Bisphenols and Their Interaction with GPER-1: The Invisible Enemy Behind Breast Cancer and Its Societal Impact

Abstract

Bisphenols are chemical compounds of industrial origin found in a wide variety of everyday consumer products and have been detected in virtually all human biological fluids. Bisphenols, especially bisphenol A (BPA), can mimic hormone activity and act as endocrine disruptors through GPER-1, a G protein-coupled receptor, mainly located in the cell membrane and with a high affinity for estradiol, whose activity commands neoplastic cell proliferation and migration, promoting the development of breast cancer. Since in modern societies bisphenols are very common in the environment, their association with breast cancer affects not only individuals but also the general population. The detrimental impacts of these substances on public health, however, have not received enough attention because their molecular and cellular effects are imperceptible, and their manifestations only become apparent over the medium and long term.

1. Introduction

For more than half a century, the plastics industry has experienced explosive growth, leaving its mark on multiple aspects of our lives. The diversity of its applications has catapulted it as the most widely used material worldwide, standing out as one of the most significant inventions of the 20th century [1]. However, the amount of plastic waste has also grown exponentially, negatively impacting ecosystems and human health.

One of the most widely used compounds of industrial origin in the production of plastics and other everyday consumer products is bisphenol. Among them, bisphenol A (BPA) is one of the most common. Currently, bisphenols can be found in a wide range of products, such as food and beverage containers, reusable water bottles, toys, electronic devices, and food can linings, among others [2, 3].

In addition to their widespread presence in the environment, bisphenols, especially BPA, have been associated with the ability to mimic hormone activity and act as endocrine disruptors. Endocrine disruptors are chemicals that can interfere with hormone regulation, altering the production, metabolism, and activity of natural hormones [4, 5, 6]. These compounds can mimic or block the action of hormones, thus disrupting organ homeostasis [4, 7, 8]. BPA and other bisphenols exhibit the ability to mimic estradiol, a key hormone in the regulation of the endocrine system [6, 9, 10, 11].

Exposure to bisphenols, either through ingestion, inhalation, or dermal absorption, has been widely described. However, attention has also been given to the parenteral route, which involves the use of medical-surgical materials containing bisphenols, as well as prenatal exposure, as it has been shown that BPA can cross the placental barrier. These forms of exposure have been associated with various adverse health effects, including reproductive and developmental disorders, metabolic dysfunction, and immune system disorders [10, 12, 13]. It is important to note that these compounds can affect individuals of all ages and genders, but particular attention has been given to their association with breast cancer [4].

Bisphenols act as endocrine disruptors in the development of breast cancer by interacting with hormone receptors. Among the most studied receptors is estrogen receptor alpha (ERα), which plays a crucial role in the genesis and development of breast cancer [14, 15]. In addition, an estrogen and membrane receptor known as GPER-1 (G Protein-Coupled Estrogen Receptor 1), belonging to the G protein-coupled receptor family, has caused increasing interest. Recent studies have revealed that bisphenols, by mimicking the action of estradiol, can affect the activity of the GPER-1 receptor, activating signaling pathways associated with breast cancer cell proliferation and migration [16, 17, 18]. This novel interaction between bisphenols and the GPER-1 receptor offers new insights into understanding the underlying mechanisms of breast cancer and could have important implications for identifying potential therapeutic targets and more effective treatment strategies.

Taken together, studies indicate that BPA exposure is much more widespread than originally assumed, generating an underlying presence that cannot be overlooked [7, 19]. In response to this concern, measures have been implemented to regulate and control the use of BPA in various consumer products, such as food and beverage packaging, children’s products, and medical devices. So far, maximum allowable limits on BPA content in certain products have been established to reduce the population’s exposure [20]. However, as scientific data continues to accumulate, it is likely that public policies will continue to evolve to more effectively address the risks associated with exposure to BPA and similar compounds.

2. Breast cancer and endocrine disruptors: the critical role of bisphenols

Breast cancer is a malignant disease that originates in breast tissue cells. It is the most frequent neoplasm in women worldwide and the leading cause of cancer death in women [21]. It is estimated that in 2020 there were about 2.3 million new cases of breast cancer, with incidence varying by region, being generally higher in North America and Europe [22].

Although breast cancer is a molecularly complex disease, dependent on a multiplicity of factors, crucial is the biological activity of estrogens, particularly that of estradiol (E2 or 17β-estradiol), a hormone involved in the development and maintenance of body homeostasis, as well as in the pathophysiology of several diseases in humans [9, 15, 23]. The most common subtype of breast cancer is the so-called “estrogen-sensitive”, which refers to the presence of ERα in tumor cells and their ability to respond to estrogenic stimuli [15, 24, 25, 26]. ERα is a nuclear protein widely expressed in nervous, reproductive, and breast tissue, with an estimated 60–80% of breast cancer cases presenting this receptor [23, 26, 27]. When estrogens bind to ERα, a series of intracellular events are activated that promote cell growth and proliferation [28]. In ERα-presenting breast tumors, the activity of this receptor contributes to the uncontrolled growth of cancer cells. Therefore, ERα is considered an important therapeutic target in the treatment of this disease. On the other hand, “estrogen-insensitive” breast cancer does not express the ERα receptor, and some of these cancers also do not express the progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), which may result in a more aggressive variant of the disease known as triple-negative breast cancer [23, 29].

Approximately 90% of breast cancer cases are sporadic or non-heritable [30, 31], which points to the predominance of environmental factors in the genesis and development of this neoplasm. In fact, lifestyle factors related to alcohol consumption, smoking, a lack of physical activity, and obesity are well-established factors that increase the likelihood of developing this neoplasm and other types of cancer [32].

A recent analysis of observational studies published between 1980 and 2020 on the relationship between endocrine chemical disruptors (ECDs) present in the environment and the risk of tumorigenesis revealed a significant increase in the risk of developing endocrine neoplasms between 43% and 67% [4]. In addition, several studies indicate that ECDs increase the risk of developing hormonal and metabolic alterations in the medium and long term [6, 7]. Since the scientific use of the term “endocrine disrupting chemicals” in 1963 [5], the concept has evolved as more evidence has been gathered about the biological effects of these substances. Currently, the Organization for Economic Cooperation and Development (OECD) defines ECDSs as endocrine-disrupting chemicals that cause adverse effects on development, reproduction, the nervous system, and the immune system in both humans and wildlife [33]. The main types of ECDs include chemicals of industrial origin, such as organochlorine pesticides, phthalates, and bisphenols; however, the term also encompasses naturally occurring compounds, such as phytoestrogens [34] (Figure 1).

Figure 1.

Classification of endocrine disruptors. According to their origin (natural or synthetic), hormone synthesis disruptors affect the endocrine release axis or mimic hormone action (estrogenic or androgenic).

The effects of endocrine disruptors on the health of individuals vary according to the stage of development or life cycle in which they are found, even affecting early stages such as embryonic, fetal, or perinatal development [6]. However, most of its manifestations can be observed in adulthood [7, 34].

Particularly bisphenols, one of the main ECDs, have strongly attracted scientific and social attention due to their wide use and distribution in our usual environment and their infiltration in ecosystems, being associated with several adverse biological effects [35, 36, 37, 38]. In turn, the history of bisphenols is linked to the development and rise of plastics in modern life [1, 39].

After Dianin was synthesized in 1891 the compound 4,40-dihydroxy-2,2-diphenylpropane, a substance much better known as BPA [40], its hormonal effects began to attract the attention of some researchers. Indeed, in the 1930s, BPA was considered a “synthetic estrogen” with some carcinogenic properties [40, 41]. During this same era, Wallace Carothers and Paul Hogan succeeded in combining BPA with phosgene to produce polycarbonate, a transparent, highly versatile, and chemically stable material [42]. Due to these properties, in the 1950s the industry began to use it massively in the manufacture of a wide variety of consumables, including electrical appliances, medical devices, toys, and other products for daily and personal use. It was also found in beverage cans, water bottles, and food containers [7, 19].

The investigation into BPA’s potential role as an endocrine disruptor did not pick up again until the 1990s when a team led by Feldman discovered BPA in the distilled water of recently autoclaved polycarbonate bottles [39]. This study provided the first evidence that packaging used in the food industry and other fields could release BPA during heat sterilization processes or simply due to prolonged use of this type of material. In fact, BPA is widely present in the environment, with one of its main sources being the containers used to store water and food. As a result, the main route of exposure to BPA is through ingestion [11, 43], although the possibility of dermal absorption and even inhalation has also been observed [44]. In this regard, the oral bioaccessibility of polyethylene microplastics in humans has recently been investigated, finding that phthalates and BPA show the highest fractions of gastric and intestinal bioaccessibility [11]. In addition, the release rates of contaminants present in plastics in the human gastrointestinal tract have been evaluated, with a significant release of BPA from high-density polyethylene (HDPE) pellets being observed [43].

Bisphenols have been associated with adverse effects on reproduction and metabolism. Importantly, BPA has generated concern in the scientific community in relation to breast cancer due to its ability to affect estrogen receptor activity, in particular ERα; however, there has been increasing interest in an unconventional estrogen receptor present in breast tissues, and highly co-expressed with ERα, which plays a role in cell proliferation and tumor progression, termed GPER-1 [9, 45, 46]. It has been suggested that exposure to bisphenols may activate the GPER-1 receptor, which would contribute to the development, aggressiveness, and progression of breast cancer.

3. GPER-1, a new approach to the understanding of breast cancer and its connection with bisphenols

As progress has been made in the understanding of the signaling pathways involved in breast cancer, new molecular factors involved in its development and progression have been identified, including GPER-1, a receptor belonging to the G protein-coupled receptor family, one of the most relevant [18, 23]. GPER-1 was initially known as GPR30 [47], an orphan receptor, however, after its affinity for estradiol was discovered, it was renamed GPER-1 [45, 48, 49]. This receptor, encoded by the gene located on chromosome 7p22.3, is expressed in various tissues, including nervous, reproductive, and mammary tissue, suggesting its involvement in relevant physiological functions [17, 49, 50, 51]. Several experimental studies have demonstrated a correlation between GPER-1 activity and an increase in cancer cell proliferation, invasion, and metastasis [16, 18]. Also, recent research indicates that GPER-1 activity may be associated with the development of resistance to drug treatment of breast cancer [16]. Clinical evidence suggests that the presence of GPER-1 in patients with estradiol-sensitive breast cancer treated with tamoxifen is unfortunately associated with reduced survival [18].

GPER-1 has been preferentially localized to the cell membrane, although it has also been described in mitochondria and the endoplasmic reticulum [23]. GPER-1 signaling involves cAMP production and intracellular calcium mobilization through Gαs proteins and Src activation via the Gβγ subunits [9]. This results in the release of HB-EGF, which activates the epidermal growth factor receptor (EGFR). In addition, GPER-1 activates phospholipase C, c-Fos, and various kinases, such as ERK1/2 and PI3K/Akt [4, 18, 27, 45]. GPER-1-dependent signaling pathways are related to the maintenance of cellular and organ homeostasis [9], and their dysregulation has been associated with the pathogenesis of several metabolic and endocrine diseases, particularly breast cancer [23].

In 1997, one of the first studies establishing a direct association between BPA and increased mammary cell proliferation was published [52]. This finding prompted numerous investigations, including clinical trials, studies in animal models and in vitro, that delved into the possible mechanisms through which BPA and other bisphenols could contribute to the development of breast cancer [12, 53, 54, 55]. Epidemiological studies and clinical data suggest a significant association between increased incidence of breast cancer and other chronic pathologies with environmental exposure to BPA [56]. In a recent study involving 1006 children aged 5–14 years in Guizhou province, northern China, serum levels of nonylphenol, dimethyl phthalate, and BPA were evaluated. The results revealed that the levels of these endocrine disrupting compounds (EDCs) exceeded the concentration limits set by the U.S. Environmental Protection Agency. In addition, an association was found between these elevated levels and alterations in liver function, as well as with later puberty in girls and earlier puberty in boys [57]. In addition, a meta-analysis including data from 11,857 adults from the National Health and Nutrition Examination Survey (NHANES) between 2003 and 2016 revealed a dose-dependent association between urinary BPA levels and the development of cardiovascular disease [58]. In this context, several studies have analyzed urine and breast adipose tissue samples from patients undergoing mastectomy for breast cancer or mammoplasty to assess BPA concentration. The findings have revealed that breast cancer patients have significantly higher levels of BPA in both urine and breast adipose tissue compared to those without cancer. In addition, a positive correlation between urine and breast adipose tissue BPA levels has been observed in the group of breast cancer patients [59, 60]. Taken together, these results suggest that the presence of BPA in the environment may increase the risk of breast cancer and other endocrine diseases in humans.

Currently, BPA has been found to be present in virtually all biological fluids, including serum, urine, semen, cerebrospinal fluid, and breast milk [7]. Embryonic exposure to BPA through the placenta has been associated with various metabolic and hormonal disorders in the medium and long term [17]. Due to these adverse effects, BPA analogs have been introduced to the market, generating products called “BPA-free”, such as bisphenol S (BPS), bisphenol F (BPF), and bisphenol AF (BPAF) [17, 55]. However, most of these compounds exhibit variable estrogenic activity, although generally of lower biological potency than BPA [44, 61].

Although BPA has a lower binding affinity for estrogen receptors compared to estradiol, it has been reported that it can trigger cellular responses even at low concentrations and with a similar biological potency to E2 [6]. In fact, environmentally relevant concentrations of BPA are estimated to be in the nanomolar range, being able to induce proestrogenic effects, such as increased proliferation or migration rate, in both normal and neoplastic cells [6, 53].

While a significant part of the research has focused on the effects of bisphenols on ERα, the interaction between bisphenols and the GPER-1 receptor is an emerging research topic that has attracted increasing interest in the field of breast cancer [44, 46].

BPA has been linked to chemotherapy resistance in ERα-positive breast cancer cells through MAPK and STAT signaling pathways [54, 62]. In MCF-7 breast cancer cells (GPER-1 positive/ERα-positive), BPA induces the expression of aldehyde dehydrogenase-1, a marker of breast stem cells, and SOX-2, a transcription factor that regulates pluripotency and self-renewal [63], which would indicate that BPA can induce the expression of dedifferentiated and more primitive cellular characteristics, close to those of neoplastic stem cells. Furthermore, in human breast tissue organoids exposed to BPA, BPS, or BPAF, changes related to the architecture and proteomics of cultured cells, which favor tumor growth, have been observed [55].

In breast cancer, the activity of BPA and its analogs on GPER-1 has also been evaluated in ERα-negative cells. For example, in SKBR3 (GPER-1 positive/ERα-negative) cells and also in cancer-associated fibroblasts, BPA induces the expression of estradiol target genes, such as c-FOS, EGR-1, and CTGF, through the GPER-1 transduction pathway, stimulating growth and migration in both cell types [64].

Recently, BPS has been reported to promote the migration of triple-negative breast cancer cells (without ERα/PR/HER2 expression) through the GPER-1/Hippo/Yap pathway [65]. Furthermore, BPA has been observed to induce the migration of triple-negative breast cancer cells through GPER-1/EGFR transactivation [66]. Coincident with these findings, it has been determined that GPER-1 expression is required for ERK1/2 and c-Fos activation in MCF-7 and SKBR3 cells in an ERα-independent manner [67]. Furthermore, in MCF-7 cells, it has been shown that BPAF promotes PI3K/AKT and ERK activity through GPER-1, which increases intracellular calcium and reactive oxygen species levels, favoring cell proliferation [67].

In summary, evidence indicates that BPA and some of its analogs may exert pro-estrogenic functions in breast cancer, independently of ERα, through interaction with the GPER-1 receptor. Bisphenols, especially BPA, activate several intracellular signaling pathways and regulate estradiol-dependent genes, which have traditionally been described as promoters of neoplastic cell development [28, 29, 68]. Importantly, further research focused on the interaction between bisphenols and estrogen receptors is needed, given their contribution to the development and progression of this devastating disease.

4. Bisphenols at the crossroads of biology and society

The effects of bisphenols on human health are largely determined by the stage of development or life cycle of individuals. These effects can remain hidden or latent for long periods of time, manifesting themselves in different ways at the physiological and morphological levels. Key areas affected by these compounds include reproduction and sexual development.

It has been shown that BPA can disrupt the normal gonadotropin-releasing hormone (GnRH) release axis, promoting alterations in early development and the human reproductive cycle [69]. These responses are related to gene reprogramming phenomena, laying the groundwork for the development of medium- or long-term diseases [35].

Interestingly, overexpression of GPER-1 has been observed in seminoma, a testicular germ cell neoplasm, while BPA generates increased proliferation of this tumor cell type in vitro [10, 70]. The above explains, at least in part, the increasing incidence of dysfunctions in the reproductive system, such as decreased sperm count and functionality and precocious puberty [13]. These facts, together with the increased incidence of breast cancer, have generated widespread social concern, raising new requirements and challenges in public health.

Alterations in reproductive function have also been found in various animal species due to environmental exposure to bisphenols. It has been reported that BPA can disrupt zebrafish oocyte development and maturation through a GPER-1/EGFR/MAPK-dependent mechanism [36]. Recently, a cytotoxic effect of various types of bisphenols on chick embryonic cells has been reported [61]. In perspective, these findings emphasize the detrimental consequences of BPA and its substitutes in early human and animal development and point to potential negative effects on organ balance and health, including exposure during pregnancy.

One of the most controversial aspects related to endocrine disruptors is the determination of their levels, which have both biological and environmental relevance. The dose–response patterns of EDCs are often non-linear, meaning that the effects of these compounds do not increase or decrease in proportion to the dose, but may exhibit complex and non-monotonic responses. In some cases, different effects have been observed at different concentration ranges, making it difficult to establish a clear biological safety threshold [20]. The establishment of a tolerable daily intake (TDI) is a process carried out by regulatory agencies for certain chemicals, including EDCs. The TDI represents the amount of a substance that is considered safe for an individual to ingest daily without presenting risks to their health, based on available data. For example, the European Food Safety Authority (EFSA) established a provisional TDI for BPA in 2015 at 4 μg/kg of body weight per day (μg/kg/day), which was subsequently revised and substantially modified in 2020 to 2.4 μg/kg/day [71].

The challenge lies in the fact that, despite regulatory agencies relying on scientific data and toxicological studies to assess risks and determine the TDI, uncertainties associated with complex dose–response curves can hinder the acquisition of a TDI that effectively protects the entire population. Therefore, it is crucial to update assessments and recommendations as new knowledge about EDCs emerges.

Despite pharmacokinetic studies indicating that BPA has an approximate half-life of 6 hours, this does not mean that BPA and its effects completely disappear during that time [72]. Once BPA enters our body, it can be metabolized and eliminated through various pathways, such as urine or feces. However, due to continuous environmental exposure, a portion of BPA may remain without immediate elimination, facilitating its accumulation in certain tissues and organs. Specifically, adipose tissue has the ability to bioaccumulate BPA due to the lipophilic characteristics of this compound [73, 74].

Furthermore, the elimination of BPA from adipose tissue is slower compared to biological fluids [75]. This gains greater biological significance when considering that adipose tissue influences endocrine regulation, meaning that the bioaccumulation of BPA may interfere with hormonal balance and promote adipogenesis [12]. This could potentially lead to negative consequences for long-term endocrine and metabolic health.

Additionally, the remarkable persistence of most endocrine disruptors in our environment and ecosystems should be considered, which facilitates the fact that these compounds tend to accumulate in tissues, a phenomenon that, in the case of phthalates and bisphenols, has been consistently associated with metabolic diseases in humans and animals [37, 76].

As discussed above, the most significant biological effects of BPA tend to occur at relatively low doses [53], whereas higher concentrations of BPA have also been reported to produce cytotoxic effects through disruption of mitochondrial activity [77]. These results suggest that the spectrum of concentrations at which BPA can have negative effects on cellular homeostasis is probably broader than previously thought.

The evidence of potential health risks associated with bisphenols has led to the adoption of regulatory measures in many countries. Some governments have banned or restricted the use of bisphenols in certain products and have established exposure limits and labeling requirements [78]. Generally, regulations have been implemented as scientific evidence has resonated with public opinion. For example, in the United States, in 2008, the Food and Drug Administration (FDA) declared that exposure to BPA is safe at low levels; however, 2 years later, the FDA decided to ban the use of BPA in baby bottles and infant products due to social apprehension about early childhood exposure [79]. Similarly, the European Chemicals Agency (ECHA) has indicated that BPA may have serious consequences for reproductive, ocular, and respiratory health, and can cause skin allergies, as well as being highly toxic to aquatic life in both the short and long term [80]. In 2012, the European Union banned the use of BPA in baby bottles across all member countries [81]. In the same vein, in the early 2010s, several Latin American countries prohibited the use of BPA in the manufacturing of baby bottles and other products intended for children under 3 years old [78].

The question of why BPA is not considered carcinogenic despite the growing evidence is framed within a broader context of chemical safety evaluation. Agencies such as the FDA and ECHA are responsible for assessing the safety of chemical substances based on available scientific information. This involves conducting toxicity studies, analyzing epidemiological data, testing on animal models, among other approaches, to determine potential risks to human health and the environment. In the specific case of BPA, numerous studies have been conducted to examine its possible relationship with cancer and other adverse health effects. However, the results have been varied. Some studies have indicated the presence of potential carcinogenic effects, while others have concluded that the available data is insufficient to establish a direct and definitive relationship [2]. It is also important to consider the inherent uncertainty in the scientific studies and possible gaps in the data. New studies and technical and methodological approaches may provide additional information that can influence existing classifications and regulations.

Additionally, agencies often face political challenges when making decisions about the safety of chemical substances. Political and economic interests can influence priorities and the interpretation of scientific data. This can lead to delays in implementing stricter regulations to protect public health [82].

In response to this, a more proactive approach based on public health protection has been proposed. This approach acknowledges the complexity of studying BPA and the possibility that underlying mechanisms may not be fully understood at present [78]. Therefore, instead of waiting for absolute scientific certainty before taking regulatory actions, advocating for acting preventively to protect the population from a public health perspective [83, 84].

In fact, in the context of breast cancer and other endocrine diseases, BPA may be socially considered an “invisible enemy” due to its permanent presence in the environment, without our being fully aware of the potential dangers to our health. This situation has led to a continuous evolution of regulations for the use of BPA and other endocrine disruptors as new experimental and clinical data are obtained [8].

Our society today is constantly confronted with a wide variety of environmental chemical pollutants, yet most risk assessments only consider an individual chemical. So far, the evidence indicates that the combination of different disruptors may have additive or synergistic effects. For example, some studies suggest that simultaneous exposure to bisphenols and phthalates may have more pronounced effects on reproductive health, fetal development, and the incidence of neoplasms than exposure to these compounds separately [38, 84].

Breast cancer has significant personal and societal impacts, including decreased quality of life, increased financial burden, and the need for increased emotional support and care from family and friends [85]. As studies point to the increasing importance of environmental factors in the genesis and development of breast cancer, the presence of chemical contaminants such as bisphenols adds another layer of complexity to the social and public policy challenges. The generation of effective prevention and early detection programs, both for the main endocrine disruptors present in communities as well as the disease itself, emerges as one of the most general measures to be implemented [8, 42, 86]. The lack of public awareness of bisphenols and their relationship to breast cancer limits society’s ability to make informed decisions about the products they consume and the environments in which they live. Much of the awareness of the potential health risks of bisphenols is due to the dissemination of both basic and clinical research. It is essential to promote education and the broadcasting of accurate information about the risks associated with bisphenols, as well as to encourage the adoption of policies that protect population health.

5. Conclusion

Breast cancer is a complex disease that has a significant impact on society. Additional questions about the pathogenesis and effects of this disease are raised by the interaction of bisphenols with the GPER-1 receptor, which suggests a direct impact of these substances on the proliferation and migration of neoplastic breast cells.

Factors contributing to BPA exposure are diverse and span a wide range of sources, from the ingestion of food and beverages packaged in BPA-containing containers to the use of plastic products in everyday life. Understanding and addressing these factors is essential to reducing exposure to BPA and its analogs, with the goal of protecting public health and decreasing the incidence of diseases related to the presence of endocrine disruptors. To achieve this, future research is needed to delve deeper into the mechanisms of action of bisphenols and their relationship with breast cancer, as well as the long-term effects of exposure to these compounds, especially during embryonic development.

The need to address BPA exposure as a modifiable risk factor arises from the knowledge of the complexity of breast cancer and the interaction of bisphenols with traditional estrogen receptors and the GPER-1 receptor. In order to limit the dangers associated with bisphenol exposure and promote safer alternatives in the manufacturing and use of plastic materials and new resins, this involves the adoption of appropriate public policies, the encouragement of further research, and the adoption of regulatory measures.

Acknowledgments

The authors thank the project USS-FIN-23-DOCI-06 (LM) and the project Fondecyt 1201635 (PE).