Jak-stat signaling in breast cancer dormancy and recurrence Hamza Turkistani

Format:

Book

Thesis/Dissertation

Author/Creator:

Turkistani, Hamza, author.

Contributor:

University of Pennsylvania. Bioengineering., degree granting institution.

Language:

English

Subjects (All):

Bioengineering.

Cellular biology.

Pharmacology.

Oncology.

Genetics.

0202.

0379.

0992.

0369.

0419.

Local Subjects:

Bioengineering.

Cellular biology.

Pharmacology.

Oncology.

Genetics.

0202.

0379.

0992.

0369.

0419.

Genre:

Academic theses

Physical Description:

1 online resource (212 pages)

Contained In:

Dissertations Abstracts International 87-12B

Place of Publication:

Ann Arbor : ProQuest Dissertations and Theses, 2026

Language Note:

English

Summary:

Breast cancer is the leading cause of cancer-related mortality among women worldwide, which is principally attributable to recurrent tumors that arise from residual tumor cells (RTCs) that survive primary tumor treatment. Due to the long latencies for recurrence observed in many patients, breast cancer RTCs have long been thought to survive for years to decades in a dormant state prior to re-entering the cell cycle. However, the mechanisms regulating dormancy and recurrence are poorly understood. JAK-STAT signaling plays important roles in mammary gland development, including pubertal development of mammary ducts, alveologenesis in lactation, and apoptosis in post-lactation involution. In cancer, JAK-STAT signaling is pro-tumorigenic and JAK1/2 are considered bona fide oncogenes. Consequently, JAK1/2 inhibitors are used to treat some hematological malignancies and are also used in the treatment of a broad array of non-malignant chronic inflammatory diseases. We therefore sought to determine if JAK- STAT signaling plays a role in breast cancer dormancy and recurrence. Contrary to their pro-tumorigenic roles, we found that Jak1 and Jak2 deletion accelerated recurrence as did deletion of Stat1, but not Stat3 or Stat5. Consistent with that, Jak1, Jak2, Stat1, but not Stat3 or Stat5, deletion increased RTC proliferation in vitro. We found that genetic or pharmacological inhibition of JAK1/2 induced RTCs dormancy exit in vivo and in vitro in both therapy-associated and microenvironment-induced models of dormancy. Remarkably, transient pharmacological inhibition of JAK1/2 in mice bearing dormant RTCs for as few as 3 days irreversibly abrogated the dormant state and promoted recurrences independently of a functional innate or adaptive immune system. Consistent with findings in mice, a patient case-control study revealed that pharmacological JAK inhibition in breast cancer survivors was also associated with accelerated recurrence. Our findings indicate that JAK1/2 signaling is required to suppress breast cancer recurrence by enforcing RTC dormancy in a tumor cell- autonomous manner, such that even brief JAK1/2 inhibition results in dormancy exit and recurrence. As millions of patients are treated each year with JAK inhibitors, the possibility that JAK1/2 inhibition could inadvertently trigger reentry of dormant RTCs into the cell cycle, ultimately resulting in lethal recurrence, is critical to investigate

Notes:

Source: Dissertations Abstracts International, Volume: 87-12, Section: B.

Advisors: Chodosh, Lewis A. Committee members: Tsourkas, Andrew; Asangani, Irfan; Gade, Terence P.

Ph.D. University of Pennsylvania 2026

Vendor supplied data

Local Notes:

School code: 0175

ISBN:

9798247973706

Access Restriction:

Restricted for use by site license