Molecular Profiling Provides Clues to Oncogenic Role of Caveolin-1 in Breast Cancer

Caveolin-1 (CAV1) appears to play an oncogenic role in breast cancer by fostering molecular hubs for signaling, and should be considered a potential target for therapeutic investigation, in particular in triple-negative disease, according to a new study.

The majority of CAV1-positive (CAV1+) breast cancers are comprised of triple-negative, higher proliferative tumors, with aberrant p53 expression as well as expression of other growth factor signaling proteins, noted researchers led by Rebecca Feldman, PhD, of Caris Life Sciences in Phoenix. Feldman presented the results of the study at the 2015 American Society of Clinical Oncology (ASCO) Breast Cancer Symposium in San Francisco (Abstract 134).

The literature suggests two roles for CAV1 in breast cancer: tumor-suppressor function and oncogene function. “We sought to provide clues as to whether one role or the other is the predominant,” Feldman said.

The researchers conducted a retrospective analysis of 2728 molecularly profiled breast cancer patients, average age 55 years, to understand the clinical and pathological characteristics of CAV 1+ tumors. The patients were referred to Caris Life Sciences from 2010-2012. Diagnoses were collected from referring physicians and classified at intake based on pathology and clinical history.

Specific testing included a combination of protein expression by immunohistochemistry (IHC), gene amplification (by in situ hybridization), and sequencing (Sanger).

Of the 2728 patients, 121 (4%) patients exhibited positive CAV1 overexpression by IHC; 2607 patients were considered negative for CAV1.

The researchers analyzed distribution by age, metastatic disease, and triple-negative breast cancer histology. Among the CAV1+ patients, 39% were metastatic and 84% had triple-negative breast cancer.

Also, the researchers evaluated the relationship between CAV1 positivity and various oncogenic pathways. Positive epidermal growth factor receptor (EGFR) protein expression and presence of EGFR gene amplification, as well as cKIT overexpression, were associated with CAV1 positivity. Human epidermal growth factor receptor 2 expression and amplification were associated with CAV1 negativity (CAV1-).

In addition, higher Ki67, p53, and TOP2A expression by IHC were observed in CAV1+ patients as compared to CAV1- patients.

There were also biomarker expression differences between CAV1+ and CAV1- triple-negative breast cancer patients. Androgen receptor was significantly higher in CAV1- patients; CK5/6, CK14, CK17, Ki67, transducing-like enhancer of split 3 (TLE3), ERCC1, platelet-derived growth factor receptor alpha (PDGFRA), and EGFR were all significantly higher in CAV1+ patients.

In conclusion, Feldman said “CAV1 identifies a subgroup of triple-negative breast cancer that exhibits high levels of growth factor receptors (EGFR and PDGFRA), resulting in higher rates of mitogenesis, as demonstrated by higher levels of Ki67 and TLE3.”

Higher levels of TLE3 in CAV1+ subgroups may point to a higher proportion of CAV1+ cancers undergoing M-phase of the cell cycle, “pointing to a particularly sensitive group of cancers to cell cycle perturbation, for example, through anti-tubulin agents (such as paclitaxel),” she said.

Kinase inhibitors of EGFR and PDGFRA should also be investigated, she added.

Investigating the therapeutic role of CAV1 is warranted, “whether targetable itself or its contribution to multidrug resistance,” Feldman said.