the help of the catabolic enzyme adipocyte triglyceride lipase (ATGL), hormone sensitive lipase (HSL), monoacylglycerol lipase (MAGL), triglycerides, or triacylglycerol (TAG) are hydrolyzed into fatty acids (Figure 2) ^[43]. ATGL converts triglycerides to diacylglycerol. Then, in the presence of HSL, diacylglycerol converts into monoacyl glycerol ^[9]. In the final step, monoacylglycerol breaks down to a free FA and glycerol via the MAGL enzyme-mediated hydrolysis process ^[9]. Thus, in obesity, there is an increased availability of circulating free fatty acid for breast cancer cells to offset their continuous metabolic needs.

The excess FAs present in the obese and inflamed breast tumor microenvironment benefit cancer cells in many ways. FAs derived from adipocytes are an energy source for breast cancer cells following β-oxidation ^[11]^[45]. FAs can produce 3–4 times the amount of energy compared to glucose ^[35]. Fatty acid oxidation generates NADH, FADH₂, and acetyl CoA ^[40]. NADH and FADH₂ then enters the electron transport chain to generate more energy ^[40].

In addition to making the microenvironment favorable for breast cancer progression, the excess consumption of dietary trans fats in obesity also plays a role in driving the breast cancer cell to a more aggressive and metastatic phenotype. Fatty acids are essential building blocks for membrane lipids, such as phospholipids, glycolipids, and cholesterol ^[40]. One in situ research reported that that the increased proportion of saturated FA used in building the membranes lipids increases the chances of the survival of breast cancer cells ^[46]. The greater incorporation of saturated FAs in membrane lipids facilitates breast cancer cells’ survival against oxidative stress because they are less susceptible to peroxidation ^[43]. Hence, under these circumstances, the proportion of saturated and unsaturated fatty acids in the cell membrane also plays a role in cancer cell survival and progression.

2.5. Obesity Favors Metastatic Behavior in Cancer Cells

Cell migration is an important fundamental biological response conserved not only in simple unicellular organisms, such as amoebas, but also in multicellular mammals where the process controls numerous biological events, such as embryonic development, wound healing, and immune cells invasion. It is also a significant biological phenomenon in pathological conditions, such as cancer metastasis. Cell migration is a mechanical phenomenon based on the coordination of the membrane protrusion formation, contractile force generation, and cell–matrix adhesion ^[47]. The complex multistep process of a tumor cell spreading from its original or primary location, by invading the basement membrane towards the blood vessel to colonize a distant location, is known as “secondary cancer” or “metastasis” ^[8]. The precise coordination and integration of signals from the adjacent cells and extracellular matrix is essential for this purpose ^[48]. Tumor cells of an epithelial origin break off the primary tumor mass to migrate to distance locations in metastasis. As a result, the attainment of migratory properties with less intracellular connection is needed ^[49]. The conversion of epithelial cells to the mesenchymal phenotype is an early event towards this multistep process ^[48]. During this transition, epithelial cells start exhibiting mesenchymal-like characteristics by losing their polarity and cell–cell adhesion, and acquiring the malignant characteristics of cell migration and invasiveness ^[50].

The epithelial-to-mesenchymal transition (EMT) was found to be aberrantly expressed under pathological conditions, such as cancer ^[51]. An large number of studies have shown the role of EMT in cancer metastasis ^[52]^[53]. The genetic alteration of transcription factors is the core regulator of EMT, causing changes in the expression of effector proteins that control cell adhesion and cell polarity ^[51]^[54]^[55]. Hypoxic conditions in the primary tumor mass aggravates the process through the expression of the hypoxia-inducible factor (HIF-1) ^[54]. Obesity further exacerbates the cancer condition in patients, as it propels primary tumor cells towards EMT events and facilitates malignant progression ^[45]^[56]. One of the hallmarks of EMT is the “cadherin switch”, characterized by a loss of E-cadherin and the increased expression of N-cadherin ^[57]. At the transcription level, the regulation of EMT is controlled by the transcription factors SNAIL, Twist, and ZEB-1 (zinc finger E-box-binding homobox 1 protein). They bind to the promoter region of EMT-targeted genes that downregulate the gene expression encoding for E-cadherin and increase the gene expression encoding for N-cadherin ^[58].

2.6. Regulatory Proteins in Obesity-Favored Signaling Pathways towards Metastasis

While genetic and epigenetic alterations typically induce cancer initiation, the progression of cancer to the advanced stage is largely influenced by the tumor microenvironment. The hyperactivation of oncogenic proteins and the deletion of tumor suppression proteins, due to genetic mutations, causes an oncogenic transformation in cells ^[59]. Many of these genetic mutations encode proteins that are components or targets of receptor tyrosine kinase (RTK) proteins controlled by PI3K-Akt and Ras-ERK cell-signaling pathways, such as the epidermal growth factor receptor (EGFR), small GTPase (e.g., Ras), serine/theonine kinases (e.g., Raf and Akt), cytoplasmic tyrosine kinase (e.g., Src), lipid kinase (e.g., phosphoinositide 3-kinase, PI3K), as well as nuclear receptors (e.g., the estrogen receptor, ER) ^[60]. Under normal physiological conditions, both of the pathways control numerous physiological responses—keeping cell growth and proliferation in check, controlling stress signals, such as cellular apoptosis and DNA damage in response to growth factors and cytokine signaling or ligand binding ^[59]. However, genetic alterations induce a constant activation of the proteins in these pathways, even in the absence of growth factor signaling. For example, Ras-ERK and PI3K-Akt cell-signaling pathways control estrogen receptor (ER)-dependent tumor cell survival, growth, and proliferation ^[59]. In the case of obesity, this already challenged cellular ecosystem is further derailed with reciprocal paracrine and juxtaparacrine interactions of non-neoplastic cells inhabiting the microenvironment ^[59]. Adipocyte-secreted factors may be critical in connecting obesity and the advanced progression of breast cancer via transducing signals from dysfunctional adipocytes to the proximal breast cancer cells ^[61]. Paracrine interaction of adipokines with the cell-surface receptors on breast cancer cells, followed by the sustained activation of PI3K-Akt and Ras-ERK cell-signaling pathways, influence the metastatic behavior in breast cancer cells. To date, in vitro and in vivo studies have confirmed that obese or dysfunctional white adipocytes stimulate breast cancer progression by increasing the survival, growth, proliferation, migration, and invasion of breast cancer cells ^[45]^[56]^[62]^[63]^[64]^[65].

To initiate their movement, cells must break off their adhesion contact with other cells and the matrix and form a protrusion in the direction of the movement. At the same time, the forward protrusion contacts the matrix as the rear portion of the cells detaches from the matrix through actomyosin contraction, pushing the cytoplasm forward in the direction of movement. The events that instigate this biological phenomenon are actin polymerization, actomyosin contraction, and cell matrix adhesion ^[66]^[67]. The Rho family of GTPase proteins (RhoA, Rac1, and Cdc42) controls these fundamental physiological processes by activating the downstream effector proteins of multiple cells-signaling pathways, including actin regulators, adapter proteins, protein kinases, and phospholipases ^[68]^[69]. By controlling those proteins, Rho family GTPase proteins influence normal cellular functions, such as cell adhesion, migration, and invasion ^[70]. The activation of Rho family GTPase proteins is controlled by the guanine nucleotide exchange factor (GEF) ^[71]. The molecular switch between the GTP and GDP bound form of Rho GTPase is catalyzed by GEFs, which displaces GDP and allows the binding of GTP on the active site of Rho family GTPase ^[70]. GTP binding then ensures conformational changes in small GTPases, which enables them to interact with downstream effector proteins ^[70]. The intracellular signal transducer proteins, Src and PI3K, work upstream of GEF and control its activation in response to the activation of RTK receptors in the presence of growth factors, cytokines and chemokines ^[72]. Cytokine receptors of the immunoglobulin (Ig) superfamily and GPCR-type receptor can also activate GEFs in response to extracellular stimuli, and can coordinate with the Rho family GTPases’ activation signaling ^[73].

While GEFs activate the small GTPases, there are two other regulatory proteins that direct their inactivation. GAP (GTPase-activating protein) is one of the regulatory proteins that induces the inactivation of small GTPases by hydrolyzing the bound GTP and switching their confirmation to the previous GDP-bound state ^[70]. Guanine nucleotide dissociation inhibitors (GDIs) are another set of regulatory proteins that inactivate small GTPase proteins by sequestering them in the cytoplasm and inhibiting their localization in the plasma membrane, mediated by masking their C-terminal lipid moieties ^[70]. Hence, any disruption to this regulatory activity increases the progression of cancer. Rho family GTPase proteins were observed to be overexpressed in cancer, including breast cancer ^[70]^[74]. Their overexpression in cancer implies that there is a constant activation of GEFs in comparison to GAPs and GDIs. This further confirms the importance of the detrimental effect of the obese tumor microenvironment in the progression of cancer.

References

Visvader, J.E. Keeping abreast of the mammary epithelial hierarchy and breast tumorigenesis. Genes Dev. 2009, 23, 2563–2577.
Harbeck, N.; Penault-Llorca, F.; Cortes, J.; Gnant, M.; Houssami, N.; Poortmans, P.; Ruddy, K.; Tsang, J.; Cardoso, F. Breast cancer. Nat. Rev. Dis. Primers 2019, 5, 662019.
American Cancer Society. Breast Cancer Facts & Figures 2019–2020; American Cancer Society: Atlanta, GA, USA; pp. 1–44. Available online: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/breast-cancer-facts-and-figures/breast-cancer-facts-and-figures-2019-2020.pdf (accessed on 26 January 2021).
American Cancer Society. Breast Cancer Facts & Figures 2017–2018; American Cancer Society: Atlanta, GA, USA. Available online: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/breast-cancer-facts-and-figures/breast-cancer-facts-and-figures-2017-2018.pdf (accessed on 26 January 2021).
Zeng, J.; Sauter, E.R.; Li, B. FABP4: A New Player in Obesity-Associated Breast Cancer. Trends Mol. Med. 2020, 26, 437–440.
Minakshi, R.; Rahman, S.; Jan, A.T.; Archana, A.; Kim, J. Implications of aging and the endoplasmic reticulum unfolded protein response on the molecular modality of breast cancer. Exp. Mol. Med. 2017, 49, e389.
Al-Zoughbi, W.; Al-Zhoughbi, W.; Huang, J.; Paramasivan, G.S.; Till, H.; Pichler, M.; Guertl-Lackner, B.; Hoefler, G. Tumor macroenvironment and metabolism. Semin. Oncol. 2014, 41, 281–295.
Leber, M.F.; Efferth, T. Molecular principles of cancer invasion and metastasis (review). Int. J. Oncol. 2009, 34, 881–895.
Nieman, K.M.; Romero, I.L.; Van Houten, B.; Lengyel, E. Adipose tissue and adipocytes support tumorigenesis and metastasis. Biochim. Et Biophys. Acta 2013, 1831, 1533–1541.
Quail, D.F.; Dannenberg, A.J. The obese adipose tissue microenvironment in cancer development and progression. Nat. Reviews. Endocrinol. 2019, 15, 139–154.
Choi, J.; Cha, Y.J.; Koo, J.S. Adipocyte biology in breast cancer: From silent bystander to active facilitator. Prog. Lipid Res. 2018, 69, 11–20.
Sánchez-Jiménez, F.; Pérez-Pérez, A.; de la Cruz-Merino, L.; Sánchez-Margalet, V. Obesity and Breast Cancer: Role of Leptin. Front. Oncol. 2019, 9, 596.
Cozzo, A.J.; Fuller, A.M.; Makowski, L. Contribution of Adipose Tissue to Development of Cancer. Compr. Physiol. 2017, 8, 237–282.
Lengyel, E.; Makowski, L.; DiGiovanni, J.; Kolonin, M.G. Cancer as a Matter of Fat: The Crosstalk between Adipose Tissue and Tumors. Trends Cancer 2018, 4, 374–384.
Iyengar, N.M.; Gucalp, A.; Dannenberg, A.J.; Hudis, C.A. Obesity and Cancer Mechanisms: Tumor Microenvironment and Inflammation. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2016, 34, 4270–4276.
Al-Jawadi, A.; Moussa, H.; Ramalingam, L.; Dharmawardhane, S.; Gollahon, L.; Gunaratne, P.; Layeequr Rahman, R.; Moustaid-Moussa, N. Protective properties of n-3 fatty acids and implications in obesity-associated breast cancer. J. Nutr. Biochem. 2018, 53, 1–8.
Divella, R.; De Luca, R.; Abbate, I.; Naglieri, E.; Daniele, A. Obesity and cancer: The role of adipose tissue and adipo-cytokines-induced chronic inflammation. J. Cancer 2016, 7, 2346–2359.
Multhoff, G.; Molls, M.; Radons, J. Chronic inflammation in cancer development. Front. Immunol. 2012, 2, 98.
Rasha, F.; Ramalingam, L.; Gollahon, L.; Rahman, R.L.; Rahman, S.M.; Menikdiwela, K.; Moustaid-Moussa, N. Mechanisms linking the renin-angiotensin system, obesity, and breast cancer. Endocr. Relat. Cancer 2019, 26, R653–R672.
Deng, T.; Lyon, C.J.; Bergin, S.; Caligiuri, M.A.; Hsueh, W.A. Obesity, inflammation, and cancer. Annu. Rev. Pathol. Mech. Dis. 2016, 11, 421–449.
Lim, B.; Woodward, W.A.; Wang, X.; Reuben, J.M.; Ueno, N.T. Inflammatory breast cancer biology: The tumour microenvironment is key. Nat. Rev. Cancer 2018, 18, 485–499.
Ellulu, M.S.; Patimah, I.; Khaza’ai, H.; Rahmat, A.; Abed, Y. Obesity and inflammation: The linking mechanism and the complications. Arch. Med. Sci. AMS 2017, 13, 851–863.
Huang, A.; Cao, S.; Tang, L. The tumor microenvironment and inflammatory breast cancer. J. Cancer 2017, 8, 1884–1891.
Engin, A.B.; Engin, A.; Gonul, I.I. The effect of adipocyte-macrophage crosstalk in obesity-related breast cancer. J. Mol. Endocrinol. 2019, 62, R201–R222.
Corrêa, L.H.; Corrêa, R.; Farinasso, C.M.; de Sant’Ana Dourado, L.P.; Magalhães, K.G. Adipocytes and Macrophages Interplay in the Orchestration of Tumor Microenvironment: New Implications in Cancer Progression. Front. Immunol. 2017, 8, 1129.
Wang, X.; Simpson, E.R.; Brown, K.A. Aromatase overexpression in dysfunctional adipose tissue links obesity to postmenopausal breast cancer. J. Steroid Biochem. Mol. Biol. 2015, 153, 35–44.
Qiu, S.Q.; Waaijer, S.J.H.; Zwager, M.C.; de Vries, E.G.E.; van der Vegt, B.; Schröder, C.P. Tumor-associated macrophages in breast cancer: Innocent bystander or important player? Cancer Treat. Rev. 2018, 70, 178–189.
Lin, E.Y.; Nguyen, A.V.; Russell, R.G.; Pollard, J.W. Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J. Exp. Med. 2001, 193, 727–740.
Poh, A.R.; Ernst, M. Targeting Macrophages in Cancer: From Bench to Bedside. Front. Oncol. 2018, 8, 49.
Yang, L.; Zhang, Y. Tumor-associated macrophages: From basic research to clinical application. J. Hematol. Oncol. 2017, 10, 58.
Williams, C.B.; Yeh, E.S.; Soloff, A.C. Tumor-associated macrophages: Unwitting accomplices in breast cancer malignancy. NPJ Breast Cancer 2016, 2, 15025.
Bhardwaj, P.; Au, C.C.; Benito-Martin, A.; Ladumor, H.; Oshchepkova, S.; Moges, R.; Brown, K.A. Estrogens and breast cancer: Mechanisms involved in obesity-related development, growth and progression. J. Steroid Biochem. Mol. Biol. 2019, 189, 161–170.
Khan, S.; Shukla, S.; Sinha, S.; Meeran, S.M. Role of adipokines and cytokines in obesity-associated breast cancer: Therapeutic targets. Cytokine Growth Factor Rev. 2013, 24, 503–513.
Baenke, F.; Peck, B.; Miess, H.; Schulze, A. Hooked on fat: The role of lipid synthesis in cancer metabolism and tumour development. Dis. Models Mech. 2013, 6, 1353–1363.
Röhrig, F.; Schulze, A. The multifaceted roles of fatty acid synthesis in cancer. Nat. Rev. Cancer 2016, 16, 732–749.
Peck, B.; Schulze, A. Lipid Metabolism at the Nexus of Diet and Tumor Microenvironment. Trends Cancer 2019, 5, 693–703.
Menendez, J.A.; Lupu, R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat. Rev. Cancer 2007, 7, 763–777.
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.
Yoon, S.; Lee, M.Y.; Park, S.W.; Moon, J.S.; Koh, Y.K.; Ahn, Y.H.; Park, B.W.; Kim, K.S. Up-regulation of acetyl-CoA carboxylase alpha and fatty acid synthase by human epidermal growth factor receptor 2 at the translational level in breast cancer cells. J. Biol. Chem. 2007, 282, 26122–26131.
Maan, M.; Peters, J.M.; Dutta, M.; Patterson, A.D. Lipid metabolism and lipophagy in cancer. Biochem. Biophys. Res. Commun. 2018, 504, 582–589.
Liberti, M.V.; Locasale, J.W. The Warburg Effect: How Does it Benefit Cancer Cells? Trends Biochem. Sci. 2016, 41, 211–218.
Ackerman, D.; Simon, M.C. Hypoxia, lipids, and cancer: Surviving the harsh tumor microenvironment. Trends Cell Biol. 2014, 24, 472–478.
Mentoor, I.; Engelbrecht, A.M.; Nell, T. Fatty acids: Adiposity and breast cancer chemotherapy, a bad synergy? Prostaglandins Leukot. Essent. Fat. Acids 2019, 140, 18–33.
Al-Jawadi, A.; Rasha, F.; Ramalingam, L.; Alhaj, S.; Moussa, H.; Gollahon, L.; Dharmawardhane, S.; Moustaid-Moussa, N. Protective effects of eicosapentaenoic acid in adipocyte-breast cancer cell cross talk. J. Nutr. Biochem. 2020, 75, 108244.
Balaban, S.; Shearer, R.F.; Lee, L.S.; van Geldermalsen, M.; Schreuder, M.; Shtein, H.C.; Cairns, R.; Thomas, K.C.; Fazakerley, D.J.; Grewal, T.; et al. Adipocyte lipolysis links obesity to breast cancer growth: Adipocyte-derived fatty acids drive breast cancer cell proliferation and migration. Cancer Metab. 2017, 5, 1.
Smith-Warner, S.A.; Spiegelman, D.; Adami, H.O.; Beeson, W.L.; van den Brandt, P.A.; Folsom, A.R.; Fraser, G.E.; Freudenheim, J.L.; Goldbohm, R.A.; Graham, S.; et al. Types of dietary fat and breast cancer: A pooled analysis of cohort studies. Int. J. Cancer 2001, 92, 767–774.
Mak, M.; Spill, F.; Kamm, R.D.; Zaman, M.H. Single-Cell Migration in Complex Microenvironments: Mechanics and Signaling Dynamics. J. Biomech. Eng. 2016, 138, 021004.
Bravo-Cordero, J.J.; Hodgson, L.; Condeelis, J. Directed cell invasion and migration during metastasis. Curr. Opin. Cell Biol. 2012, 24, 277–283.
Etienne-Manneville, S. Polarity proteins in migration and invasion. Oncogene 2008, 27, 6970–6980.
Sato, R.; Semba, T.; Saya, H.; Arima, Y. Concise Review: Stem Cells and Epithelial-Mesenchymal Transition in Cancer: Biological Implications and Therapeutic Targets. Stem Cells 2016, 34, 1997–2007.
Lu, W.; Kang, Y. Epithelial-Mesenchymal Plasticity in Cancer Progression and Metastasis. Dev. Cell 2019, 49, 361–374.
Ribatti, D.; Tamma, R.; Annese, T. Epithelial-Mesenchymal Transition in Cancer: A Historical Overview. Transl. Oncol. 2020, 13, 100773.
Mittal, V. Epithelial Mesenchymal Transition in Tumor Metastasis. Annu. Rev. Pathol. 2018, 13, 395–412.
Tsai, J.H.; Yang, J. Epithelial–mesenchymal plasticity in carcinoma metastasis. Genes Dev. 2013, 27, 2192–2206.
Sung, W.J.; Kim, H.; Park, K.K. The biological role of epithelial-mesenchymal transition in lung cancer (Review). Oncol. Rep. 2016, 36, 1199–1206.
Gyamfi, J.; Lee, Y.H.; Eom, M.; Choi, J. Interleukin-6/STAT3 signalling regulates adipocyte induced epithelial-mesenchymal transition in breast cancer cells. Sci. Rep. 2018, 8, 8859.
Janiszewska, M.; Primi, M.C.; Izard, T. Cell adhesion in cancer: Beyond the migration of single cells. J. Biol. Chem. 2020, 295, 2495–2505.
Ieda, T.; Tazawa, H.; Okabayashi, H.; Yano, S.; Shigeyasu, K.; Kuroda, S.; Ohara, T.; Noma, K.; Kishimoto, H.; Nishizaki, M.; et al. Visualization of epithelial-mesenchymal transition in an inflammatory microenvironment-colorectal cancer network. Sci. Rep. 2019, 9, 16378.
Sever, R.; Brugge, J.S. Signal transduction in cancer. Cold Spring Harb. Perspect. Med. 2015, 5, a006098.
Huveneers, S.; Danen, E.H. Adhesion signaling-crosstalk between integrins, Src and Rho. J. Cell Sci. 2009, 122, 1059–1069.
Landskron, G.; De la Fuente, M.; Thuwajit, P.; Thuwajit, C.; Hermoso, M.A. Chronic inflammation and cytokines in the tumor microenvironment. J. Immunol. Res. 2014, 2014, 149185.
Picon-Ruiz, M.; Pan, C.; Drews-Elger, K.; Jang, K.; Besser, A.H.; Zhao, D.; Morata-Tarifa, C.; Kim, M.; Ince, T.A.; Azzam, D.J.; et al. Interactions between Adipocytes and Breast Cancer Cells Stimulate Cytokine Production and Drive Src/Sox2/miR-302b-Mediated Malignant Progression. Cancer Res. 2016, 76, 491–504.
Wang, C.; Gao, C.; Meng, K.; Qiao, H.; Wang, Y. Human adipocytes stimulate invasion of breast cancer MCF-7 cells by secreting IGFBP-2. PLoS ONE 2015, 10, e0119348.
Wang, Y.Y.; Attané, C.; Milhas, D.; Dirat, B.; Dauvillier, S.; Guerard, A.; Gilhodes, J.; Lazar, I.; Alet, N.; Laurent, V.; et al. Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells. JCI Insight 2017, 2, e87489.
Rasha, F.; Kahathuduwa, C.; Ramalingam, L.; Hernandez, A.; Moussa, H.; Moustaid-Moussa, N. Combined Effects of Eicosapentaenoic Acid and Adipocyte Renin-Angiotensin System Inhibition on Breast Cancer Cell Inflammation and Migration. Cancers 2020, 12, 220.
Kutys, M.L.; Yamada, K.M. Rho GEFs and GAPs: Emerging integrators of extracellular matrix signaling. Small GTPases 2015, 6, 16–19.
Lawson, C.D.; Ridley, A.J. Rho GTPase signaling complexes in cell migration and invasion. J. Cell Biol. 2018, 217, 447–457.
Devreotes, P.; Horwitz, A.R. Signaling networks that regulate cell migration. Cold Spring Harb. Perspect. Biol. 2015, 7, a005959.
Pajic, M.; Herrmann, D.; Vennin, C.; Conway, J.R.; Chin, V.T.; Johnsson, A.K.; Welch, H.C.; Timpson, P. The dynamics of Rho GTPase signaling and implications for targeting cancer and the tumor microenvironment. Small GTPases 2015, 6, 123–133.
Porter, A.P.; Papaioannou, A.; Malliri, A. Deregulation of Rho GTPases in cancer. Small GTPases 2016, 7, 123–138.
Parri, M.; Chiarugi, P. Rac and Rho GTPases in cancer cell motility control. Cell Commun. Signal. CCS 2010, 8, 23.
Millar, F.R.; Janes, S.M.; Giangreco, A. Epithelial cell migration as a potential therapeutic target in early lung cancer. Eur. Respir. Rev. Off. J. Eur. Respir. Soc. 2017, 26, 160069.
Schwartz, M. Rho signalling at a glance. J. Cell Sci. 2004, 117, 5457–5458.
Orgaz, J.L.; Herraiz, C.; Sanz-Moreno, V. Rho GTPases modulate malignant transformation of tumor cells. Small GTPases 2014, 5, e29019.

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Lauren Gollahon

Noshin Mubtasim

Naima Moustaid-Moussa

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Update Date: 08 Apr 2022

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