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A reciprocal feedback loop between HIF-1α and HPIP controls phenotypic plasticity in breast cancer cells.

Publication ,  Journal Article
Khumukcham, SS; Penugurti, V; Soni, A; Uppala, V; Hari, K; Jolly, MK; Dwivedi, A; Salam Pk, A; Padala, C; Mukta, S; Bhopal, T; Manavathi, B
Published in: Cancer letters
February 2022

While phenotypic plasticity is a critical factor contributing to tumor heterogeneity, molecular mechanisms underlying this process are largely unknown. Here we report that breast cancer cells display phenotypic diversity in response to hypoxia or normoxia microenvironments by operating a reciprocal positive feedback regulation of HPIP and HIF-1α. We show that under hypoxia, HIF-1α induces HPIP expression that establishes cell survival, and also promotes cell migration/invasion, EMT and metastatic phenotypes in breast cancer cells. Mechanistic studies revealed that HPIP interacts with SRP14, a component of signal recognition particle, and stimulates MMP9 synthesis under hypoxic stress. Whereas, in normoxia, HPIP stabilizes HIF-1α, causing the Warburg effect to support cell growth. Concurrently, mathematical modelling corroborates this reciprocal feedback loop in enabling cell-state transitions in cancer cells. Clinical data indicate that elevated levels of HPIP and HIF-1α correlate with unfavorable prognosis and shorter survival rates in breast cancer subjects. Together, this data shows a reciprocal positive feedback loop between HPIP and HIF-1α that was unknown hitherto. It unveils how the tumor microenvironment influences phenotypic plasticity that has an impact on tumor growth and metastasis and, further signifies considering this pathway as a potential therapeutic target in breast cancer.

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Published In

Cancer letters

DOI

EISSN

1872-7980

ISSN

0304-3835

Publication Date

February 2022

Volume

526

Start / End Page

12 / 28

Related Subject Headings

  • Phenotype
  • Oncology & Carcinogenesis
  • Mice
  • Intracellular Signaling Peptides and Proteins
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Humans
  • Female
  • Cell Line, Tumor
  • Breast Neoplasms
  • Animals
 

Citation

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Khumukcham, S. S., Penugurti, V., Soni, A., Uppala, V., Hari, K., Jolly, M. K., … Manavathi, B. (2022). A reciprocal feedback loop between HIF-1α and HPIP controls phenotypic plasticity in breast cancer cells. Cancer Letters, 526, 12–28. https://doi.org/10.1016/j.canlet.2021.11.002
Khumukcham, Saratchandra Singh, Vasudevarao Penugurti, Anita Soni, Veena Uppala, Kishore Hari, Mohit Kumar Jolly, Anju Dwivedi, et al. “A reciprocal feedback loop between HIF-1α and HPIP controls phenotypic plasticity in breast cancer cells.Cancer Letters 526 (February 2022): 12–28. https://doi.org/10.1016/j.canlet.2021.11.002.
Khumukcham SS, Penugurti V, Soni A, Uppala V, Hari K, Jolly MK, et al. A reciprocal feedback loop between HIF-1α and HPIP controls phenotypic plasticity in breast cancer cells. Cancer letters. 2022 Feb;526:12–28.
Khumukcham, Saratchandra Singh, et al. “A reciprocal feedback loop between HIF-1α and HPIP controls phenotypic plasticity in breast cancer cells.Cancer Letters, vol. 526, Feb. 2022, pp. 12–28. Epmc, doi:10.1016/j.canlet.2021.11.002.
Khumukcham SS, Penugurti V, Soni A, Uppala V, Hari K, Jolly MK, Dwivedi A, Salam Pk A, Padala C, Mukta S, Bhopal T, Manavathi B. A reciprocal feedback loop between HIF-1α and HPIP controls phenotypic plasticity in breast cancer cells. Cancer letters. 2022 Feb;526:12–28.
Journal cover image

Published In

Cancer letters

DOI

EISSN

1872-7980

ISSN

0304-3835

Publication Date

February 2022

Volume

526

Start / End Page

12 / 28

Related Subject Headings

  • Phenotype
  • Oncology & Carcinogenesis
  • Mice
  • Intracellular Signaling Peptides and Proteins
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Humans
  • Female
  • Cell Line, Tumor
  • Breast Neoplasms
  • Animals