Endocrinology of breast cancer: results, tasks and hopes

The term ‘breast cancer’ is present in approximately nine out of ten publications on oncoendocrinology. When one considers the social and medical significance of the pathogenesis, prevention and treatment of mammary carcinomas, the high level of interest of endocrinologists in this cancer needs no further comment. The last decade was no exception in terms of the great growth of information concerning the topic of hormones and breast cancer. This makes even more reasonable the choice of the editors of Expert Review of Endocrinology and Metabolism to focus on not just ‘cancer endocrinology’ but on the two leading hormone-dependent neoplasms, one of which is certainly breast cancer, in this special focus issue of the journal.

An answer to the straightforward question of whether the development of breast cancer is associated with hormonal effects is unlikely to be negative. However, the high heterogeneity of breast cancers, which include subtypes distinguished on the basis of clinicopathological, molecular, genetic, epidemiological and other data [1,2] and some other relevant information, suggest that such an answer is still possible. Nevertheless, the tendency to assume that endocrine factors play a role in the pathogenesis of breast cancer may be justified by a number of considerations. First, it is well known that, starting from the embryonal period and during the subsequent decades, the mammary gland goes through an evolutionary process, an important aspect of which are changes in the state of the ductal system. Duct elongation is controlled, in particular, by estrogens, growth hormone, IGF and EGF, whereas duct ramification and alveolar patterning also involve progesterone, prolactin and thyroid hormones. The example of thyroid hormones, which seem to be marginally involved in mammary cancer, highlights the danger of under-rating other factors of seemingly minor importance. This can be seen in the role of anti-thyroid antibodies in breast cancer patients and in the ability of the mammary gland to uptake iodine at a rate that at least partly matches that of the thyroid. Appropriately, this may partly explain the low incidence of mammary cancer in Japan where seaweed foods that are rich in iodine are routinely consumed.

At the same time, associations between the endocrine and metabolic background and mammary cancer development are undoubtedly more multifaceted than they may initially appear. In support of this assertion are the results of studies of breast cancer epidemiology and some phenotypic features that promote the development of this cancer. For example, the pre- and post-menopausal variants of breast cancer differ not only in many clinical features but also in their risk factors and in the spectra of associated endocrine and metabolic disorders. A typical example is provided by excess body mass and body composition (the fat:lean mass ratio). ‘Pure endocrinologists’ should be reminded that excess body mass and high body fat value increase the risk of postmenopausal breast cancer and ‘protect’ against premenopausal breast cancer. This is believed by some to underlie differences in the effects of estrogen on these two, essentially different, types of disease. On the other hand, obesity is associated with disorders in several endocrine subsystems, with insulin resistance being a factor, which, along with disorders in steroid hormone production, is believed to be a leading element of predisposition to breast cancer. Certain differences between insulin and IGF-1, in this regard, include, according to prospective studies, the ability of excess blood IGF-1 to predispose mainly to the premenopausal breast cancer; whereas hyperinsulinemia and insulin resistance associated with sluggish chronic inflammation and certain changes in the pattern of adipokine production are believed to increase the risk of both forms of breast cancer.

The fact that mammary cancer occurs in women at a rate at least two orders higher than that in men has long made researchers assume that the assessment of the condition of the reproductive system must be important for insight into the pathogenesis of this cancer. Indeed, in addition to age, mammary cancer cases among blood relatives and the number of positive biopsies performed for hyperplastic alterations in the mammary gland, breast cancer risk factors include early menarche, delayed menopause and late childbirth. Most of the aforementioned characteristics were included in a model for predicting individual breast cancer risk during the next 5 years or throughout life [3]. Combinations of some of these factors are used in other models [4]. At the same time, it should be emphasized that not all of these models take into account risk factors such as mammographic tissue density, the aforementioned BMI and body composition, bone density and the use of replacement hormonal therapy, among others, which have long attracted (and still do) the interest of endocrinologists and oncoendocrinologists. Considering this multitude of factors, it is hardly reasonable to focus strictly and exclusively on estrogens. It seems to be more accurate to talk about excessive/prolonged hormonal stimulation of the target tissue, that is, the mammary epithelium, and about hormonal influences on interactions between different cells in the mammary gland.

These interactions undoubtedly relate to the important observation that cell differentiation in the mammary gland, following its onset in the juvenile period, reaches its peak after the first childbirth and lactation, and then regresses during the menopausal period. An important characteristic of these changes is the relationship between the primitive ducts, which are classified as lobules 1 and 2, and the differentiated glandular structures (lobules 3 and 4), which together constitute the so-called terminal lobular–ductal units. It is believed that the higher proliferation level in lobules 1 and 2 is the result of their higher sensitivity to hormonal stimulation; therefore, in these lobules, compared with lobules 3 and 4, the signs of atypia and in situ carcinomas are more frequent and genomic alterations are more expressed. The association of genomic shifts with mammary gland architectonics reminds us that the wild-type BRCA1 gene is implicated in duct branching and lobule maturation [5]. Of note, although BCRA1 mutations are highly correlated with the early onset of breast cancer, adequate physical activity and the absence of obesity during the adolescent period in carriers of such mutations significantly reduce the risk of tumor development [6]. This appears to be both surprising and important in itself, in particular in view of the concept that hormonal support is necessary for the realization of genetic predisposition to mammary carcinomas [7]. Finally, since the development of mammary gland architectonics and its evolution and involution are age dependent, it is important in this regard that a significant role is ascribed to the perinatal and, especially, intrauterine, periods and, correspondingly, to the endocrine effects, both endogenous and external, on the mammary gland in utero[8,9].

This assertion, preceded by the previous introduction, sets the stage for a brief discussion of the papers and problems covered by the present issue of Expert Review of Endocrinology and Metabolism, which is specifically dedicated to breast cancer.

At the opposite end of the ontogenetic range to the aforementioned, that is, in the menopausal period, mammary cancer risk factors are plentiful and include, among others, the use of replacement or menopausal hormonal therapy (MHT). As discussed by Usha Salagame, Karen Canfell and Emily Banks in their paper ‘An epidemiological overview of the relationship between hormone replacement therapy and breast cancer’, an area of recent interest relates to the ‘estrogen timing hypothesis’ where some researchers have suggested favorable effects for coronary heart disease when HRT is commenced soon after menopause [10]. However, reanalyses of the Women Health Initiative data, as stated by Salagame et al.[10], do not support this hypothesis for coronary heart disease. On the whole, the risks outweighed the benefits for combined hormone therapy, while there was a lack of net benefit from the use of estrogen-only therapy. At the same time, mammary cancer incidence in women treated with a combination of estrogens and progestins during the menopause is higher than that in women treated with estrogens alone. The causes of this seemingly unexpected finding are being studied by researchers from different disciplines, including genetics (gene polymorphisms associated with sensitivity to MHT) and cell biology. One important related issue that has been in the spotlight for several decades includes the questions of whether progestins are mitogenic for the mammary gland epithelium and how this effect, if it exists, may be realized. These questions are partly answered in depth by Andreas Daniel, Christy Hagan and Carol Lange in their article ‘Progesterone receptor action: defining a role in breast cancer’ [11]. In their analysis, the authors reasonably mention that progress in studying the problem has been hindered by estrogen receptor (ER)-centric experimental approaches. They conclude that progesterone receptor (PR) isoforms are important drivers of early breast cancer progression as they are multifunctional transcription factors and ER modulators, playing a role in the rapid activation of cytoplasmic or membrane-associated protein kinases (c-Src and PI3K/Akt) and downstream signaling cascades (MAPKs). Importantly, PR rapid signaling (through the cellular plasma membrane) and transcriptional activity are integrated events. Progesterone is a potent breast mitogen implicated (in combination with PR) in the maintenance and expansion of breast stem and progenitor cells, as has been demonstrated for the first time by Kathryn Horwitz’s group [12]. In addition, assaying of well-characterized phosphorylated residues on both ER and PR, as suggested by Daniel et al.[11], may more accurately predict clinical outcome in breast cancer patients. Furthermore, the authors proclaim that there is a need for the development of preclinical models that clearly evaluate PR action and PR cross-talk with ER, with the goal of advancing towards routine use of PR-targeted therapies.

Additional and important information concerning the role of stem cells in mammary carcinogenesis is presented by Marie-Liesse Asselin-Labat, Geoffrey Lindeman and Jane Visvader in their article ‘Mammary stem cells and their regulation by steroid hormones’ [13]. As indicated by these experts, an entire mammary epithelial outgrowth, capable of full differentiation, may comprise the progeny of a single cellular antecedent – that is, it may be generated from a single mammary epithelial stem cell. More recent studies have indicated that a hierarchy of mammary stem/progenitor cells exists within the mammary epithelium and that their behavior and maintenance depends on signals generated both locally and systemically, including hormones. Whereas the ovarian hormones estrogens and progesterone profoundly influence breast cancer risk, it was demonstrated by the authors that mouse mammary stem cells (MaSCs) are highly responsive to steroid hormone signaling, despite lacking the ER and PR. Ovariectomy and aromatase inhibitor letrozole markedly diminished MaSC number, whereas MaSC activity increased in mice treated with a combination of estrogen and progesterone. As stated by the authors, these findings can be used as a further indication that breast cancer hormone-associated chemoprevention may be achieved, in part, through suppression of MaSC function [13]. In addition, RANK ligand (RANKL), which is secreted by luminal cells following progesterone exposure, is an important paracrine effector of MaSC function, while inhibition of RANK signaling attenuates MaSC function. Therefore, suppression of RANKL/RANK signaling is thought to represent a novel chemoprevention strategy for women at high risk of developing breast cancer.

Besides changes in estrogens and certain progestins, some breast cancer risk is caused by altered production of androgens, primarily testosterone [14]. The fact that testosterone generation by the gonads is regulated by insulin and is enhanced upon insulin resistance provides one of many examples of the interactions between steroid hormones and peptide factors that may lead to predisposition to mammary cancer. In this regard, it is important to mention the role of moderate hyperprolactinemia suggested by prospective studies and, in particular, the possibility of mediation and consolidation of the estrogenic effects by peptide growth factors (IGF-1, EGF, TGF-β, and so on), their receptors and prolactin receptors (see later).

Talking of estrogens, it is also worth considering their local production in tumor tissue, in addition to their systemic production by the gonads. This issue is addressed by Evan Simpson and Kristy Brown in their thoughtful review ‘Obesity, aromatase and breast cancer’ [15], in which the authors do not limit themselves to the intratumoral biosynthesis of estrogens and discuss a no less relevant problem, which may be described as a global epidemic of excessive weight. The authors present evidence that the suppression of the serine/threonine kinase 11 (LKB1)/AMP-kinase system is associated with aromatase activation mediated by cAMP response element-binding (CREB)-regulated transcription coactivators (CRTCs). Leptin stimulates CRTC2 translocation to the nucleus while adiponectin impedes this process. As was demonstrated, aromatase expression via promoter II is regulated by prostaglandin E2 via a cAMP-dependent pathway involving protein kinase A, CRTC2, and CREB and LKB1/AMPK inhibition. On the other hand, the biguanide metformin, which is a well-known AMPK activator, inhibits aromatase expression in breast stroma cells by increasing the phosphorylation of AMPK at T172 and the expression of LKB1.

The importance of the extragonadal estrogen production in a tumor is determined by its association with cell proliferation and tumor mass expansion and, presumably, by its ability to regulate the intratumor levels of progesterone and estrogen receptors, including both ERα and ERβ, which remains poorly understood. The significance of ER isoforms in mammary carcinomas and the prospects of studying this phenomenon are discussed in the article ‘Comparative evaluation of ERα and ERβ significance in breast cancer: state of the art’ by one group of pioneers in this field, Etienne Leygue and Leigh Murphy [16]. These authors remind the readers that ERα remains ‘imperfect’ because the mechanisms by which estrogens mediate their activity are far more complex than originally anticipated. In addition, important questions with respect to the design, selection and normalization of the most appropriate methods for assaying expression and functionality of both ERα and ERβ remain to be answered. The note of practical and fundamental importance is that future assays will have to be performed on decreasing amounts of tumor tissue and, in this case, evidently a nanotechnology approach will play a critical role.

The absence of steroid receptors in mammary neoplasias is often combined with the abundance of HER-2/neu receptors, which are related to the EGF family, or with the ‘totally receptorless’ status (the so-called triple-negative tumors), which are associated with poor prognosis and are important for the choice of hormonal and other therapy. The phenomenon of primary or acquired resistance to endocrine therapy, in particular with aromatase inhibitors and tamoxifen, also supports the conclusion that it is unreasonable to limit the breast cancer problem by the assumption of the primary role of steroid hormones without taking account of the RAS–MAPK cascade and other elements of peptidergic signaling (so-called cross-talk).

The present issue of this journal includes several articles addressing mammary cancer resistance to hormonal therapy. In the paper ‘Src kinase: a therapeutic opportunity in endocrine-responsive and resistant breast cancer’, Stephen Hiscox and Robert Nicholson emphasize that Src kinase plays a key role in multiple signaling pathways regulating proliferation, differentiation and invasion, among others [17]. Both Src protein levels and kinase activity are often elevated in breast cancer cells. Of note, recent evidence has revealed a role for Src in acquired endocrine resistance. As a consequence, a number of small-molecule inhibitors of Src kinase have been developed that appeared to be effective in preclinical studies. Furthermore, additional benefit has been demonstrated when these agents were given in combination with anti-estrogens. In line with these observations, it is anticipated that clinical trials investigating Src inhibitors alongside endocrine agents will be initiated to investigate whether this therapeutic approach can be used to improve endocrine response and better treat mammary carcinoma when relapses occur.

The review by Gila Idelman et al., ‘Lactogens and estrogens in breast cancer chemoresistance’, focuses on lactogens (including prolactin, growth hormone and placental lactogen), all of which can activate the prolactin receptor (PRLR) and estrogenic hormones [18]. The latter group covers endogenous steroids and nonsteroidal compounds from the environment, called endocrine disruptors. All these compounds antagonize cytotoxicity of multiple chemotherapeutic agents through different mechanisms, some of which include cross-talk of PRLR and ERα. In addition, prolactin reduces the amount of cis-platinum bound to DNA and activates glutathione-S-transferase, a phase II detoxification enzyme. Many studies link estrogen-induced chemoresistance to activation of Bcl-2; however, it should be remembered that under certain conditions, estrogen can stimulate apoptosis. Another mechanism by which estrogens (natural and environmental, such as bisphenol A) can increase chemoresistance is by affecting membrane drug exporters. Therefore, effective blockade of the PRLR in combination with anti-estrogen therapy should, as suggested by the authors, significantly increase the efficacy of certain anticancer drugs and overcome resistance.

Perspectives in the area of ‘Markers of sensitivity, dependence and resistance to endocrine therapy for breast cancer’ are brilliantly discussed by an expert in the aromatase and aromatase inhibitors field, William R Miller, who focuses on the mechanisms of resistance to hormonal therapy and on mammary cancer sensitivity markers, including genomic ones [19]. The author indicates that breast cancers respond to endocrine therapy in a variety of ways, and a range of end points can be used to monitor hormone dependence, sensitivity and resistance to treatment. Different forms of endocrine therapies may have distinct mechanisms of action. Consequently, markers of sensitivity or response can vary between treatments and there may be correspondingly differing mechanisms of resistance. Furthermore, it is predicted that within 5 years’ time, tumor phenotyping and molecular profiling at multiple genomic and transcriptomic levels will be employed to select patients for endocrine treatment. Presumably, such screening will be performed on tumor biopsies before and after a short period of therapy to make the choice of ‘real’ treatment more efficient and justified.

The solutions to problems related to antihormonal treatment of breast cancer receive a remarkable impulse in the editorial ‘Endocrine therapy after aromatase inhibitor therapy in breast cancer’, expertly written by Mohit K Verma, Yasuhiro Miki and Hironobu Sasano [20]. As indicated by these authors, independently of aromatase activity, other enzymatic pathways also play pivotal roles in intratumoral estrogen production. Thus, 17β-hydroxysteroid dehydrogenases (17β-HSDs) catalyze the interconversion of estradiol and estrone (E1), while steroid sulphatase (STS) hydrolyzes circulating E1 sulfate to E1 in various human tissues in situ, which confers potent estrogenic actions. Recent data from this group on an increment in both STS and 17β-HSD1 expression level following neoadjuvant therapy with aromatase inhibitors in ER-positive postmenopausal breast carcinoma patients may explain some of the mechanisms of aromatase inhibitor resistance and are among additional reasons for paying attention to targeted pharmacologic modulation of STS and 17β-HSDs activity.

In conclusion, addressing both the objectives of, and expectations associated with, further studies in the field of mammary cancer endocrinology, one can only agree with L Carey [21] in that “…despite therapeutic advances and the development of a number of agents against hormone receptor signaling, HER2, and angiogenesis, we have significant challenges to overcome. These include the need for more tissue-based studies to allow us to understand the hormonal mechanisms of sensitivity and resistance within and across subtypes, and the need to revisit antihormonal approach to the risk and prevention by subtype”. Undoubtedly, this conclusion is relevant for the treatment and prevention, as well as for the pathogenesis of mammary cancer. Hopefully, the present issue of this journal will be useful for further understanding of the aforementioned problems and for consolidating the links between cancer endocrinology and classical endocrinology.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.