Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 3/2016

01-10-2016 | Brief Report

Multiplexed imaging reveals heterogeneity of PI3K/MAPK network signaling in breast lesions of known PIK3CA genotype

Authors: Thomas Jacob, Joe W. Gray, Megan Troxell, Tania Q. Vu

Published in: Breast Cancer Research and Treatment | Issue 3/2016

Login to get access

Abstract

Purpose

Activating genetic changes in the phosphatidylinositol-3-kinase (PI3K) signaling pathway are found in over half of invasive breast cancers (IBCs). Previously, we discovered numerous hotspot PIK3CA mutations in proliferative breast lesions. Here, we investigate the spatial nature of PI3K pathway signaling and its relationship with PI3K genotype in breast lesions.

Methods

We identified PI3K phosphosignaling network signatures in columnar cell change (CCL), usual ductal hyperplasia (UDH), ductal carcinoma in situ (DCIS), and IBC in 26 lesions of known PIK3CA genotype from 10 human breast specimens using a hyperspectral-based multiplexed tissue imaging platform (MTIP) to simultaneously quantitate PI3K/MAPK pathway targets (pAKT473, pAKT308, pPRAS40, pS6, and pERK) in FFPE tissue, with single-cell resolution.

Results

We found that breast lesional epithelia contained spatially heterogeneous patterns of PI3K pathway phosphoprotein signatures, even within microscopic areas of CCL, UDH, DCIS, and IBC. Most lesions contained 3–12 unique phosphoprotein signatures within the same microscopic field. The dominant phosphoprotein signature for each lesion was not well correlated with lesion genotype or lesion histology, yet samples from the same patient tended to group together. Further, 5 UDH/CCL lesions across different patients had a common phosphosignature at the epithelial–stromal interface (possible myoepithelial cells) that was distinct from both the adjacent lesional epithelium and distinct from adjacent stroma.

Conclusion

We present the first spatial mapping of PI3K phosphoprotein networks in proliferative breast lesions and demonstrate complex PI3K signaling heterogeneity that defies simple correlation between PIK3CA genotype and phosphosignal pattern.
Literature
1.
2.
Baselga J (2011) Targeting the phosphoinositide-3 (PI3) kinase pathway in breast cancer. Oncologist 16(Suppl 1):12–19CrossRefPubMed
3.
Zardavas D, Phillips WA, Loi S (2014) PIK3CA mutations in breast cancer: reconciling findings from preclinical and clinical data. Breast Cancer Res 16(1):201CrossRefPubMedPubMedCentral
4.
Arnedos M et al (2015) Precision medicine for metastatic breast cancer-limitations and solutions. Nat Rev Clin Oncol 12(12):693–704CrossRefPubMed
5.
Klarenbeek S, van Miltenburg MH, Jonkers J (2013) Genetically engineered mouse models of PI3K signaling in breast cancer. Mol Oncol 7(2):146–164CrossRefPubMed
6.
Gonzalez-Angulo AM, Blumenschein GR Jr (2013) Defining biomarkers to predict sensitivity to PI3K/Akt/mTOR pathway inhibitors in breast cancer. Cancer Treat Rev 39(4):313–320CrossRefPubMed
7.
Dunlap J et al (2010) Phosphatidylinositol-3-kinase and AKT1 mutations occur early in breast carcinoma. Breast Cancer Res Treat 120(2):409–418CrossRefPubMed
8.
9.
Li H et al (2010) PIK3CA mutations mostly begin to develop in ductal carcinoma of the breast. Exp Mol Pathol 88(1):150–155CrossRefPubMed
10.
Kalinsky K et al (2011) PIK3CA mutations rarely demonstrate genotypic intratumoral heterogeneity and are selected for in breast cancer progression. Breast Cancer Res Treat 129(2):635–643CrossRefPubMed
11.
Ang DC et al (2014) Frequent phosphatidylinositol-3-kinase mutations in proliferative breast lesions. Mod Pathol 27(5):740–750CrossRefPubMed
12.
Newburger DE et al (2013) Genome evolution during progression to breast cancer. Gen Res 23(7):1097–1108CrossRef
13.
Jahn SW et al (2016) Mutation profiling of usual ductal hyperplasia of the breast reveals activating mutations predominantly at different levels of the PI3K/AKT/mTOR pathway. Am J Pathol 186(1):15–23CrossRefPubMed
14.
Isakoff SJ et al (2005) Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells. Cancer Res 65(23):10992–11000CrossRefPubMed
15.
Dogruluk T et al (2015) Identification of variant-specific functions of PIK3CA by rapid phenotyping of rare mutations. Cancer Res 75(24):5341–5354CrossRefPubMed
16.
Stemke-Hale K et al (2008) An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res 68(15):6084–6091CrossRefPubMedPubMedCentral
17.
Korkola JE et al (2015) Decoupling of the PI3K pathway via mutation necessitates combinatorial treatment in HER2 + breast cancer. PLoS ONE 10(7):e0133219CrossRefPubMedPubMedCentral
18.
Roberts E, et al Mapping cancer signaling networks by an integrated multiplexed tissue imaging platform. Technology (in publication)
19.
Hermanson GT (2008) Bioconjugate techniques, 2nd edn. Academic press, New York
20.
21.
Shah SP et al (2009) Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature 461(7265):809–813CrossRefPubMed
22.
Jensen Dupont et al (2011) PIK3CA mutations may be discordant between primary and corresponding metastatic disease in breast cancer. Clin Cancer Res 17(4):667–677CrossRef
23.
24.
25.
Arthur LM et al (2014) Changes in PIK3CA mutation status are not associated with recurrence, metastatic disease or progression in endocrine-treated breast cancer. Breast Cancer Res Treat 147(1):211–219CrossRefPubMed
26.
Lacroix-Triki M et al (2003) Value of cytokeratin 5/6 immunostaining using D5/16 B4 antibody in the spectrum of proliferative intraepithelial lesions of the breast. A comparative study with 34betaE12 antibody. Virchows Arch 442(6):548–554PubMed
27.
Lee AH (2013) Use of immunohistochemistry in the diagnosis of problematic breast lesions. J Clin Pathol 66(6):471–477CrossRefPubMed
28.
29.
Janiszewska M et al (2015) In situ single-cell analysis identifies heterogeneity for PIK3CA mutation and HER2 amplification in HER2-positive breast cancer. Nat Genet 47(10):1212–1219CrossRefPubMedPubMedCentral
30.
Hammond ME et al (2010) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer (unabridged version). Arch Pathol Lab Med 134(7):e48–e72PubMed
31.
Polyak K et al (2005) Do myoepithelial cells hold the key for breast tumor progression? J Mammary Gland Biol Neoplasia. 10(3):231–247CrossRefPubMed
32.
Russell TD et al (2015) Myoepithelial Cell differentiation markers in ductal carcinoma in situ progression. Am J Pathol. 185(11):3076–3089CrossRefPubMed
Metadata
Title
Multiplexed imaging reveals heterogeneity of PI3K/MAPK network signaling in breast lesions of known PIK3CA genotype
Authors
Thomas Jacob
Joe W. Gray
Megan Troxell
Tania Q. Vu
Publication date
01-10-2016
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 3/2016
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-016-3962-1

Other articles of this Issue 3/2016

Breast Cancer Research and Treatment 3/2016 Go to the issue

Brief Report

Cost-effectiveness analysis of trastuzumab emtansine (T-DM1) in human epidermal growth factor receptor 2 (HER2): positive advanced breast cancer

Review

Cost-effectiveness of febrile neutropenia prevention with primary versus secondary G-CSF prophylaxis for adjuvant chemotherapy in breast cancer: a systematic review

Epidemiology

A collaborative approach to cancer risk assessment services using genetic counselor extenders in a multi-system community hospital

Epidemiology

A prospective study of endometriosis and risk of benign breast disease

Preclinical Study

Exercise regulates breast cancer cell viability: systemic training adaptations versus acute exercise responses

Epidemiology

Subsequent risk of ipsilateral and contralateral invasive breast cancer after treatment for ductal carcinoma in situ: incidence and the effect of radiotherapy in a population-based cohort of 10,090 women
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits