Sex hormones are an important part of both the pathogenesis and progression of breast cancer. Each of them has its own molecular actions on tumor cells, mediated by their interaction with nuclear receptors that function as transcription factors. Breast cancer is consistently very responsive to estrogens, except for the triple-negative form that has virtually no receptors whatsoever and grows through other types of cell signaling. The high presence of androgens is associated, however, with both ER+ and ER-negative tumor forms; this casts some doubt on the real tumorigenic potential of steroids in the absence of their receptors. Furthermore, there is strong epidemiological evidence indicating that estrogens are not the only type of sex hormones that drive breast cancer.
It has been previously shown that the androgenic cellular environment resulting from aromatase inhibitor therapies induces androgen receptor-alpha (AR-alpha)-dependent genetic variations associated with poor response to conventional anti-estrogen therapy (e.g. tamoxifen). Given the extreme heterogeneity of the tumor population, it is therefore important to also consider in vivo the importance of precursor steroids found in the bloodstream, which metabolically transformed can stimulate tumor growth with alternative mechanisms, including that dependent on the AR-alpha receptor. While the concept of bioavailable androgens driving tumor endocrine resistance is not new, research must take into account all the metabolic facets of the tumor mass itself, given the aforementioned cellular heterogeneity.
A very recent study reanalyzed the expression of AR-alpha receptors through immunohistochemistry with very stringent parameters. The authors determined that its expression is not of prognostic value in the context of ER+ postmenopausal breast cancer. However, they observed in patients treated with letrozole monotherapy that the expression of the receptor was non-significantly associated with a poorer disease-free interval. However, that high AR-alpha expression denotes a cell survival advantage that cannot be attributed to regular subtyping (ER+), nor is it associated with a favorable response to endocrine therapy. Many extensive studies have examined the AR:ER protein ratio in cohorts of clinical patients and have concluded that a high AR:ER ratio is indicative of a poor response to traditional therapies.
AR agonists are often targeted to antagonize the pro-proliferative action of ER-alpha in estrogen receptor positive (ER+) and androgen receptor positive (AR+) tumors, while AR antagonists counteract the pseudo-ER role of AR in the triple negative setting. This reflects the landscape of clinical trials targeting AR-alpha where agonists and antagonists all show some degree of efficacy. The AR-alpha receptor is reported to antagonize the oncogenic potential of ER-alpha; which makes sense that AR+/ER+ breast cancers behave less aggressively. However, under anti-aromatase therapy the survival advantage is diminished, perhaps because AR-alpha fails to effectively counteract estrogen signaling. Here too it must be understood that, given the cellular and biochemical heterogeneity of the tumor, its survival and growth does not depend on a single type of cellular signal.
A very recently published biochemical analysis used the Philips OncoSignal platform to analyze the cross-expression of androgens and estrogens in breast cancer cells. While the activity of the signaling pathways for both steroid hormones was evident, the analysis showed a preponderance of androgen signaling over estrogen in tumors treated with aromatase inhibitors such as letrozole. Additionally, analysis of an independent cohort of patients treated with letrozole showed that while estrogen biomarkers decreased, breast cancer-specific AR-alpha biomarkers remained stable or even increased. Also noteworthy is the information that gene variations associated with 4-androstenedione (androgen precursor) were greater in letrozole resistance than in “dormant” tumors, indicating that tumors with availability of steroid precursors can adapt very well to any need.
These data are consistent with those published for a phase 2 clinical trial, where patients with high cellular expression of AR-alpha and ER-alpha had greater benefit from a combined treatment of enzalutamide (5-alpha reductase inhibitor) and exemestane (aromatase inhibitor). A possible explanation for this is that the decreased genomic activation of both receptors may become permissive towards intracellular signals of another type, but with similar biological function. The reduced production of sex hormones in post-menopausal or elderly women, accompanied by an excess of their weak precursors, may provide a therapeutic rationale for pharmacological associations that guide the genomic activity of steroid receptors in the event of the onset of breast carcinomas. But we must not forget the other hormone that still has its equivocal, although suspect, role in the biology and biochemistry of this tumor: progesterone.
It should be remembered that the major progesterone receptor (PR-A), is itself a target gene of the estradiol cellular signal. But how much its presence affects the parameters of malignancy, cellular replication and metastatic potential are still concepts open to discussion. A study from a few years ago aimed to ascertain whether this was true. Scientists injected ER+ breast tumor cells and malignant cells derived from patients into the mammary ducts of mice with compromised immune defenses. The mice received estrogen and progesterone at physiological concentrations and here is the surprise: separately, the hormones stimulated tumor growth while together they also made metastatic potential sprout. The cellular growth responses were patient-specific and the response to progesterone depended on PR-A and the c-Myc oncogene.
The progesterone receptor, therefore, is required for cancer growth in samples taken from patients. Furthermore, it is sufficient to maintain this in tumors that have also been genetically ablated for the presence of the estrogen receptor. This information confirms even more that the trend of the last few years regarding the management of breast cancer is more than true: therapy must be personalized, “modeled” to the individual patient and that suppression of PR-A expression can very well be considered a feasible pharmacological option. All this, to encourage personalized medicine that integrates with “precision medicine”.
- Edited Dr. by Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Bartholomew SK et al. J Neuroinflammation. 2024; 21(1):316.
Chávez-Reyes J et al. J Xenobiot. 2024 May; 14(2):604-612.
Wu QL et al. Cell Mol Neurobiol. 2022 Nov; 42(8):2489-2504.
Martinez A, Al-Ahmad AJ. Toxicol Lett. 2019 Apr; 304:39-49.