• What is PTEN?
  • PTEN in Breast Cancer
  • PTEN c.697C>T (R233*)
  • Clinical Trials

PTEN

PTEN (phosphatase and tensin homolog deleted on chromosome ten) is a lipid/protein phosphatase that plays a role in multiple cell processes, including growth, proliferation, survival, and maintenance of genomic integrity. PTEN acts as a tumor suppressor by negatively regulating the PI3K/AKT signaling pathway (Figure 1) via dephosphorylation of phosphatidylinositol (3,4,5)-trisphosphate (PIP3) at the cell membrane.

Cancer-associated alterations in PTEN often result in PTEN inactivation and thus increased activity of the PI3K-AKT pathway. Somatic mutations of PTEN occur in multiple malignancies, including gliomas, melanoma, prostate, endometrial, breast, ovarian, renal, and lung cancers. Germline mutations of PTEN lead to inherited hamartoma and Cowden syndrome (for reviews see Chalhoub and Baker 2009 and Maehama 2007). PTEN activity can also be lost through other mechanisms such as epigenetic changes or post-translational modifications (Leslie and Foti 2010). Immunochemistry is often used to detect changes in expression of PTEN in tumor tissues; low expression is thought to indicate loss of PTEN expression, which would result in increased activity of the PI3K-AKT pathway.

mapk-pk13.png

Figure 1.
Schematic of the MAPK and PI3K pathways. Growth factor binding to receptor tyrosine kinase results in activation of the MAPK signaling pathway (RAS-RAF-MEK-ERK) and the PI3K pathway (PI3K-AKT-mTOR). The letter "K" within the schema denotes the tyrosine kinase domain.

Related Pathways

Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014)

Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. PTEN. My Cancer Genome https://www.padiracinnovation.org/content/disease/breast-cancer/pten/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

PTEN in Breast Cancer

Somatic mutations in PTEN have been found in a fraction of breast cancers (see Table).

Gene Mutation Invasive Breast Cancer Hormone Receptor Positive (ER+ and/or PR+) Invasive Breast Cancer HER2 positive Invasive Breast Cancer Triple-negative Invasive Breast Cancer
PTEN 7% (O'Brien et al. 2010) 3.4% (Stemke-Hale et al. 2008)a 5% (Stemke-Hale et al. 2008)a <1% (Stemke-Hale et al. 2008)a

a small sample size <100 patients

Contributors: Justin M. Balko, Pharm. D., Ph.D., Ingrid A. Mayer, M.D., M.S.C.I., Mia Levy, M.D., Ph.D., Carlos L. Arteaga, M.D.

Suggested Citation: Balko, J., I. Mayer, M. Levy, C. Arteaga. 2015. PTEN in Breast Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/breast-cancer/pten/ (Updated June 18).

Last Updated: June 18, 2015

PTEN c.697C>T (R233*) Mutations in Breast Cancer

Properties
Location of mutation Exon 7
Frequency of PTEN mutations in breast cancer 7% (O'Brien et al. 2010)
Frequency of R233* mutations among PTEN-mutated breast cancers <1%
Implications for Targeted Therapeutics
Response to PI3K inhibitors Unknown at this timea
Response to AKT inhibitors Unknown at this time
Response to mTOR inhibitors Unknown at this time
Response to PI3K/mTOR inhibitors Unknown at this time
Response to HER2 inhibitors (lapatinib) Unknown at this time
Response to anti-HER2 antibodies (trastuzumab) Unknown at this time​

The R233* mutation results in the introduction of a premature stop codon into the PTEN gene. This mutation occurs within exon 7, which encodes a portion of the C2 domain (Lee et al. 1999). C2 domains are known to be involved in targeting proteins to cell membranes.

In vitro studies have shown that inactivating mutations in the PTEN gene confer sensitivity to PI3K-AKT inhibitors [for review, see (Courtney, Corcoran, and Engelman 2010)] as well as FRAP/mTOR inhibitors (Neshat et al. 2001). These findings have yet to be confirmed in clinical trials.

a PI3Kβ inhibitors have shown antitumor activity in preclinical studies of PTEN-deficient breast and prostate cancer, but not in a study of endometrial cancer (Hancox et al. 2015; Schwartz et al. 2014; Weigelt et al. 2013).

pten-r233.png

Figure 1.
Schematic of R233* mutation. Functional domains of PTEN are depicted.

Contributors: Justin M. Balko, Pharm. D., Ph.D., Ingrid A. Mayer, M.D., M.S.C.I., Mia Levy, M.D., Ph.D., Carlos L. Arteaga, M.D.

Suggested Citation: Balko, J., I. Mayer, M. Levy, C. Arteaga. 2015. PTEN c.697C>T (R233*) Mutations in Breast Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/breast-cancer/pten/25/ (Updated October 12).

Last Updated: October 12, 2015

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