What is Endometrial Cancer?Endometrial cancer, also known as endometrial carcinoma, is a type of cancer that begins in the inner lining of the uterus (endometrium). This is the most common type of cancer in the uterus, and about 50,000 women in America are diagnosed with endometrial cancer each year [1]. Because it is the most common form of uterine cancer it is also often referred to as uterine cancer.
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Risk Factors
- Risk factors for endometrial cancer include obesity, type 2 diabetes, endometrial hyperplasia, PCOS (polycystic ovarian syndrome), family history, use of tamoxifen to treat breast cancer, and postmenopausal use of estrogen-only hormone replacement therapy [2].
Symptoms
FOXA1 (Forkhead box A1)
FOXA1, know as Forkhead box A1, and previously a part of the hepatocyte nuclear factor (HNF) family is a pioneer factor and facilitates the binding of other transcription factors according to Adamczyk-Gruszka et. al (2022) [3]. As stated by Fu et. al (2019), it is involved in chromatin binding and implicated in the function of lineage specific and oncogenic transcription factors [4]. It has been identified as binding to promoters of more than 100 genes, and is involved in many cellular processes [3]. This protein is recognized as being significantly involved in androgen receptors (AR) according to Rodriguez et.al (2019) [5} as well as being involved with estrogen receptor β, and being necessary for estrogen receptors to bind to chromatin (ER) [3].
How is FOXA1 related to endometrial cancer?
It is well documented that hormone receptors are associated with prognosis and survival rates of hormonal cancers [3]. In the case of endometrial cancer, FOXA1 acts as a pioneer factor to estrogen receptors (ER) and is responsible for recruiting other transcription factors and maintaining chromatin accessibility [5].
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Gap in Knowledge
Literature surrounding FOXA1 and its relationship between endometrial cancer and either high or low expression is conflicting.
Karpathiou et. al (2021)Proposes the knockdown of FOXA1 is associated with deterioration of cells in endometrial cancer as well as proliferation of cancer cells. Knockdown of FOXA1 is also seen to decrease the expression of estrogen receptors (ER). Estradiol (E2) is also dependent on FOXA1 to function normally and the author suggests a molecular mechanism prevents the recruitment of pioneer factor binding of FOXA1, antagonizing the glucocorticoid receptor-dependent induction of specific genes [6].
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Yildirim et. al (2021)Increased FOXA1 expression is associated with higher tumor grade lymph node invasion, and myometrial invasion in endometrial cancer. They propose that similar to how FOXA1 acts in breast cancer, it may be involved in cancer/tumor progression at some stages while suppressing progression in others [7].
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As such, the role of FOXA1 in endometrial cancer cell proliferation largely remains unknown.
References
[1] “Endometrial Cancer.” Endometrial Cancer | Johns Hopkins Medicine, Johns Hopkins Medicine, 8 Aug. 2021, https://www.hopkinsmedicine.org/health/conditions-and-diseases/endometrial-cancer.
[2] “Endometrial Cancer Treatment (PDQ®)–Patient Version.” Endometrial Cancer Treatment, National Cancer Institute, 13 Nov. 2020, https://www.cancer.gov/types/uterine/patient/endometrial-treatment-pdq#:~:text=and%20treatment%20options.-,Endometrial%20cancer%20is%20a%20disease%20in%20which%20malignant%20(cancer)%20cells,is%20about%203%20inches%20long.
[3] Adamczyk-Gruszka, Olga, et al. “Endometrial Cancer in Aspect of Forkhead Box Protein Contribution.” International Journal of Environmental Research and Public Health, vol. 19, no. 16, 2022, p. 10403., https://doi.org/10.3390/ijerph191610403.
[4] Fu, Xiaoyong, et al. “FOXA1 Upregulation Promotes Enhancer and Transcriptional Reprogramming in Endocrine-Resistant Breast Cancer.” Proceedings of the National Academy of Sciences, vol. 116, no. 52, 2019, pp. 26823–26834., https://doi.org/10.1073/pnas.1911584116.
[5] Rodriguez, Adriana C., et al. “Estrogen Signaling in Endometrial Cancer: A Key Oncogenic Pathway with Several Open Questions.” Hormones and Cancer, vol. 10, no. 2-3, 2019, pp. 51–63., https://doi.org/10.1007/s12672-019-0358-9.
[6] Karpathiou, Georgia, et al. “FOXA1 Expression by Immunohistochemistry in Carcinosarcomas of the Endometrium and Ovary/Fallopian Tube.” International Journal of Gynecological Pathology, vol. 40, no. 6, 2021, pp. 611–616., https://doi.org/10.1097/pgp.0000000000000772.
[7] Tosun Yıldırım, Hülya, et al. “FOXA1 Is Associated with High Tumor Grade, Myometrial Invasion and Lymph Node Invasion in Endometrial Endometrioid Carcinoma.” Ginekologia Polska, vol. 92, no. 8, 2021, pp. 544–549., https://doi.org/10.5603/gp.a2021.0016.
This website was produced as an assignment for Genetics 564, an undergraduate capstone at UW-Madison.
Kerstin Hurd
[email protected]
Last updated: 2/23/23