p53 regulates the expression of histone modifiers to restrict stemness and maintain differentiated luminal identity in breast cancer

Yael Aylon; Noa Furth; Anna C. Pirona; Adi Lavie; Olga Fedorova; Ori Hassin; Nuno Padrão; Maxime Steinmetz; Avital Sarusi-Potuguez; Liat Fellus-Alyagor; Irit Shimoni; Bareket Dassa; Wilbert Zwart; Efrat Shema; Moshe Oren

doi:10.1073/pnas.2522646122

p53 regulates the expression of histone modifiers to restrict stemness and maintain differentiated luminal identity in breast cancer

Yael Aylon^*
, Noa Furth
, Anna C. Pirona
, Adi Lavie
, Olga Fedorova
, Ori Hassin
, Nuno Padrão
, Maxime Steinmetz
, Avital Sarusi-Potuguez
, Liat Fellus-Alyagor
, Irit Shimoni
, Bareket Dassa
, Wilbert Zwart
, Efrat Shema^*
, Moshe Oren^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Breast cancer is the leading cause of death in women under 50. The majority of breast cancers are estrogen receptor α-positive (ER+) and are commonly treated with hormonal therapies such as tamoxifen that inhibit ER activity. The TP53 tumor suppressor gene, encoding the p53 protein, is the most frequently mutated gene in breast cancer, and TP53 mutations are associated with diminished tamoxifen response and worse prognosis for breast cancer patients. Here, we report that in breast cancer cells p53 and ER cooperate to regulate the transcription of a set of genes encoding chromatin modifiers. The net result is a global increase in H3K4me3 and decrease in H3K9me3 chromatin marks. The resultant “open” chromatin is associated with increased transcription of luminal cell identity genes and enhanced tamoxifen sensitivity. Conversely, diminished p53 control of these chromatin modulators is associated with the evolution of tamoxifen resistance and cancer stem cell properties.

Original language	English
Article number	e2522646122
Journal	Proceedings of the National Academy of Sciences - PNAS
Volume	122
Issue number	44
DOIs	https://doi.org/10.1073/pnas.2522646122
Publication status	Published - 4 Nov 2025

Funding

This work was supported in part by grants from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and the German-Israeli Cooperation in Cancer Research (Grant CA-209) (to M.O.) and research grants from the Morris Kahn Institute for Human Immunology and the Fabrikant-Morse Families Research Fund for Humanity and from the Quinquin Foundation (to L.F.-A.). E.S. is supported by grants from the European Research Council (ERC101115455), The Israeli Science Foundation (1349/24), the Ministry of Innovation, Science & Technology, Israel, as part of the German-Israeli Cooperation in Cancer Research, Israel Cancer Research Fund-Diane and Guilford Glazer Foundation Acceleration Grant (839119, 1263267), European Research Area Networks Sustained collaboration of national and regional programmes in cancer research, TRANSCAN-3 Joint Transnational Call (EPIPROPER), Emerson Collective, and the Weizmann—Swiss Society Institute for Cancer Prevention Research. W.Z. received funding from the Dutch Cancer Society and Alpe d’HuZes (grant number 12018). W.Z. is a member of the Oncode Institute, which is partly financed by the Dutch Cancer Society. Research at the Netherlands Cancer Institute is supported by institutional grants of the Dutch Cancer Society and the Dutch Ministry of Health, Welfare and Sport. We are grateful to Nastacia Adler-Berke from Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science for CUT&RUN library prep; Tomer Meir Salame, Department of Life Sciences Core Facilities, Weizmann Institute of Science, for EpiTOF assistance; Dean Ranmar, Department of Life Sciences Core Facilities, Weizmann Institute of Science, for image analyses; Cindy Korner, Division of Molecular Genome Analysis, German Cancer Research Center Heidelberg, for aid with German BioBank; Franziska Sommermeyer and Dr. Kathrin Lerchl from the Stiftung PATH—Patients’ Tumor Bank of Hope, München.

All Science Journal Classification (ASJC) codes

General

Access to Document

10.1073/pnas.2522646122Licence: CC BY-NC-ND

Cite this

Aylon, Y., Furth, N., Pirona, A. C., Lavie, A., Fedorova, O., Hassin, O., Padrão, N., Steinmetz, M., Sarusi-Potuguez, A., Fellus-Alyagor, L., Shimoni, I., Dassa, B., Zwart, W., Shema, E., & Oren, M. (2025). p53 regulates the expression of histone modifiers to restrict stemness and maintain differentiated luminal identity in breast cancer. Proceedings of the National Academy of Sciences - PNAS, 122(44), Article e2522646122. https://doi.org/10.1073/pnas.2522646122

@article{55696b8491164aedb44b31222b59f556,

title = "p53 regulates the expression of histone modifiers to restrict stemness and maintain differentiated luminal identity in breast cancer",

abstract = "Breast cancer is the leading cause of death in women under 50. The majority of breast cancers are estrogen receptor α-positive (ER+) and are commonly treated with hormonal therapies such as tamoxifen that inhibit ER activity. The TP53 tumor suppressor gene, encoding the p53 protein, is the most frequently mutated gene in breast cancer, and TP53 mutations are associated with diminished tamoxifen response and worse prognosis for breast cancer patients. Here, we report that in breast cancer cells p53 and ER cooperate to regulate the transcription of a set of genes encoding chromatin modifiers. The net result is a global increase in H3K4me3 and decrease in H3K9me3 chromatin marks. The resultant “open” chromatin is associated with increased transcription of luminal cell identity genes and enhanced tamoxifen sensitivity. Conversely, diminished p53 control of these chromatin modulators is associated with the evolution of tamoxifen resistance and cancer stem cell properties.",

author = "Yael Aylon and Noa Furth and Pirona, \{Anna C.\} and Adi Lavie and Olga Fedorova and Ori Hassin and Nuno Padr{\~a}o and Maxime Steinmetz and Avital Sarusi-Potuguez and Liat Fellus-Alyagor and Irit Shimoni and Bareket Dassa and Wilbert Zwart and Efrat Shema and Moshe Oren",

note = "Publisher Copyright: Copyright {\textcopyright} 2025 the Author(s).",

year = "2025",

month = nov,

day = "4",

doi = "10.1073/pnas.2522646122",

language = "English",

volume = "122",

journal = "Proceedings of the National Academy of Sciences - PNAS",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "44",

}

Aylon, Y , Furth, N, Pirona, AC, Lavie, A, Fedorova, O, Hassin, O, Padrão, N, Steinmetz, M, Sarusi-Potuguez, A, Fellus-Alyagor, L , Shimoni, I , Dassa, B, Zwart, W, Shema, E & Oren, M 2025, 'p53 regulates the expression of histone modifiers to restrict stemness and maintain differentiated luminal identity in breast cancer', Proceedings of the National Academy of Sciences - PNAS, vol. 122, no. 44, e2522646122. https://doi.org/10.1073/pnas.2522646122

TY - JOUR

T1 - p53 regulates the expression of histone modifiers to restrict stemness and maintain differentiated luminal identity in breast cancer

AU - Aylon, Yael

AU - Furth, Noa

AU - Pirona, Anna C.

AU - Lavie, Adi

AU - Fedorova, Olga

AU - Hassin, Ori

AU - Padrão, Nuno

AU - Steinmetz, Maxime

AU - Sarusi-Potuguez, Avital

AU - Fellus-Alyagor, Liat

AU - Shimoni, Irit

AU - Dassa, Bareket

AU - Zwart, Wilbert

AU - Shema, Efrat

AU - Oren, Moshe

PY - 2025/11/4

Y1 - 2025/11/4

N2 - Breast cancer is the leading cause of death in women under 50. The majority of breast cancers are estrogen receptor α-positive (ER+) and are commonly treated with hormonal therapies such as tamoxifen that inhibit ER activity. The TP53 tumor suppressor gene, encoding the p53 protein, is the most frequently mutated gene in breast cancer, and TP53 mutations are associated with diminished tamoxifen response and worse prognosis for breast cancer patients. Here, we report that in breast cancer cells p53 and ER cooperate to regulate the transcription of a set of genes encoding chromatin modifiers. The net result is a global increase in H3K4me3 and decrease in H3K9me3 chromatin marks. The resultant “open” chromatin is associated with increased transcription of luminal cell identity genes and enhanced tamoxifen sensitivity. Conversely, diminished p53 control of these chromatin modulators is associated with the evolution of tamoxifen resistance and cancer stem cell properties.

AB - Breast cancer is the leading cause of death in women under 50. The majority of breast cancers are estrogen receptor α-positive (ER+) and are commonly treated with hormonal therapies such as tamoxifen that inhibit ER activity. The TP53 tumor suppressor gene, encoding the p53 protein, is the most frequently mutated gene in breast cancer, and TP53 mutations are associated with diminished tamoxifen response and worse prognosis for breast cancer patients. Here, we report that in breast cancer cells p53 and ER cooperate to regulate the transcription of a set of genes encoding chromatin modifiers. The net result is a global increase in H3K4me3 and decrease in H3K9me3 chromatin marks. The resultant “open” chromatin is associated with increased transcription of luminal cell identity genes and enhanced tamoxifen sensitivity. Conversely, diminished p53 control of these chromatin modulators is associated with the evolution of tamoxifen resistance and cancer stem cell properties.

UR - https://www.scopus.com/pages/publications/105020480334

U2 - 10.1073/pnas.2522646122

DO - 10.1073/pnas.2522646122

M3 - Article

C2 - 41160600

AN - SCOPUS:105020480334

SN - 0027-8424

VL - 122

JO - Proceedings of the National Academy of Sciences - PNAS

JF - Proceedings of the National Academy of Sciences - PNAS

IS - 44

M1 - e2522646122

ER -

p53 regulates the expression of histone modifiers to restrict stemness and maintain differentiated luminal identity in breast cancer

Abstract

Funding

All Science Journal Classification (ASJC) codes

Access to Document

Other files and links

Fingerprint

Cite this