28th October 2022

Steroid sulphatase: A promising target for treating breast cancer?

Breast cancer is the most common cancer in the UK, with 1 in 7 women developing breast cancer during their lifetime.1 Primary breast cancer survival rates have markedly improved over the last four decades, both in absolute terms and relative to other cancers.2 This improvement has been achieved, at least partially, by developing therapies that target the hormone-signalling pathway.3,4

Breast cancer has a well-established dependence on classically female sex steroid hormones: oestrogens and progesterone – particularly in early stages. In fact, more than 90% of breast cancer cases are initially hormone-dependent.5 Oestrogen is suspected to play a key role in carcinogenesis by stimulating cell proliferation through binding to oestrogen receptors and activating down-stream transcription.6 Thus, the World Health Organisation (WHO) refer to biologically active hormones as the primary cancer growth stimulants.4 The prominence of these active hormones in the aetiology and persistence of breast cancer is reflected in the effectiveness of therapeutic approaches based on oestrogen depletion or blockade.3

Targeted endocrine treatment strategies include the modulation of oestrogen receptor signalling, as well as enzymatic pathways implicated in the biosynthesis of active hormones.3,4 Examples of currently used therapies that target an enzyme implicated in the steroidogenesis process are Letrozole (Femara)7 and Anastrozole (Arimidex)8, which inhibit aromatase from converting androgens into oestrogen.4 However, many breast cancers fail to respond to such therapies, which leads to relapses and tumour progression.10 Therefore, the study of a wider range of steroidogenic pathways in breast cancer is becoming a core component of ongoing research and of high therapeutic importance.

Steroid Sulphatase

Steroid sulphatase is another enzyme that plays a key role in regulating the formation of active oestrogens and androgens and has been considered a potential candidate for breast cancer therapy.4,10,11 In contrast to aromatase, steroid sulphatase is increased in malignancy and is present in 90% of breast tumours. In fact, steroid sulphatase expression has been found to be associated with worse outcomes and increased recurrence.3,4

 Steroid sulphatase catalyses the hydrolysis of sulphated steroids to their unsulphated derivatives, which may subsequently be transformed into bioactive hormones.4The presence of steroid sulphatase, therefore, reflects the production of an oestrogen-rich microenvironment that sustains tumour growth and proliferation.3,4 Steroid sulphatase therefore plays a pivotal role in breast cancer tumourigenesis; thus, the inhibition of steroid sulphatase is considered to be extremely attractive, potentially effective, therapeutic option.

Research focussed on the development of steroid sulphatase inhibitors has been carried out over the last three decades, although only irosustat has been evaluated in phase I/II clinical trials in patients with oestrogen receptor-positive breast cancer.3,4 Clinical trial data showed that irosustat was not only effective at blocking steroid sulphatase action, it also reduced tumour and cell growth, lowered steroid levels, and prolonged patient survival.12-15 While the results from these trials are highly encouraging – showing that irosustat is an effective and relatively safe steroid sulphatase inhibitor, further research is still required, particularly into more potent steroid sulphatase inhibitors. There is also considerable potential for the design and development of multitargeting agents that can effectively inhibit steroid sulphatase and other enzymes involved in the hormone biosynthesis pathway, which may enhance the efficacy of these treatment methods.4 That said, combination therapy of steroid sulphatase inhibitors with agents targeting other enzymes may also be of scientific merit, as demonstrated by the clinical trial which showed that administration of Irosustat followed by an aromatase inhibitor resulted in considerable success in treating patients with oestrogen receptor-positive breast cancer.11,12

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References

  1. Cancer Research UK. What is breast cancer? [Online] Available via https://www.cancerresearchuk.org/about-cancer/breast-cancer/about Accessed on 17th October 2022
  2. Cancer Research UK. Breast cancer statistics. [Online]. Available via https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/breast-cancer#heading-Two Accessed on 17th October 2022
  3. McNamara KM, et al. In breast cancer subtypes steroid sulfatase (STS) is associated with less aggressive tumour characteristics. Br J Cancer. 2018;118(9):1208-1216.
  4. Daśko M, et al. Recent progress in the development of steroid sulphatase inhibitors – examples of the novel and most promising compounds from the last decade. J Enzyme Inhib Med Chem. 2020 Dec;35(1):1163-1184.
  5. Pasqualini JR. The selective estrogen enzyme modulators in breast cancer: a review. Biochim Biophys Acta. 2004;1654(2):123-43.
  6. Yager JD, Davidson NE. Estrogen carcinogenesis in breast cancer. N Engl J Med. 2006;354(3):270-82.
  7. Cancer Research UK. Letrozole (Femara). [Online] Available via: https://www.cancerresearchuk.org/about-cancer/cancer-in-general/treatment/cancer-drugs/drugs/letrozole-femara Accessed on 18th October 2022
  8. Cancer Research UK. Anastrozole (Arimidex). [Online] Available via: https://www.cancerresearchuk.org/about-cancer/cancer-in-general/treatment/cancer-drugs/drugs/anastrozole Accessed on 18th October
  9. National Cancer Institute. Hormone Therapy for Breast Cancer. [Online] Available via: https://www.cancer.gov/types/breast/breast-hormone-therapy-fact-sheet Accessed on 18th October 2022
  10. Reed MJ, et al. Steroid sulfatase: molecular biology, regulation, and inhibition. Endocr Rev. 2005;26(2):171-202.
  11. Foster PA. Steroid Sulphatase and Its Inhibitors: Past, Present, and Future. 2021;26(10):2852.
  12. Palmieri C, et al. IRIS study: a phase II study of the steroid sulfatase inhibitor Irosustat when added to an aromatase inhibitor in ER-positive breast cancer patients. Breast Cancer Res Treat. 2017 Sep;165(2):343-353.
  13. Stanway SJ, et al. Phase I study of STX 64 (667 Coumate) in breast cancer patients: the first study of a steroid sulfatase inhibitor. Clin Cancer Res. 2006 Mar 1;12(5):1585-92.
  14. Palmieri C, et al. IPET study: an FLT-PET window study to assess the activity of the steroid sulfatase inhibitor irosustat in early breast cancer. Breast Cancer Res Treat. 2017 Nov;166(2):527-539.
  15. Coombes RC, et al. A phase I dose escalation study to determine the optimal biological dose of irosustat, an oral steroid sulfatase inhibitor, in postmenopausal women with estrogen receptor-positive breast cancer. Breast Cancer Res Treat. 2013;140(1):73-82.

 

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